Dr. McDaniel is a psychiatrist at the Mental Health Clinic at the Hampton VA Medical Center in Virginia and associate clinical professor of the Community Faculty in the Department of Psychiatry and Behavioral Science at Eastern Virginia Medical School in Norfolk. Dr. Spiegel is associate clinical  professor in the Department of Psychiatry and Behavioral Science at Eastern Virginia Medical School.

Disclosures: Dr. McDaniel reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Spiegel is on the speaker’s bureaus of AstraZeneca, Janssen, Merck, and Pfizer.

Off-label disclosure: This article contains discussion of uapproved treatments for catatonia, including minocycline and amantadine.

Please direct all correspondence to: William W. McDaniel, MD, MS, Psychiatrist, Mental Health Clinic, Hampton VA Medical Center, 100 Emancipation Dr, Hampton, VA 23667; Tel: 757-722-9961; Fax: 757-728-3174; E-mail: william.mcdaniel@va.gov.



Four cases are presented in whom psychotic illness was associated with both catatonia and hyponatremia with polydipsia and concentrated urine. Furthermore, one of the patients ingested foreign objects during the same episode of illness. The presence of concentrated urine in these and many reported cases suggests a role for vasopressin in generating the abnormal excessive ingestion of water, producing hyponatremia with concentrated urine (and perhaps ingestion of foreign objects, as in one case). It may be that hyponatremia in psychosis, and abnormal ingestion of either water or foreign objects, should be regarded as potential signs of catatonia

Focus Points

• Hyponatremia may be associated with catatonia.
• Hyponatremia associated with catatonia may share an underlying mechanism, rather than causing the alteration in mental state.
• Hyponatremia in catatonia is often associated with psychogenic polydipsia, which as a repeated, stereotyped, self-injurious behavior may represent a stereotypy, and thus a sign of the catatonic state.
• Hyponatremia associated with catatonia is likely to be associated with concentrated urine, or increased urine sodium, and thus the syndrome of inappropriate antidiuretic hormone.



Hyponatremia has been reported in association with catatonia, in a case in which it appeared that the electrolyte abnormality might have caused the catatonic state.1 The authors of this article report four cases in which there seemed to be evidence that the hyponatremia and associated excessive water intake (and in one case, eating foreign objects) did not cause catatonia, but were produced by the same underlying process that generated the catatonic state. It may be that excessive water drinking and hyponatremia can be manifestations of catatonia, and understood and treated as such.

Catatonia is a relatively common syndrome of psychomotor dysregulation characterized by symptoms such as mutism, immobility, negativity, or, alternately, extreme agitation, often with echolalia or echopraxias. Signs such as catalepsy or “waxy” rigidity (limbs will hold a position after being passively positioned), are commonly associated with mutism and immobility. Other signs such as gegenhalten (German, literally “going and stopping”, in which patients initially permit passive movement, but then resist) may be noted with either presentation. Catatonia may be associated with bipolar disorder, depression, or schizophrenia, and may be the presenting sign of medical problems including infectious, metabolic, neoplastic, autoimmune, and toxic disorders.2-7



Patients were encountered in inpatient units, on the consultation service, and in the course of outpatient care. As they improved to their baseline, permission was obtained to report their course of illness, with the promise to conceal their identities. All subjects signed consent. Records were reviewed, and features of the episodes of illness were recorded and tabulated, with special attention to the presence and interaction of signs of catatonia with the behaviors of ingesting excess fluids or foreign objects. The Bush-Francis Catatonia Rating Scale (BFCRS)8 was used to rate the severity of symptoms of catatonia in each patient during the episode of illness described, based on the recorded signs and symptoms. Measures of osmolality were not available for any of the cases. Plasma and urine osmolality were assumed to be low when sodium levels were low. This assumption is not always true, but was thought to be true in these cases because of the association with excessive water drinking behavior.


Patient “A”

“A” was a 30-year-old male diagnosed as suffering from schizoaffective disorder and cocaine dependence, who presented in two different hospitalizations within 2 weeks with exacerbations of psychosis due to cessation of his medications (divalproex 1,500 mg/day and risperidone 4 mg qHS), and abuse of crack cocaine. During one case, he demonstrated euphoria and rapid, pressured speech intermittently, alternating with periods of mute immobility, frequently in uncomfortable positions (such as squatting to sit on a sofa, but having come to rest about two inches above the cushions, for several hours). BFCRS score was 33. During the first day of each hospitalization, he seized paper clips from the nursing station desk and swallowed them. Despite being put on watch to prevent another ingestion, he worked a steel bracket and its screw loose from the wall, and swallowed them. He never seemed to suffer from these foreign object ingestions, but allowed the authors  to obtain abdominal x-rays to catalog his ingestions and to obtain a surgical consultation in case he developed an acute abdomen. The x-ray films demonstrated the presence of several paper clips, the bracket and screw, the cap and wires used to secure the cork stopper of a champagne bottle, and a couple of pieces of metal the authors could not identify. The surgeon prescribed a high-fiber diet in hope that surgical intervention would not be necessary. It was not, as the patient passed all of the objects in his stool over the next few days. He never permitted the drawing of laboratory studies during that hospitalization. During a second hospital stay 1 week later, the patient demonstrated mute, immobile catatonia only on the first day, after which treatment with lorazepam (he required 2 mg 3–4 times daily) allowed him to move and respond more normally (BFCRS score was 33). The authors took precautions against further ingestion of metal objects, but initially did not notice how much water he was drinking. On the second hospital day, the rounding team took note of the collection of 17 Styrofoam cups on his bedside table. He explained he had drunk that many cups of water since admission, which was about 26 hours. His admission laboratory studies were remarkable for serum sodium of 124 mEQ/L. The patient’s psychosis and agitation resolved fairly quickly after initiation of lorazepam therapy and reinstatement of his usual divalproex and risperidone. Internal medicine consultation was obtained, and a urine sodium was obtained (the result was 40 mEq/L), which was thought consistent with the syndrome of inappropriate antidiuretic hormone (SIADH) rather than psychogenic polydipsia. The patient was treated with demeclocycline by the consultant, who reasoned the patient might leave the hospital against advice again. This resulted in resolution of hyponatremia and the excessive water intake was treated with fluid restriction. Mania remitted with resumption of valproate and risperidone therapy, as did signs of catatonia and excessive water drinking.


Patient “B”

“B” was a 65-year-old female treated with citalopram for a recurrence of depression. A previous episode of depression after a death in the family at ~30 years of age was associated with catatonia with muteness and immobility, and with auditory and visual hallucinations of the deceased. None of these psychotic symptoms presented at first, and she was initially treated with citalopram alone. After ~3 weeks, depression was reported to be lifting, but shortly thereafter the patient developed a severe degree of anxiety and agitation. The patient was hospitalized medically for chest pain, and developed rapid, pressured speech during that hospital stay. Plasma sodium level at that time was 129 mEq/L, with urine sodium 88 mEq/L. Divalproex therapy was begun with initial success, and citalopram was discontinued. Plasma sodium then normalized to 143 mEq/L. Anxiety and agitation recurred and were treated with lorazepam until the patient demonstrated abuse of the drug and suffered a motor vehicle accident under its influence. A brief hospitalization permitted adjustment of divalproex therapy so that the patient returned home in a normal mood state. However, she unilaterally discontinued the medication and over the next 2 months became sleepless, agitated, and anxious. She was nearly immobile and was thought to be weak by loved ones who brought her to the hospital. She ambulated with an odd gait that appeared to be tremulous, and she had a tremor. Testing of muscle tone did not reveal a paratonia, however, but gegenhalten were observed. BFCRS score was 24. Laboratory studies revealed she was hyponatremic with serum sodium of 125 mEq/L. Urine sodium was 51 mEq/L. Urinary tract infection (UTI) was detected incidentally, and was treated with minocycline in hope of providing some relief of catatonia as well. Divalproex therapy was maintained, and the UTI was treated with minocycline, in hopes of further benefitting her catatonic symptoms. The catatonia remitted, but serum sodium was re-tested at 125 mEq/L. Because catatonic agitation appeared to be relapsing, divalproex therapy was augmented with amantadine 100 mg BID. Further worsening of catatonic, mood, and psychotic symptoms finally prompted treatment with electroconvulsive therapy, which resulted in full remission after 12 treatments with right unilateral electrode placement.


Patient “C”

“C” was a 58-year-old female with bipolar disorder and alcohol dependence. She had several hospitalizations under the authors’ care for agitated, psychotic states with paranoid delusions and auditory hallucinations, following periods of manic agitation and heavy alcohol abuse. Her mood disorder was responsive to divalproex, which was reinstated, with lorazepam for alcohol detoxification and for catatonic agitation. She was uniformly agitated at the time of admission. She retained normal orientation. During two admissions, she was agitatedly catatonic, with hyperkinetic state, constant meaningless activity, verbigeration, echolalia and echopraxia. During both of those hospital admissions (and several when she did not show signs of catatonia), she was hyponatremic, and was treated with either fluid restriction or demeclocycline by the consulting internist. Hyponatremia during the episodes associated with catatonic agitation was once associated with dilute urine one time (serum sodium was 123 mEq/L with urine sodium of 18 mEq/L), and with concentrated urine during another admission (serum sodium 121 mEq/L, urine sodium 40 mEq/L). The BFCRS was 23 during the first episode, and 28 during the second. The patient was never able to explain her excessive thirst and drinking, and resisted advice to restrict fluid intake. She was treated for SIADH with demeclocycline 300 mg BID with successful remission of hyponatremia. Fluid restriction was still required to prevent recurrence. Her mood disorder was treated with valproic acid 1,500 mg/day, with apparently complete remission of mood and catatonic symptoms. Excessive water intake ceased about the time mania remitted.


Patient “D”

“D” was a 54-year-old female with a 30-year history of bipolar disorder, with several episodes of mania associated with psychosis, and one mixed state during which she was psychotic with increased energy, simultaneously felt depressed, and attempted suicide. She had been stable and had not required hospitalization for 25 years since starting lithium therapy. She did well with lithium 900 mg/day, sustaining plasma levels of lithium between 0.8–1.3 mEq/L. She also took fluphenazine 5 mg/day, fluoxetine 60 mg/day and lorazepam 1 mg TID. Attempts to withdraw or taper fluoxetine uniformly resulted in relapsing depression. She was quite thirsty, and drank a good deal of water, a habit of many years, pre-dating lithium and fluoxetine therapy; she said it had begun during her last hospitalization 25 years earlier. She had been diagnosed as suffering from psychogenic polydipsia at that time, and she regarded it as a chronic condition, which she attempted to deal with by consciously resisting the urge to drink more. She was most successful when her mood state was most normal, and consistently began to drink more whenever her mood started to become more depressed or more hypomanic. Serum electrolytes were followed regularly, and were in normal range until an exacerbation occurred, as follows. A recent episode of depressed and labile mood, hallucinations, and circumscribed paranoid delusions was accompanied by greatly increased fluid intake, and catatonic symptoms comprising motor excitement, interspersed with periods of brief muteness and staring, perseveration, and verbigeration. She demonstrated odd mannerisms, including saluting people and always ending and beginning conversations with a “hearty handshake” (announced out loud), and stereotypical repeated motions, mostly with her hands and feet. The BFCRS was just 15. Serum electrolytes were evaluated as soon as her increased fluid intake was ascertained. The results were remarkable for sodium of 123 mEq/L. Her urine was concentrated with urine sodium of 40 mEq/L. Her lithium level was below therapeutic level, due to missed doses. Resuming regular doses of lithium restored a therapeutic level, and her agitation, including catatonic symptoms, improved within 2 days of increasing lorazepam dose. She was able to resume her voluntary fluid restriction, and was helped by purchasing a 1-liter polycarbonate bottle that she filled with water once per day, using that to limit herself to that much water daily.



Severity of catatonia as expressed by the BFCRS was not significantly correlated to the serum or urine sodium, nor to the ratio between the serum and urine sodium levels (Pearson’s Coefficient of Correlation=10.2, P>.05).

Hyponatremia was observed during catatonia of both types (mute/immobile and hyperkinetic/agitated). Concentrated urine was associated with it during catatonia of both types, and one patient demonstrated dilute urine during one episode, and concentrated urine during another episode. The eating of foreign objects was observed in one patient experiencing an episode of illness during which he was mute and immobile at some times, and agitated and hyperkinetic at others. That patient was hyponatremic during that illness (the two admissions ~1 week apart) and had concentrated urine.



There are two recognized forms of catatonic agitation: the mute-immobile form that is familiar to most practitioners, and the agitated, hyperkinetic form. The patients described above all demonstrated catatonia of varying degrees of severity, and during the same episode of illness, hyponatremia, excessive water drinking, and in the first case described, eating foreign objects.

Hyponatremia and psychogenic polydipsia are well described among psychotic patients, though only a single case was associated with diagnosed catatonia.1 In the cases of “B” and “D”, there were some signs of catatonia present before hyponatremia or polydipsia were observed, and, in fact, when normal sodium levels were documented. If this is not a simply accidental finding, it may mean either that polydipsia and hyponatremia were caused by the catatonia in those cases, or that hyponatremia, polydipsia, and catatonia share common underlying mechanisms. The authors’ knowledge of some pathophysiology of both catatonia and hyponatremia as it occurs in psychotic illness may permit making useful inferences about each and about their association.

These patients all shared common features of an agitated impulse to drink water (and in one case also to eat metal objects), responded with verbigeration when they asked to be allowed to do what they wished, but did not seem more anxious or agitated when this was not allowed. All of them demonstrated signs of catatonia during the same episode of illness. The authors suggest that perhaps the act of “ritualistic” water drinking (psychogenic polydipsia) could be considered a stereotypy, meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision,9 criteria as repetitive, nonfunctional behaviors present for at least 4 weeks, that markedly interfere with normal activities or possibly cause self-injuries. The behaviors also share features with the category of bizarre mannerisms, in the sense of repeatedly wanting or doing things that one should not. They may be a perseveration at a normal behavior (drinking or eating), or may in part reflect autonomic changes, other kinds of which are well-described in catatonic patients.2,6 When associated with catatonia, psychogenic polydipsia and ingesting foreign objects may be part of part of the same process in the brain. How might this work?

There are many reported cases of psychotic patients developing hyponatremia, sometimes so severe that osmotic cellular swelling occurs, disrupting brain function and causing confusion, headache, nausea, vomiting, and death. In such cases, hyponatremia is often associated with concentrated urine, which may be inferred from elevated urine sodium, the threshold for which there is some disagreement between 20 mEqL and 40 mEq/L. Concentrated urine in the presence of hyponatremia with hypo-osmolar plasma is abnormal, and is termed SIADH.10-14 There appear to be several mechanisms by which antidiuretic hormone (vasopressin [AVP]) function can be altered to produce the syndrome of hyponatremia in psychotic patients, including excess AVP release.10,11 Other mechanisms are more subtle, and produce a syndrome of excessive water drinking, hyponatremia, and concentrated urine with normal blood levels of AVP.11-13 None of the authors’ patients had yet developed symptoms of the hypo-osmolar delirium, but a recent case that had progressed to death after discharge had prompted a higher degree of caution than usual in approaching hyponatremia. The authors suggest that the evidence for SIADH (hyponatremia with concentrated urine or elevated urine sodium) in many reported cases besides theirs suggests a role for AVP in the genesis of hyponatremia, and its link with catatonia.

Catatonia involves hyperdopaminergic, hyperglutamatergic, and hypo-g-aminobutyric acid (GABA)-ergic signaling.15 The evident possible role of AVP in hyponatremia and the behavior of psychogenic polydipsia may be the clue to the association with catatonia. AVP is one of several peptide neurohormones that also serve as neurotransmitters. AVP is known to function as a neurotransmitter in several areas in the brain. The paraventricular nucleus (PVN) in the hypothalamus is an important site for autonomic and endocrine homeostasis,16 including fluid and electrolyte homeostasis. The magnocellular neurosecretory cells in the supraoptic nuclei (SON) and PVN secrete AVP (and oxytocin) into the circulation. There is increasing evidence that glutamate acts as a transmitter in the neuronal control of release of AVP and oxytocin from the neurohypophysis. These cells express two types of ionic glutamate receptors characterized by the synthetic agonists a-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) and N-methyl-d-aspartic acid (NMDA). Immunochemical and ultrastructural studies demonstrate glutamatergic axon terminals in the SON and PVN in synaptic contact with cells secreting both AVP and oxytocin.17 Additionally, in rats under ethanol anesthesia in which a diuresis was maintained by a constant fluid load, the intracerebroventricular injection of glutamate and synthetic agonists of AMPA and NMDA receptors produced an antidiuretic response which was abolished by an AVP antagonist.17 Furthermore, in the same rat model, secretion of AVP and oxytocin was inhibited by injection of GABA or its agonist muscimol.18

Pathophysiologically, motor stereotypy is a common component of several developmental, genetic, and neuropsychiatric disorders. In animals, these behaviors can be induced or attenuated via pharmacologic manipulation of specific neural loci comprising cortico-basal ganglia-cortical feedback circuits, including the striatum. Some findings support a role of the striatal glutamatergic system in the mediation of spontaneous stereotypic behavior and suggest a potential neuronal mechanism by which transition to stereotypy occurs in these mice.

If this pre-clinical evidence is accurate, then in a hyper-glutamatergic state, ie, catatonia, glutamate can theoretically not only result in secretion of AVP, resulting in hyponatremia, but also motor stereotypies, such as “water drinking.” The authors recognize that the ultimate development of “repetitive water drinking” cannot be simply ascribed as above, but that the etiology of repetitive water drinking is multi-factorial; they propose this hyper-glutamatergic pathogenesis as a possible putative mechanism, which has not been evaluated in humans.19

AVP has been shown to interact specifically with hypocretin/orexin neurons in a manner that increases locomotor activity.20 If AVP has a role in catatonia, it would imply that the agitated, hyperkinetic form of catatonia might be more often associated with hyponatremia. The prevalence was equal in the authors’ cases.

AVP interacts with the cells that secrete it by feedback through auto-receptors, and indirectly as well, by the consequences of its secretion in excess. The magnocellular neurons that release AVP (and oxytocin) into the circulation from the hypothalamus are adversely affected by chronic hyponatremia.21

The effect of demeclocycline in reversing hyponatremia in SIADH is thought to be at the renal tubules, where aquaporin molecules within the tubule epithelial cell membrane initiate pinocytosis of water in response to AVP.10-13 Minocycline has not been reported to have this effect, and one of the authors’ patients whose mute, immobile catatonia responded to minocycline, continued to demonstrate low sodium and concentrated urine. There are several reports of minocycline exerting beneficial effects on psychotic or catatonic states.22-25 The postulated mechanism, which remains to be proven, has been minocycline inhibition of caspase, and resultant neuroprotection. A second neuroprotective mechanism is inhibition of mitochondrial poly-(adenosine diphosphate-ribose)-polymerase-1. This is an effect minocycline shares with doxycycline, demeclocycline, and chlortetracycline, in descending order of potency.26

AVP injected into the anterior hypothalamus elicits aggressive behavior, manifested as biting in rodents. There is evidence that AVP functions normally as a neurotransmitter in that brain region, controlling aggression via a tension with serotonin release.27 It thus may not be too great a leap to suppose that excess AVP transmission may be related to abnormal water drinking, or perhaps ingestion of foreign objects during psychotic states.

It is less certain to infer a role for AVP in the behavior of ingesting foreign objects. The majority of cases reported of adults ingesting foreign objects are among prison inmates who hope to manipulate their environment, or other malingering. It is associated with severe personality disorders (possibly as a self-destructive behavior) and with bulimia (sometimes inadvertent swallowing of an object one hopes will induce vomiting), as well as with psychosis.28 Psychotic patients ingesting foreign objects may be responding to delusions, such as a man who believed he was a machine in need of spare parts. When this behavior occurs in the setting of catatonia, the authors suggest it may, just as excessive drinking, represent a stereotypy, and may thus be a sign of the catatonic state.

The authors’ study depends on a very small number of patients, constituting a case series. Any study with such a small number of subjects is vulnerable to sampling error. Any study of a phenomenon as common as hyponatremia in psychiatric patients may also be vulnerable to finding accidental associations that are without meaning. The authors believe their cases may indicate a true and significant association. Their hypothesis regarding that association has some theoretical support from recent developments in the neuroscience of AVP. It would be very valuable to examine this question prospectively across a large number of catatonic patients and a large number of hyponatremic patients.


The association of catatonia with abnormal ingestion of water or non-food objects may be more common than has been appreciated, and may be linked by changes or abnormalities in AVP neurotransmission. the authors suggest that hyponatremia in a psychotic patient may be regarded potentially as an autonomic sign of catatonia, and the behavior of abnormal water ingestion may constitute a class of stereotypy that should be regarded as a possible sign of catatonia. The physiologic link, suggested in the presented cases by concentrated urine in the face of hyponatremia, may be abnormal vasopressin transmission and secretion.  PP



1.    Lee JW, Schwartz JL. Catatonia associated with hyponatremia. Neuropsychiatry Neuropsychol Behav Neurol. 1997;10(1):63-64.
2.    Taylor MA, Fink M: Catatonia in psychiatric classification: a home of its own. Am J Psychiatry. 2003;160(7):1233-1241.
3.    Taylor MA. Clinical examination. In: Caroff S, Mann S, Francis A, Fricchione G, eds. Catatonia: From Psychopathology to Neurobiology. Washington, DC: American Psychiatric Press; 2004;45-52.
4.    Fink M, Taylor MA. Catatonia: A Clinican’s Guide to Diagnosis and Treatment. Cambridge, UK: Cambridge University Press; 2003.
5.    Losonczy MF, Song JS, Mohs RC, Small NA, Davidson M, Johns CA, Davis KL. Correlates of lateral ventricular size in chronic schizophrenia. 1. Behavioral and treatment response measures. Am J Psychiatry. 1986;143(9):976-981.
6.    Taylor MA, Abrams R. Catatonia: prevalence and importance in the manic phase of manic-depressive illness. Arch Gen Psychiatry. 1977;34(10):1223-1225.
7.    Abrams R, Taylor MA, Stolorow KA. Catatonia and mania: patterns of cerebral dysfunction. Biol Psychiatry. 1979;14(1):111-117.
8.    Bush G, Fink M, Petrides G, Dowling F, Francis A. Catatonia I: rating scale and standard examination. Acta Psychiatrica Scand. 1996;93(2):129-136.
9.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
10.    Illowsky BP, Kirch DC. Polydipsia and hyponatremia in psychiatric patients. Am J Psychiatry. 1988;145(8):675-683.
11.    Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med. 2009;342(21):1581-1589.
12.    Yamauchi T, Makinodan M, Nagashima T, Kiuchi K, Noriyama Y, Kishimoto T. Type D Syndrome of inappropriate antidiuretic hormone secretion in a schizophrenia patient with polydipsia. J Brain Dis. 2009;1(1):25-27.
13.    Zerbe R, Stropes L, Robertson G, et al. Vasopressin function in the syndrome of inappropriate antidiuresis. Annu Rev Med. 1980;31:315-327.
14.    Goldman MB, Luchins DJ, Robertson GL. Mechanisms of altered water metabolism in psychotic patients with polydipsia and hyponatremia.  N Engl J Med. 1988;318(7):397-403.
15.    Northoff G, Ecker J, Fritze J. Glutamatergic dysfunction in catatonia? Successful treatment of three acute akinetic catatonic patient with the NMDA antagonist amantadine. J Neurol Neurosurg Psychiatry. 1997;62(4):404-406.
16.    Pyner S. Neurochemistry of the paraventricular nucleus of the hypothalamus: implications for cardiovascular regulation. J Chem Neuroanatomy. 2009;38(3):197-208.
17.    Bisset GW, Fairhall KM. Release of vasopressin and oxytocin by excitatory amino acid agonists and the effect of antagonists on release by muscarine and hypertonic saline in the rat in vivo. Br J Pharmacol. 1996;117(2):309-314.
18.    Bisset GW, Chowdrey HS, Fairhall KM, Gunn LK. Central inhibition by gamma-aminobytyric acid and muscimol of release of vasopressin and oxytocin by an osmotic stimulus in the rat. Br J Pharmacol. 1990;99(3):529-535.
19.    Presti MF, Watson CJ, Kennedy RT, Yang M, Lewis MH. Behavior-related alterations of striatal neurochemistry in a mouse model of stereotyped movement disorder. Pharmacol Biochem Behav. 2004;77(3):501-507.
20.    Tsunematsu T, Fu LY, Yamanaka A, et al. Vasopressin increases locomotion through a VIa receptor in orexin/hypocretin neurons: implications for water homeostasis. J Neuroscience. 2008;28(1):228-238.
21.    Dohanics J, Hoffman GE, Verbalis JG. Chronic hyponatremia reduces survival of magnocellular vasopressin and oxytocin neurons after axonal injury. J Neuroscience. 1996;16(7):2373-2380.
22.    Ahuja N, Carroll BT. Possible anti-catatonic effects of minocycline in patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(4):968-969.
23.    Miyaoka T, Yasukawa R, Yasuda H, Hayashida M, Inagaki T, Horiguchi J. Possible antipsychotic effects of minocycline in patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(1):304-307.
24.    Miyaoka T, Yasukawa R, Yasuda H, Hayashida M, Inagaki T, Horiguchi J. Minocycline as adjunctive therapy for schizophrenia. Clin Neuropharmacol. 2008;31(5):287-292.
25.    Fujita Y, Ishima T, Kunitachi S, et al. Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the antibiotic drug minocycline. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(2):336-339.
26.    Alano, CC, Kauppinen TM, Valis AV, Swanson RA. Minocycline inhibits poly(ADP-ribose) polymerase-1 at nanomolar concentrations. Proc Natl Acad Sci USA. 2006;103(25):9685-9690.
27.    Ferris CF, Melloni RH, Koppel G, Perry KW, Fuller RW, Delville Y. Vasopressin/serotonin interactions in the anterior hypothalamus control aggressive behavior in golden hamsters. J Neuroscience. 1997;17(11):4331-4340.
28.    O’Sullivan ST, Reardon CM, McGreal GT, Hehin DJ, Kirwan WO, Brady MP. Deliberate ingestion of foreign bodies by institutionalized psychiatric patients. Ir J Med Sci. 1996;165(4):294-296.



Childhood-Onset Social Anxiety Disorder Associated With Later Development of Major Depressive Disorder

According to the National Institute of Mental Health, social anxiety disorder (SAD), also called social phobia, affects approximately 15 million American adults ≥18 years of age. The disorder, which is characterized by extreme anxiety and self-consciousness in response to everyday social situations, often can lead to or occur comorbid with other mental health disorders such as major depressive disorder (MDD). Patients typically first experience SAD symptoms around 13 years of age.

Although studies have shown that patients with SAD have an increased risk of subsequently developing MDD, results from prospective longitudinal analyses on the association between MDD development and SAD in children and adolescents have been mixed. Recently, researchers at the Institute of Clinical Psychology and Psychotherapy at Dresden University of Technology in Germany sought to determine the prevalence of SAD in children and adolescents as well as rates of MDD development from childhood through young adulthood.

Katja Beesdo, PhD, and colleagues, studied 3,021 patients 14–24 years of age at baseline and 21–34 years of age at the study follow-up. Beesdo and colleagues also sought to determine distal and proximal predictors for the development of MDD in SAD patients. All patients were evaluated using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Munich–Composite International Diagnostic Interview through in-person interviews. Incidence of dysthymia and major depressive episodes were the main outcome measures of the study.

The authors found that 11% of patients met diagnostic criteria for SAD and 27% of patients had MDD or dysthymia. For patients 10–19 years of age, SAD prevalence was highest (0.72% per person/year), while SAD incidence rates dropped for patients younger or older than that age range. Of SAD patients, 50% had MDD at the study follow-up.

The later development of MDD was significantly associated with SAD incidence, which was a result independent of the patient’s age of SAD onset. In addition, Beesdo and colleagues found that proximal factors, such as the severity and persistence of SAD symptoms, and distal factors, such as parental anxiety and depression, were each predictors of MDD development. Behavioral inhibition and occurrence of a panic attack were also MDD predictors.

Beesdo and colleagues concluded that childhood- and early adolescent-onset SAD is associated with an increased risk for the development of MDD in young adults. As prior studies have shown that SAD severity is associated with a more severe course of MDD and other depressive disorders, the authors found that targeted prevention and treatment of SAD symptoms is crucial. Future studies should also examine the role of proximal and distal predictors for MDD development. (Arch Gen Psychiatry. 2007;64(8):903-912). —CP


Use of MRIs and fMRIs Could Lead to Personalized Treatment for Major Depressive Disorder

The use of magnetic resonance imaging (MRI) and functional magnetic resonance imaging (fMRI) for the treatment of major depressive disorder (MDD) was recently studied by Edward Bullmore, MRCP, MRCPsych, PhD, and colleagues, at Addenbrooke’s Hospital in Cambridge, United Kingdom. Bullmore and colleagues believe that personalized treatment for depression via MRIs can help physicians predict which method of treatment will be the most beneficial for each individual patient.

Bullmore and colleagues evaluated structural MRIs and fMRIs as predictors of symptom change in people with depression. They conducted MRIs on 17 patients before, during, and after receiving antidepressant treatment and measured the structure and functioning of each patient’s brain. All patients were suffering from MDD and began receiving fluvoxamine 20 mg/day after the baseline MRI. fMRIs were conducted to record brain activity as the patients were presented with sad faces (each face represented a different intensity of sadness). The Hamilton Rating Scale for Depression was used to assess clinical response.

Bullmore and colleagues found that there were faster rates of MDD improvement in patients with greater grey matter volume in the anterior cingulate cortex, insula, and right temporo-parietal cortex. Some patients were found to have more than the average amount of grey matter and these patients had faster rates of improvement and lower residual symptom scores at endpoint. Patients with greater functional activation in the anterior cingulate cortex also had faster improvement.

The researchers believe that structural MRIs of the anterior cingulate cortex in patients suffering from MDD could provide useful data as to the efficacy of antidepressant use and lead to greater individualized treatment responses in each patient. (Biol Psychiatry. 2007;62(5):407-414). —CN


Overweight Teens at Risk for Disordered Eating

Obesity and eating disorders are both significant issues for adolescents. While disordered eating behaviors are commonly thought to affect thin teenagers, a new study suggests that thin teenagers are not the only ones in danger of developing eating disorders or disordered eating habits.

Dianne Neumark-Sztainer, PhD, at the University of Minnesota, and colleagues, looked at 2,516 adolescents first in 1998–1999 and then 5 years later in 2003–2004. The teenagers were questioned on eating patterns, exercise, disordered-eating behaviors, weight teasing by family and friends, exposure to weight-related messages from the media, and family meal practices. The researchers found weight-related problems in 44% of female teenagers and 29% of male teenagers. Additionally, they found that 40% of overweight females and 20% of overweight males used at least one disordered-eating behavior to control their weight. Disordered-eating behaviors ranged from taking diet pills or laxatives to vomiting after meals.

The study also found that teasing from family or friends was one of the strongest predictors for both extreme dieting as well as being overweight. Teasing from family members about weight, even if not intended to be malicious, was detrimental to the teenagers’ weight. Those who reported being teased by family members were twice as likely to be overweight at the time of the second survey. However, families could also have a positive effect on teenagers’ weight as well. Factors such as eating meals as a family and fostering a sense of connection were both found to be protective factors.

Dr. Neumark-Sztainer notes that positive reinforcement and modeling healthy behavior are the keys to decreasing unhealthy eating habits and weight-loss practices. Although this study cannot prove a causal relationship between any of the factors studied, the hope is that future research will be able to determine whether decreasing any of these factors will lead to a decrease in childhood obesity. (Am J Prev Med. 2007;33(5):359-369). —VJ

Psychiatric Dispatches is written by Virginia Jackson, Christopher Naccari, and Carlos Perkins, Jr.



Needs Assessment: Suicide is a major public health concern. Because of the weak predictive values of psychological, social, and environmental factors, understanding of the neurobiology of suicide offers a promising approach to identifying the risk factors associated with it. This cannot only clarify the etiology but also the treatment and prevention of suicide. This article focuses on the role of the signal transduction molecule protein kinase A in the pathophysiology of suicide.

Learning Objectives:

• Explain the importance of understanding the neurobiology of suicide.
• Describe the relevance of signal transduction molecules in understanding the risk factors associated with suicide.
• List the changes in protein kinase A (PKA) in suicide subjects as revealed by postmortem brain studies.
• Describe how the changes in PKA differ in teenage versus adult suicide and how changes in PKA during stress may be related to suicide.

Target Audience: Primary care physicians and psychiatrists.

CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: October 16, 2007.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by November 1, 2009 to be eligible for credit.

Release date: November 1, 2007. Termination date: November 30, 2009. The estimated time to complete all three articles and the posttest is 3 hours.


Dr. Dwivedi is tenured associate professor in the Departments of Psychiatry and Pharmacology and faculty member at the Graduate College at the University of Illinois in Chicago. Dr. Pandey is professor of psychiatry in the Department of Psychiatry at the University of Illinois College of Medicine.

Disclosures: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest. Funding for this research was provided by the American Foundation for Suicide Prevention, the National Alliance for Research on Schizophrenia and Depression, and the National Institute of Mental Health.

Please direct all correspondence to: Yogesh Dwivedi, PhD, Associate Professor, Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor St, Chicago, IL 60612; Tel: 312-413-4557; Fax: 312-355-3857; E-mail: ydwivedi@psych.uic.edu.



In modern society, suicide is a major public health problem, yet currently the neurobiologic risk factors associated with suicide are still poorly understood. Recent studies demonstrate that alteration in synaptic and structural plasticity is key to affective disorders and suicide. Signal transduction molecules play an important role in such plastic events. Protein kinase A (PKA) is one of the crucial signaling molecules that, by phosphorylating proteins, affects a wide array of physiologic functions in the brain. This article focuses on recent findings that indicate alterations in activation and expression of PKA may be involved in the pathophysiology of suicide. The authors critically discuss these findings in human postmortem brain and in pre-clinical models as well as attempt to elucidate how stress, one of the major risk factors in suicide, may be crucial in altering PKA. In addition, the functional significance of altered PKA in respect to its target molecules cyclic adenosine monophosphate response element binding protein and brain-derived neurotrophic factor is also discussed. These findings provide a better understanding of the neurobiology of suicide and indicate that altered PKA may be one of the important neurobiologic risk factors associated with suicide.



Suicide is a major public health concern. Each year, approximately 30,000 people commit suicide in the United States, and 1 million people commit suicide worldwide.1,2 Suicide is the third leading cause of death among adolescents, after motor vehicle accidents and homicide.3 Over 90% of suicides are associated with mental illnesses4 and 60% of them occur in the context of depressive disorders.5 Because almost all psychiatric disorders are characterized by an increased risk of suicidal behavior, the existence of suicidal syndromes independently of psychiatric illnesses has been proposed.6 Recently, Mann and colleagues7 proposed a stress-diathesis model, which postulates that suicidal behavior may be understood as a function of the interplay between state-dependent factors such as illness and life events, and trait-dependent factors which include biologic markers for suicidal behavior.

Recently, research on the biologic perspective of suicide has gained a stronghold and appears to provide a promising approach to identifying potential risk factors associated with suicide. An emerging hypothesis suggests that the pathogenesis of suicide/depression involves altered plasticity of neuronal pathways.8 Even structural abnormalities in the brains of mood disorder patients and suicide subjects have been reported.9 Intracellular signaling coordinates the behavior of individual cells within the brain in various physiologic processes. This signaling requires three essential components, including a molecular signal, also known as a neurotransmitter, that sends the information from one cell to another; a receptor that receives the signal and transmits the information provided by the signal; and a target molecule that mediates the cellular responses. Numerous studies suggest the involvement of serotonergic and to some extent noradrenergic systems in suicide, which includes alterations in levels of serotonin and norepinephrine, their metabolites, and the receptors to which these neurotransmitters bind in the brain and peripheral tissues of suicide subjects.10-12 However, emerging evidence suggests that downstream abnormalities in signal transduction mechanisms, particularly at the level of protein phosphorylation (whereby proteins are activated or deactivated through the addition of a phosphate group via an enzyme), are important mediators of neural plasticity and adaptations. Given the critical importance of intracellular signaling in amplifying, integrating, and regulating physiologic processes and in mediating gene expression, recent studies have focused on the role of signaling molecules in the pathophysiology of mood disorders and suicide.13 Protein kinase A (PKA) is one such key phosphorylating enzyme, which upon activation triggers a wide variety of physiologic responses in the brain that are important for cell survival, synaptic plasticity, and activation or repression of gene transcription.14,15

This article critically discusses recent findings implicating a role for PKA in suicide. In addition, the article discusses the functional importance of changes in PKA with respect to alterations in its target molecules, in particular the transcription factor cyclic adenosine monophosphate response element binding protein (CREB) and neurotrophin brain-derived neurotrophic factor (BDNF). Such studies attempt to elucidate the neurobiologic basis of suicide and pinpoint the abnormalities in a specific gene or gene product that may serve as potential vulnerability factor(s) associated with suicide and provide target(s) for future therapeutic interventions.


Protein Kinase A: Role in Suicide

Protein Kinase A: General Aspects

PKA is a phosphorylating enzyme in the adenylyl cyclase-cyclic adenosine monophosphate (cAMP) signaling pathway, which is one of the major signal transduction pathways and is linked to many neurotransmitter receptors, including β-adrenergic and serotonergic receptors, either in a stimulatory or an inhibitory mode. A diagram illustrating the adenylyl cyclase-cAMP signaling pathway is presented in Figure 1. In this pathway, a neurotransmitter binding to receptors causes activation of the intermediary molecule guanine nucleotide-binding protein (G protein). These G proteins then modulate the activity of the enzyme adenylyl cyclase, which in turn causes conversion of adenosine triphosphate to cAMP, which then activates PKA. Once activated, PKA can phosphorylate proteins in the cytoplasm or can translocate into the nucleus, where it can change the transcriptional machinery involved in gene synthesis by phosphorylating and therefore activating transcription factors. These phosphorylation events modify hormonal and neurotransmitter responses, including receptor downregulation/desensitization, alteration in neurotransmitter release, neurite outgrowth, neuronal differentiation, cell survival, and activation/repression of gene expression.14,15 One of the most important targets of PKA in the nucleus is the transcription factor CREB. The activation of CREB causes alterations in expression of several genes that have been implicated in synaptic and structural plasticity. One such gene is BDNF, which is essential for the maintenance of neuronal phenotypes, cell survival, and neuronal plasticity.16


PKA is a holoenzyme composed of two homodimeric regulatory (R) and two catalytic (C) subunits. In the absence of cAMP, PKA is inactive and exists as a stable tetramer. After an increase in intracellular cAMP, the regulatory PKA subunits bind to cAMP in a cooperative manner, which results in the disassociation of the holoenzyme into a dimeric regulatory unit and two monomers of catalytic subunits. The free catalytic subunits then phosphorylate substrates in the cytosol or translocate into the nucleus and phosphorylate nuclear proteins (Figure 1). Thus, both the catalytic and the regulatory subunits are important in facilitating PKA-mediated functions.

On the basis of the elution profile on diethylaminoethyl exchange chromatography, two major forms of PKA have been identified, ie, Type I and Type II. These two types differ in their structure and in the regulatory subunits incorporated, termed RI or RII, whereas their catalytic subunits are either identical or very similar. Cloning studies have revealed multiple isoforms for each regulatory and catalytic subunit. Two RI subunits, termed RIα and RIβ, and two RII subunits, termed RIIα and RIIβ, have been identified. Furthermore, three distinct catalytic subunits have been identified, termed Cα, Cβ, and Cγ. Each regulatory and catalytic subunit is a separate gene product and has a distinct expression pattern in different tissues.17


Role of Protein Kinase A in Suicide: Evidence from Human Postmortem Brain Studies

The role of PKA in suicide was examined in a comprehensive study. Dwivedi and colleagues18 determined cAMP binding to regulatory subunits of PKA and catalytic activity of PKA in the prefrontal cortex (PFC) of adult suicide subjects and well-matched nonpsychiatric normal control subjects obtained from the Maryland Psychiatric Research Center in collaboration with the Medical Examiner’s Office in Baltimore. It was observed that cAMP binding to regulatory subunits of PKA was significantly decreased in PFC of suicide subjects; however, there were no significant differences in the affinity of cAMP binding to these subunits. In addition, it was observed that PKA activity was decreased in the PFC of adult suicide subjects compared with normal control subjects in both the presence and the absence of cAMP, which suggests that decreased activation of PKA is not dependent on less availability of cAMP but on other factors such as altered expression of certain catalytic and/or regulatory subunits. To confirm this finding, in a different cohort of brain samples, the authors studied similar paradigms in postmortem brain of suicide subjects and well-matched normal control subjects obtained from Semmelweis University, Budapest, Hungary. Dwivedi and colleagues19 found similar changes in cAMP binding and PKA activity in the PFC of suicide subjects to those observed in the Maryland cohort.

To examine if the decreases in PKA activity and cAMP binding in postmortem brain of suicide subjects are related to changes in expression of specific catalytic and/or regulatory subunits, the authors19 determined the protein and gene expression of all the regulatory and catalytic subunits of PKA in the same postmortem brain samples in which they studied PKA activity and cAMP binding. Interesting observations were noted in both cohorts of brain samples; there was a significant and selective decrease in gene and protein expression of regulatory RIIβ and catalytic Cβ subunits in the PFC of suicide subjects without any changes in expression levels of RIα, RIIα, RIβ, or Cα subunits.19 These findings were independently confirmed by Odagaki and colleagues.20 These results suggest that decreases in cAMP binding and PKA activity could be due to decreases in the gene expression of RIIβ and Cβ, respectively, and changes in expression of catalytic and regulatory subunits of PKA are quite specific.

Recently, Pandey and colleagues21 examined whether the changes in PKA in adult suicide are similar to those in the teenage population. The rationale behind this determination was that the characteristics and risk factors for teenage suicide may be similar to those of adult suicide in some respects but differed in others. One distinct difference is that teenage suicide is driven primarily by impulsive aggressive behavior.22,23 Similarly, as in the adult population, PKA activity was found to be decreased in the PFC of teenage suicide subjects. However, when the protein and gene expression levels of PKA subunits were determined, a different pattern of changes in expression of PKA emerged. Whereas the protein and messenger ribonucleic acid (mRNA) expression of RIIβ and Cβ were decreased in the PFC of adult suicide subjects, the data in the PFC of teenage suicide subjects showed that expression not of RIIβ or Cβ but of RIα and RIβ was significantly decreased. This is quite distinct from what was observed in the adult population. When teenage suicide subjects were divided into those with a history of major mental disorders and those with no such history, no significant differences in PKA activity or protein and mRNA expression of any of the subunits were noted between the two groups,21 which suggests that the observed changes were not related to specific mental disorders but to suicide. The question is why are different regulatory and catalytic subunits altered in teenage versus adult populations? Is this related to specific behavioral characteristics such as affective disorders or impulsive aggressive behavior? There is currently no explanation for such contrasting results in teenage versus adult suicide, but overall there is decreased activation of PKA in the brains of both these populations. Further molecular studies are required to delineate this issue.

Interestingly, several studies in peripheral tissues obtained from depressed patients have also shown abnormalities in PKA. For example, Perez and colleagues24 found that the level of the Type II PKA regulatory subunit was significantly lower in platelets of untreated depressed patients compared with euthymic patients or normal controls. Shelton and colleagues25 and Manier and colleagues26 reported significantly decreased β-adrenergic receptor-stimulated PKA activity in fibroblasts of depressed patients, which was present only in melancholic depressed patients.27 More recently, Akin and colleagues28 reported reduced PKA activity along with reduced expression of PKA RIIα, Cα, and Cβ subunits in fibroblasts of melancholic depressed subjects.


Role of Protein Kinase A in Suicide: Preclinical Studies

Effect of Stress on Protein Kinase A
Stress is known to cause changes in the hypothalamic-pituitary-adrenal (HPA) axis in both humans and non-human models. Numerous studies point to a strong relationship between a hyperactive HPA axis and suicidal behavior,29,30 as is evident from studies showing increased corticotropin releasing hormone (CRH) in CSF,31 an altered ratio of CRH-I/II receptor mRNA in the pituitary,32 downregulation of corticotropin releasing factor receptors in PFC,33 an increase in mRNA of the  precursor molecule of adrenocorticotropic hormone in the pituitary34 of suicide subjects, and an increased volume of urinary free cortisol in violent suicide attempters.35 Therefore, it is of interest to examine whether changes in PKA are related to stress.

In a detailed study, Dwivedi and Pandey36 examined the effect of glucocorticoids after bilateral adrenalectomy and supplementation with exogenous glucocorticoid, as well as the effect of endogenous glucocorticoids, on various measures of PKA in rat brain. For this, rats were given various doses of corticosterone at different time intervals, and in a separate experiment, an adrenalectomy was performed and these rats were then given various doses of corticosterone. The authors observed that 1 day of corticosterone treatment had no significant effects, but 4 days of corticosterone treatment decreased cAMP binding to the regulatory subunit of PKA and PKA catalytic activity in the rat cortex and hippocampus. These changes were much more profound after 14 days of corticosterone. These effects were also dose dependent. A higher dose of corticosterone was much more effective in causing changes in PKA than a lower dose. Adrenalectomy produced the opposite results, increasing PKA activity and cAMP binding in both cortex and hippocampus in a time-dependent manner. These changes were reversed by corticosterone treatment in a dose-dependent manner. The higher dose of corticosterone completely reversed the changes in PKA after adrenalectomy.36 Interesting results were noted when the authors examined the expression levels of regulatory and catalytic subunits; mRNA and protein expressions of RIα, RIIβ, and Cβ isoforms were significantly decreased in cortex and hippocampus after corticosterone treatment. Removal of adrenal glands increased the expression of these subunits, and corticosterone treatment of adrenalectomized rats reversed the adrenalectomy-induced changes in PKA RIα, RIIβ, and Cβ isoforms.36 These changes were very similar to what were observed in postmortem brain of adult suicide subjects.18,19 Thus, these studies suggest that the expression of specific isoforms of PKA regulatory and catalytic subunits may be under the regulation of glucocorticoids and that stress may be playing an important role in such changes in the brain of suicide subjects.

Effect of Learned Helpless Behavior on Protein Kinase A
Since the ability to cope with stress is critical for humans, parallel studies of the effects of uncontrollable stress have been performed in animals, with the result of proactive interference with the acquisition of escape/avoidance responding.37 This phenomenon is termed learned helplessness and has been used extensively as an animal model of stress-induced behavioral depression, which is a common risk factor in suicide.38,39 To examine whether alterations in PKA occur during learned helplessness behavior, PKA in the brains of learned helpless rats were studied. Dwivedi and colleagues40 found that cAMP binding and PKA activity were both significantly decreased in the brains of learned helpless rats, and this was associated with selectively decreased expression of RIIβ and Cβ subunits. These changes were well-correlated with stress-induced behavioral paradigms. For example, learned helplessness behavior dissipated 4 days after the induction of learned helplessness, and the changes in PKA also reverted to the normal level, which suggests that changes in PKA are specific to stress-induced behavioral depression. The findings in PKA in learned helplessness rats were very similar to those observed in postmortem brains of suicide subjects.


Functional Significance of Altered Protein Kinase A

The findings that PKA activation is reduced in postmortem brains of suicide subjects and is also dysregulated during stress suggest the interesting possibility that many physiologic functions in the brain mediated by PKA may be altered in suicide subjects. However, although it is a matter for further research, the findings that expression of specific catalytic and regulatory subunits is decreased in suicide subjects and during stress in laboratory animals provide further evidence that there is a defect in the transcription of genes corresponding to certain catalytic and regulatory subunits of PKA; as discussed above, this defect could be associated with altered levels of glucocorticoids. The question is what could be the relevance of such changes in expression of specific PKA regulatory and catalytic subunits with respect to their role in suicide and depression? The specific functions of RIIβ and Cβ are not clearly known; however, tissue distribution studies suggest that RIIβ is predominantly expressed in brain, adrenal, and adipose tissues and is the principal mediator of cAMP activity in the mammalian central nervous system (CNS),41 whereas Cβ is expressed primarily in the brain.42 Ludvig and colleagues43 showed that RIIβ immunolabeling is associated with postsynaptic structures, suggesting that this subunit is involved in several postsynaptic neuronal functions. In addition, many studies have demonstrated that RIIβ and Cβ subunits may be specifically involved in neuronal and behavioral functions. For example, Constantinescu and colleagues44 showed that the RIIβ subunit can translocate to the nucleus and induce phosphorylation of one of the most important substrates of PKA, ie, CREB. In addition, RIIβ-mutant mice exhibit defective motor behavior45 and show an increased tendency to consume ethanol.46 Cβ-mutant mice, on the other hand, show impaired hippocampal plasticity.47 Targeted disruption of the RIβ subunit gene results in mice that exhibit defects in long-term depression and depolarization, which suggests a deficit in a learning-related form of synaptic plasticity.45 It has also been shown that an RIβ deficiency produces selective defects in mossy fiber long-term potentiation.45 Whether these abnormalities are relevant to suicide is not clear at present; however, given the significance of PKA in many biologic actions in the brain, together with emerging studies demonstrating specific roles for its catalytic and regulatory subunits in physiologic and behavioral manifestations, the observations of decreased catalytic and regulatory activities and expression of specific regulatory and catalytic subunits in postmortem brains of suicide subjects suggest that abnormalities in PKA may be of critical importance in the pathophysiology of suicidal behavior.

Transcription Factor CREB in Suicide
The regulation of gene expression is a fundamental mechanism of brain development, homeostatics, and adaptation to the environment. Transcription factor CREB is a member of the leucine zipper family, which binds to the consensus motif 5’-TGACGTCA-3’, found in the promoters of many neuronally expressed genes, and thereby activates or represses the transcription of target genes.14 Phosphorylation of CREB at Ser133 by PKA is the critical step in its activation. In its active form, CREB regulates many aspects of neuronal functioning, including excitation of nerve cells, CNS development, and long-term synaptic plasticity.48 BDNF is one of the many important genes whose transcription is mediated through the activation of PKA/CREB. To determine if CREB could possibly be involved in suicide, Dwivedi and colleagues49 recently examined the mRNA and protein expression as well as cAMP response element (CRE)-deoxyribonucleic acid (DNA)–binding activity (a measure of functional characteristics) of CREB in the PFC and hippocampus of suicide victims. The protein expression of CREB was found to be significantly decreased in the nuclear fractions of PFC and hippocampus obtained from suicide victims compared with normal control subjects. It was also observed that this decrease in protein expression levels was associated with a significant decrease in the mRNA levels of CREB in both the PFC and hippocampus of suicide victims. The authors also found decreased functional activity of CREB, such that CRE-DNA binding activity was significantly decreased in the nuclear fractions of both PFC as well as hippocampus of suicide subjects. These changes in CREB were present in all suicide subjects irrespective of psychiatric diagnosis. Similar results were noted in the postmortem brains of teenage suicide subjects.50 In addition, Young and colleagues51 reported altered levels of phospho-CREB in the amygdala of suicide subjects. The results of these studies suggest that not only PKA but also expression and functional characteristics of one of the important substrates of PKA, ie, CREB, are abnormal in the brains of suicide subjects.

These findings may have important clinical implications. For example, it has been shown that all antidepressants activate or upregulate the expression of CREB in the brains of rats.52 Similar results have been shown in postmortem brains of depressed patients treated with antidepressants.53 In contrast, the phosphorylation and the expression of CREB are decreased in postmortem brain of depressed patients, which could be associated with a decrease in PKA activity.54 Given the role of CREB in various physiologic actions in the brain, the findings of its increased expression by antidepressants and of its decreased expression and functional characteristics in the brain of depressed/suicide subjects are quite important and implicate this gene in depression/suicidal behavior.

Interestingly, at the genetic level, Zubenko and colleagues55 performed a linkage analysis of six polymorphic markers located in a 15 cM region of chromosome 2q33-35 and unipolar depression. They found a significant linkage of unipolar depression to a 451 Kb region of 2q33-34, which contains the CREB1 gene. This study further suggests that the CREB1 gene may be an attractive candidate for a susceptibility gene for depression.

BDNF as a Target Gene of Protein Kinase A: Role in Suicide
Among the epigenetic factors that may influence the development and survival of neurons in the CNS are neurotrophins. The most important and widely distributed member of the neurotrophin family in the brain is BDNF. It has been shown that PKA/CREB activation increases BDNF transcription through a Ca2+/CRE within exon III of BDNF.56 BDNF-mediated activation of its cognate receptor, tropomycin-related kinase B, influences neurite outgrowth, phenotypic maturation, morphologic plasticity, and synthesis of proteins for differentiated functioning of neurons and synaptic functioning.16 Several studies suggest that BDNF is also involved in nerve regeneration, structural integrity, and maintenance of neuronal plasticity in the adult brain, including activity-dependent regulation of synaptic activity and in neurotransmitter synthesis.57 Thus, pathologic alteration of the neurotrophic factor system may lead not only to altered neural maintenance and regeneration, and therefore structural abnormalities in the brain, but also to reduced neural plasticity. The result could be an impairment of an individual’s ability to adapt to crisis situations.

The suggestion that BDNF may play a role in the pathophysiology of suicide/depression is derived from many preclinical and clinical studies. For example, Siuciak and colleagues58 found that midbrain infusion of BDNF in rats greatly reduced learned helpless behavior. Shirayama and colleagues59 reported that bilateral infusion of BDNF into the dentate gyrus of rats produced an antidepressant-like effect in animal models of depression. In contrast, acute and repeated restraint stress or glucocorticoid administration causes a rapid decrease in the expression of BDNF in hippocampus and other brain areas,60 which suggests that a hyperactive HPA axis may cause a downregulation of BDNF. Chronic treatment with antidepressants prevents the stress-induced lowering of BDNF.61 Direct evidence of the role of BDNF in depression is derived from studies showing that serum BDNF levels are significantly decreased in drug-free depressed patients and are negatively correlated with Montgomery-Asberg-Depression Rating Scale scores.62 Recently, Shimizu and colleagues63 reported that the serum level of BDNF was significantly decreased in antidepressant-free depressed patients compared with those medicated with antidepressants or normal controls. These investigators also reported that the serum BDNF level was negatively correlated with Hamilton Rating Scale for Depression scores. Sen and colleagues64 reported that the val allele of the BDNF val66met polymorphism is associated with neuroticism, a heritable risk factor for depression. Recently, Dwivedi and colleagues65 reported decreased expression of BDNF in various areas of postmortem brain of suicide subjects, which was not related to any specific psychiatric diagnosis. Similar results were found by Karege and colleagues,66 who reported a decreased level of BDNF in postmortem brains of suicide subjects. More recently, Kim and colleagues67 found that the plasma level of BDNF is reduced in suicidal patients.

The findings of lower BDNF levels in depressed and suicide subjects have important implications. For example, emerging studies suggest that stress, affective disorders, and suicide are associated with structural abnormalities in the brain, including reduced hippocampal volume, reduced density and size of cortical neurons in the dorsolateral prefrontal cortex and orbitofrontal cortex, reduced density of nonpyramidal neurons, and layer-specific reduction in interneurons in the anterior cingulate cortex and in nonpyramidal neurons in the hippocampal formation. Similarly, several studies show that stress or glucocorticoid administration causes neuronal atrophy, a decrease in the number or length of apical dendrites, and even loss of hippocampal neurons in rodents or nonhuman primates.61 A few studies have demonstrated that the size of the parahippocampal cortex and the cortical laminar thickness are reduced in suicide brain.68,69 Taken together, these studies indicate that depression and suicide could be associated with atrophy or loss of neurons and/or glia. Because of the role played by BDNF in preventing neuronal atrophy and in survival and maintenance of neurons, decreased levels of BDNF could be associated with such structural abnormalities in the brain of affective disorder patients and suicidal subjects. It is pertinent to mention that besides BDNF, there are other growth factors whose transcription is mediated by the phosphorylation of transcription factors. These growth factors may also be affected in depression and suicide. Recent studies demonstrate that fibroblast growth factor and vascular endothelial growth factors may play important roles in depression and in the mechanism of action of antidepressants.70,71 Whether the expression of these growth factors is altered in suicide needs to be studied.



This article summarized and integrated recent findings that implicate the crucial phosphorylating enzyme PKA in suicide, the results of research which ranges from human postmortem brain studies to preclinical studies in rodents. In addition, the article discussed whether changes in PKA have any functional consequences in terms of the responsiveness of the cAMP signaling cascade as well as of its signaling molecules. A summary of findings pertaining to PKA and functional response of altered PKA in postmortem brains of suicide subjects is provided in Figure 2. It appears that there is a reduction in the activation of PKA in the brains of suicide subjects. In addition, there are reductions in specific regulatory and catalytic subunits of PKA in postmortem brains of suicide subjects. An interesting point is that there is specificity in the subunits that are affected in adult versus teenage suicide. Stress and glucocorticoid treatments in rats reduce the same subunits that are altered in the adult suicide population. Does this mean that the findings in adult suicide are related more to stress factors whereas in teenage suicide some other factors may be involved, such as impulsivity and/or aggressive behavior? Another important question is whether the changes in PKA are causative or consequences of stress or depressive/suicidal behavior. At this juncture, it would be premature to speculate, and further studies are needed to clarify these issues. Additional behavioral phenotypes will shed some light on this aspect, and currently, the laboratory of this article’s authors is engaged in delineating various behavioral and molecular aspects of mutations in specific PKA regulatory subunits in mice. Interestingly, in contrast to the differences in expression of specific PKA subunits in teenage and adult populations, the downstream target molecules, namely, CREB and BDNF, were less activated and expressed in postmortem brains of both adult and teenage suicide subjects. This is to be expected, since the overall outcome of decreased PKA is a reduction in the activation of CREB and a reduction in transcription of the BDNF gene. Thus, findings of reduced activation of CREB and expression of BDNF in both adult and teenage populations are not surprising.


In contrast, a few studies found results that are contradictory to what the authors of this article as well as other investigators have reported in postmortem brains of suicide subjects. For example, Lowther and colleagues72 reported no change in cAMP binding to regulatory subunits in postmortem brains of depressed suicides, whereas Odagaki and colleagues20 reported increased expression of total and phosphorylated CREB (an active form of CREB) in the PFC of depressed suicide subjects. Even a few animal study findings argue against the BDNF hypothesis of depression (reviewed by Groves73). Thus, although caution is required interpreting the data, nonetheless, the majority of studies show abnormalities in PKA-CREB-BDNF in suicide and depression.

Another important issue is whether the changes in PKA, CREB, and BDNF are specific to suicide or are related to mental disorders. Most suicidal patients have one or another form of psychiatric illness. As mentioned earlier, some of the findings observed in PKA signaling in suicide have been found in depressed patients. Since a large percentage of suicidal patients suffer from depression,74 it is to be expected that such findings would be present in depressed patients as well. In fact, in the authors’ study population, >60% of the subjects had a history of major depression. Therefore, although it appears that alterations in PKA are related to suicide, the possibility that changes in PKA signaling could be associated with a depressed mood or the inability to experience pleasure cannot be ruled out.

Overall, the discussed findings of abnormalities in various intracellular signaling molecules have provided insight into the molecular mechanisms associated with suicide. In the coming years, continuing studies will further advance our understanding of the pathophysiology of suicide, for they hold much promise not only for clarifying the neurobiologic risk factors associated with suicide but also for pinpointing specific genes that may be useful for developing novel “site-specific” therapeutic interventions. Finally, it will be important to investigate whether there is a genetic linkage of these abnormalities to suicide. PP



1.    Committee on Pathophysiology and Prevention of Adolescent and Adult Suicide, Board on Neuroscience and Behavioral Health, Institute of Medicine of the National Academies. In: Goldsmith SK, Pellmar TC, Kleinman AM, Bunney WE, eds. Reducing Suicide, A National Imperative. Washington, DC: The National Academies Press; 2002.
2.    Minino AM, Smith BL. Deaths: preliminary data for 2000. Natl Vital Stat Rep. 2001;49(12):1-40.
3.    National Center for Health Statistics: advance report of final mortality statistics. NCHS Monthly Vital Stat Rep. 1992;40(2).
4.    Moscicki EK. Identification of suicide risk factors using epidemiologic studies. Psychiatr Clin North Am. 1997;20(3):499-517.
5.    Hagnell O, Rorsman B. Suicide in the Lundby study: a comparative investigation of clinical aspects. Neuropsychobiology. 1979;5(2):61-73.
6.    Ahrens B, Linden M. Is there a suicidality syndrome independent of specific major psychiatric disorders? Result of a split half multiple regression analysis. Acta Psychiatr Scand. 1996;94(2):79-86.
7.    Mann JJ, Waternaux C, Haas GL, Malone KM. Toward a clinical model of suicidal behavior in psychiatric patients. Am J Psychiatry. 1999;156(2):181-189.
8.    Garcia R. Stress, synaptic plasticity, and psychopathology. Rev Neurosci. 2002;13(3):195-208.
9.    Soares JC, Mann JJ. The anatomy of mood disorders–review of structural imaging studies. Biol Psychiatry. 1997;41(1):86-106.
10.    Pandey GN, Dwivedi Y. Monoamine receptors and signal transduction mechanisms in suicide. Curr Psychiatry Rev. 2006;2:51-75.
11.    Pandey, GN, Dwivedi Y. Noradrenergic function in suicide. Arch Suicide Res. 2007;11(3):235-246.
12.    Stockmeier CA. Neurobiology of serotonin in depression and suicide. Ann N Y Acad Sci. 1997;836:220-232.
13.    Dwivedi Y. The concept of dysregulated signal transduction and gene expression in the pathophysiology of mood disorders. Curr Psychiatry Rev. 2005;1:227-254.
14.    Borrelli E, Montmayeur JP, Foulkes NS, Sassone-Corsi P. Signal transduction and gene control: the cAMP pathway. Crit Rev Oncog. 1992;3(4):321-338.
15.    Nestler EJ, Greengard P. Protein phosphorylation and the regulation of neuronal function. In: Siegel GJ, Albers RW, Agranoff BW, Molinoff P, eds. Basic Neurochemistry: Molecular, Cellular, and Medical Aspects. Boston, MA: Little Brown Press; 1994:449-474.
16.    Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci. 2001;24:677-736.
17.    Skalhegg BS, Tasken K. Specificity in the cAMP/PKA signaling pathway. Differential expression, regulation, and subcellular localization of subunits of PKA. Front Biosci. 2000;5:D678-D693.
18.    Dwivedi Y, Conley RR, Roberts RC, Tamminga CA, Pandey GN. [3H]cAMP binding sites and protein kinase A activity in the prefrontal cortex of suicide victims. Am J Psychiatry. 2002;159(1):66-73.
19.    Dwivedi Y, Rizavi HS, Shukla PK, et al. Protein kinase A in postmortem brain of depressed suicide victims: altered expression of specific regulatory and catalytic subunits. Biol Psychiatry. 2004;55(3):234-243.
20.    Odagaki Y, Garcia-Sevilla JA, Huguelet P, La Harpe R, Koyama T, Guimon J. Cyclic AMP-mediated signaling components are upregulated in the prefrontal cortex of depressed suicide victims. Brain Res. 2001;898(2):224-231.
21.    Pandey GN, Dwivedi Y, Ren X, et al. Brain region specific alterations in the protein and mRNA levels of protein kinase A subunits in the postmortem brain of teenage suicide victims. Neuropsychopharmacology. 2005;30(8):1548-1556.
22.    Brent D, Bridge J, Johnson B, Connolly J. Suicidal behavior runs in families. A controlled family study of adolescent suicide victims. Arch Gen Psychiatry. 1996;53(12):1145-1149.
23.    Brent D, Kolko D, Wartella M, et al. Adolescent psychiatric inpatients’ risk of suicide attempt at 6-month follow-up. J Am Acad Child Adolesc Psychiatry. 1993;32(1):95-105.
24.    Perez J, Tardito D, Racagni G, Smeraldi E, Zanaardi R. Protein kinase A and Rap1 levels in platelets of untreated patients with major depression. Mol Psychiatry. 2001;6(1):44-49.
25.    Shelton RC, Manier DH, Sulser F. cAMP-dependent protein kinase activity in major depression. Am J Psychiatry. 1996;153(8):1037-1042.
26.    Manier DH, Eiring A, Shelton RC, Sulser F. β-adrenoceptor-zalinked protein kinase A (PKA) activity in human fibroblasts from normal subjects and from patients with major depression. Neuropsychopharmacology.1996;15(6):555-561.
27.    Shelton RC, Manier DH, Peterson CS, Eillis TC, Sulser F. Cyclic AMP-dependent protein kinase in subtypes of major depression and normal volunteers. Int J Neuropsychopharmacol. 1999;2(3):187-192.
28.    Akin D, Manier DH, Sanders-Bush E, Shelton RC. Signal transduction abnormalities in melancholic depression. Int J Neuropsychopharmacol. 2005;8(1):5-16.
29.    Clayton PJ. Suicide. Psychiatr Clin North Am. 1985;8(2):203-214.
30.    Monk M. Epidemiology of suicide. Epidemiol Rev. 1987;9:51-69.
31.    Arato M, Banki CM, Bissette G, Nemeroff CB. Elevated CSF CRF in suicide victims. Biol Psychiatry. 1989;25(3):355-359.
32.    Hiroi N, Wong ML, Licinio J. Expression of corticotropin releasing hormone receptors type I and type II mRNA in suicide victims and controls. Mol Psychiatry. 2001;6(5):540-546.
33.    Nemeroff CB, Owens MJ, Bissette G, Andorn AC, Stanley M. Reduced corticotrophin releasing factor binding sites in the frontal cortex of suicide victims. Arch Gen Psychiatry. 1988;45(6):577-579.
34.    Lopez JF, Palkovits M, Arato M, Mansour A, Akil H, Watson SJ. Localization and quantification of pro-opiomelanocortin mRNA and glucocorticoid receptor mRNA in pituitaries of suicide victims. Neuroendocrinology. 1992;56(4):491-501.
35.    Van Heeringen K, Audenaert K, Van de Wiele L, Verstraete A. Cortisol in violent suicide attempters: association with monoamines and personality. J Affect Disord. 2000;60(3):181-189.
36.    Dwivedi Y, Pandey GN. Adrenal glucocorticoids modulate [3H]cyclic AMP binding to protein kinase A (PKA), cyclic AMP-dependent PKA activity, and protein levels of selective regulatory and catalytic subunit isoforms of PKA in rat brain. J Pharmacol Exp Ther. 2000;294(1):103-116.
37.    Seligman ME, Maier SF. Failure to escape traumatic shock. J Exp Psychol. 1967;74(1):1-9.
38.    Sherman AD, Sacquitne JL, Petty F. Specificity of the learned helplessness model of depression. Pharmacol Biochem Behav. 1982;16(3):449-454.
39.    Petty F, Sherman AD. Reversal of learned helplessness by imipramine. Commun Psychopharmacol. 1979;3(5):371-373.
40.    Dwivedi Y, Mondal AC, Shukla PK, Rizavi HS, Lyons J. Altered protein kinase A in brain of learned helpless rats: effects of acute and repeated stress. Biol Psychiatry. 2004;56(1):30-40.
41.    Sarkar D, Erlichman J, Rubin CS. Identification of a calmodulin-binding protein that co-purifies with the regulatory subunit of brain protein kinase II. J Biol Chem. 1984;259(15):9840-9846.
42.    Uhler MD, Chrivia JC, McKnight GS. Evidence for a second isoform of the catalytic subunit of cAMP-dependent protein kinase. J Biol Chem. 1986;261(33):15360-15363.
43.    Ludvig N, Ribak CE, Scott JD, Rubin CS. Immunocytochemical localization of the neural-specific regulatory subunit of the type II cyclic AMP-dependent protein kinase to postsynaptic structures in the rat brain. Brain Res. 1990;520(1-2):90-102.
44.    Constantinescu A, Gordon AS, Diamond I. cAMP-dependent protein kinase types I and II differentially regulate cAMP response element-mediated gene expression. J Biol Chem. 2002;277(21):18810-18816.
45.    Brandon EP, Logue SF, Adams MR et al. Defective motor behavior and neural gene expression in RIIβ-protein kinase A mutant mice. J Neurosci. 1998;18(10):3639-3649.
46.    Thiele TE, Willis B, Stadler J, Reynolds JG, Bernstein IL, McKnight GS. High ethanol consumption and low sensitivity to ethanol-induced sedation in protein kinase A-mutant mice. J Neurosci. 20(10):RC75.
47.    Qi M, Zhuo M, Skalhegg BS et al. Impaired hippocampal plasticity in mice lacking the Cβ catalytic subunit of cAMP-dependent protein kinase. Proc Natl Acad Sci U S A. 1996;93(4):1571-1576.
48.    Marshall R, Dragunow M. Is CREB a key to neuronal survival? Trends Neurosci. 2000;23:48-53.
49.    Dwivedi Y, Rao JS, Rizavi HS et al. Abnormal expression and functional characteristics of cyclic adenosine monophosphate response element-binding protein in postmortem brain of suicide subjects. Arch Gen Psychiatry. 2003;6(3)0:273-282.
50.    Pandey GN, Dwivedi Y, Ren X, Rizavi HS, Roberts RC, Conley RR. Cyclic AMP response element-binding protein in post-mortem brain of teenage suicide victims: specific decrease in the prefrontal cortex but not the hippocampus. Int J Neuropsychopharmacol. 2007;10(5):621-629.
51.    Young LT, Bezchlibnyk YB, Chen B, Wang J-F, MacQueen GM. Amygdala cyclic adenosine monophosphate response element-binding protein phosphorylation in patients with mood disorders: effects of diagnosis, suicide, and drug treatment. Biol Psychiatry. 2004;55(6):570-577.
52.    Nibuya M, Nestler EJ, Duman RS. Chronic antidepressant administration increases the expression of cAMP response element-binding protein (CREB) in rat hippocampus. J Neurosci. 1996;16(7):2365-2372.
53.    Dowlatshahi D, MacQueen GM, Wang JF, Young LT. Increased temporal cortex CREB concentrations and antidepression treatment in major depression. Lancet. 1998;352(9142):1754-1755.
54.    Yamada S, Yamamoto M, Ozawa H, Piederer P, Saito T. Reduced phosphorylation of cyclic AMP responsive element-binding protein in the postmortem orbitofrontal cortex of patients with major depressive disorder. J Neural Transm. 2003;110(6):671-680.
55.    Zubenko GS, Hughes HB III, Maher BS, Stiffler JS, Zubenko WN, Marazita ML. Genetic linkage of region containing the CREB1 gene to depressive disorders in women from families with recurrent, early-onset, major depression. Am J Med Genet. 2002;114(8):980-987.
56.    Finkbeiner S. Calcium regulation of the brain-derived neurotrophic factor gene. Cell Mol Life Sci. 2000;57(3):394-401.
57.    Thoenen H. Neurotrophins and neuronal plasticity. Science. 1995;270(5236):593-598.
58.    Siuciak JA, Lewis DR, Wiegand SJ, Lindsay R. Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav. 1997;56(1):131-137.
59.    Shirayama Y, Chen ACH, Nakagawa S, Russell DS, Duman RS. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci. 2002;22(8):3251-3261.
60.    Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Arch Gen Psychiatry. 1997;54(7):597-606.
61.    Duman RS. Structural alterations in depression: cellular mechanisms underlying pathology and treatment of mood disorders. CNS Spectr. 2002;7(2):140-142.
62.    Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry J-M. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res. 2002;109(2):143-148.
63.    Shimizu E, Hashimoto K, Okamura N, Koike et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry. 2003;54(1):70-75.
64.    Sen S, Nesse RM, Stoltenberg SF et al. A BDNF coding variant is associated with the NEO personality inventory domain neuroticism, a risk factor for depression. Neuropsychopharmacology. 2003;28(2):397-401.
65.    Dwivedi Y, Rizavi HS, Conley RR., Roberts RC, Tamminga CA, Pandey GN. Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. Arch Gen Psychiatry. 2003;60(8):804-815.
66.    Karege F, Vaudan G, Schwald M, Perroud N, La Harpe R. Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs. Mol Brain Res. 2005;136(1-2):29-37.
67.    Kim YK, Lee HP, Won SD, et al. Low plasma BDNF is associated with suicidal behavior in major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(1):78-85.
68.    Altshuler LL, Casanova MF, Goldberg TE, Kleinman JE. The hippocampus and paraphippocampus in schizophrenia, suicide, and control brains. Arch Gen Psychiatry. 1990;47(11):1029-1034.
69.    Rajkowska G. Morphometric methods for studying the prefrontal cortex in suicide victims and psychiatric patients. Ann N Y Acad Sci U S A. 1997;836:253-268.
70.    Turner CA, Akil H, Watson SJ, Evans SJ. The fibroblast growth factor system and mood disorders. Biol Psychiatry. 2006;59(12):1128-1135.
71.    Iga J, Ueno S, Yamauchi K et al. Gene expression and association analysis of vascular endothelial growth factor in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(3):658-663.
72.    Lowther S, Katona CL, Crompton MR, Horton RW. Brain [3H]cAMP binding sites are unaltered in depressed suicides, but decreased by antidepressants. Brain Res. 1997;758(1-2):223-228.
73.    Groves JO. Is it time to reassess the BDNF hypothesis of depression? Mol Psychiatry. 2007. In press.
74.    Isacsson G, Bergman U, Rich CL. Epidemiological data suggest antidepressants reduce suicide risk among depressives. J Affect Disord. 1996;41(1):1-8.


Letter to the Editor

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Modafinil-Induced Mania in a Patient with Bipolar Affective Disorder


August 5, 2007

To the Editor:

Modafinil has been approved for the treatment of excessive daytime sleepiness associated with narcolepsy, shift-work sleep disorder, and obstructive sleep apnea/hypopnea syndrome. The notable side effects of modafinil use are headache, nervousness, anxiety, insomnia, nausea, hypertension, and palpitations.1 Apart from its use to control sedation associated with certain antidepressants2 and neuroleptics,3 it has been used in the treatment of unipolar and bipolar depression as a single agent or as an augmenting agent.2,4,5 Modafinil has been reported to be rather safe in inducing manic switches while treating depression.2,6,7 However, some case reports suggest induction of mania with modafinil treatment.8-10 The following is a case report of mania induced by modafinil in a patient with bipolar affective disorder.

A 36-year-old man with a 6-year history of bipolar disorder type I who was in remission for the last 2 years on oxcarbazepine 600 mg/day maintenance therapy, presented to our outpatient department with complaints of decreased concentration and mild depression. He was prescribed modafinil 100 mg/day for 3 days to be increased to 200 mg/day on the fourth day. However, from the first day, the patient started taking modafinil 200 mg/day on his own and after 2 days developed florid mania. Modafinil was immediately stopped; oxcarbazepine was increased to 900 mg/day; and haloperidol 10 mg/day, trihexiphenidyl 4 mg/day, and clonazepam 2 mg/day was started. The patient achieved euthymia within 2 weeks; over the next 4 weeks, all medications except oxcarbazepine 900 mg/day were tapered off.

The temporal course of events in the present case suggests a modafinil-induced switch to mania even in the presence of a mood stabilizer. This calls for a cautious use of modafinil in bipolar depression even if the patient is on a mood stabilizer.


Ravi C. Sharma, MD

Dr. Sharma is professor and head of the Department of Psychiatry at the Indira Gandhi Medical College & Hospital Shimla in Himachal Pradesh, India.

Disclosure: Dr. Sharma reports no affiliation with or financial interest in any organization that may pose a conflict of interest.



1. Stahl SM. Essential Psychopharmacology: The Prescriber’s Guide. Rev ed. 1st South Asian Edition. Daryaganj, New Delhi: Cambridge University Press India Pvt. Ltd.; 2007.
2. Menza MA, Kaufman KR, Castellanos A. Modafinil augmentation of antidepressant treatment in depression. J Clin Psychiatry. 2000;61(5):378-381.
3. Makela EH, Miller K, Cutlip WD 2nd. Three case reports of modafinil use in treating sedation induced by antipsychotic medications. J Clin Psychiatry. 2003;64(4):485-486.
4. Kaufman KR, Menza MA, Fitzsimmons A. Modafinil monotherapy in depression. Eur Psychiatry. 2002;17(3):167-169.
5. Frye MA, Grunze H, Suppes T, et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry. 2007;164(8):1242-1249.
6. Fernandes PP, Petty F. Modafinil for remitted bipolar depression with hypersomnia. Ann Pharmacother. 2003;37(12):1807-1809.
7. Berigan T. Modafinil treatment of excessive sedation associated with divalproex sodium. Can J Psychiatry. 2004;49(1):72-73.
8. Vorspan F, Warot D, Consoli A, Cohen D, Mazet P. Mania in a boy treated with modafinil for narcolepsy. Am J Psychiatry. 2005;162(4):813-814.
9. Ginsberg DL. Modafinil-associated mania. Primary Psychiatry. 2007;14(1):23-25.
10. Wolf J, Fiedler U, Anghelescu I, Schwertfeger N. Manic switch in a patient with treatment-resistant bipolar depression treated with modafinil. J Clin Psychiatry. 2006;67(11):1817.

Please send letters to the editor to Primary Psychiatry, c/o Norman Sussman, MD, 333 Hudson St., 7th Floor, New York, NY 10013; E-mail: lla@mblcommunications.com.



Dr. Belzer is research fellow and Dr. Liebowitz is director of the Anxiety Disorders Clinic at New York State Psychiatric Institute in New York City. Dr. McKee is clinical assistant professor of psychology in psychiatry at the Weill Medical College of Cornell University and research scientist at the Anxiety Disorders Clinic at the New York State Psychiatric Institute in New York City.

Disclosure: Drs. Belzer and McKee receive research support from the National Institute of Mental Health. Dr. Liebowitz is a consultant to Eli Lilly, Forest, and GlaxoSmithKline; is on the speaker’s bureaus of Bristol-Myers Squibb, Pfizer, and Wyeth; and receives grant support from Eli Lilly, Forest, GlaxoSmithKline, Pfizer, and Wyeth.

Please direct all correspondence to Kenneth D. Belzer, PhD, New York State Psychiatric Institute, 1051 Riverside Drive, Unit 69, New York, NY 10032; Tel: 212-543-5132; Fax: 212-543-6515; E-mail: belzerk@nyspi.cpmc.columbia.edu.



This article provides a clinically relevant overview of issues related to social anxiety disorder (SAD), with particular emphasis on its diagnosis and treatment. The history and evolution of SAD as a clinical syndrome are briefly reviewed, and the phenomenology and clinical presentation of SAD are discussed. Data on prevalence, onset, course, comorbidity, and functional impairment associated with SAD in clinical and epidemiological samples are reviewed. An overview of assessment and treatment via pharmacotherapy and cognitive-behavioral therapy, with a focus on practical clinical applications, is also presented. Finally, research aimed at integrating pharmacologic and psychotherapeutic interventions to maximize long-term treatment effectiveness is considered.   



Subjective distress and discomfort in particular social situations are to some degree both natural and expected. It is reasonable to assume that all people, at one time or another, have experienced embarrassment or stage fright, or perhaps have become tongue-tied in the midst of conversation. When such experiences become ubiquitous in everyday life, however, and ordinary social interactions elicit fear and/or anxiety severe enough to foster significant and maladaptive avoidance behavior, a threshold has been crossed into the province of pathological social anxiety. This condition is known clinically as social anxiety disorder (SAD), an impairing and often chronic anxiety disorder that has profoundly adverse consequences on the quality of life and adaptive functioning of the afflicted individual.1-5 The syndrome is strongly associated with, and appears to serve as a vulnerability factor for, several other debilitating psychiatric conditions.6-7 Moreover, SAD has been found to be the most common anxiety disorder and third most common psychiatric disorder in the United States, exceeded only by major depressive disorder (MDD) and substance use disorders.8-9

Given the scope of the problem, its robust association with other forms of psychopathology, and the overwhelming human burden of this illness, clinicians should be proficient in detecting and diagnosing SAD, and should be knowledgeable about evidence-based treatment modalities. The purpose of this article is to provide a clinically relevant overview of some of the more substantive issues concerning the diagnosis and treatment of SAD. The article begins with a brief account of the evolution of SAD from its early beginnings as an undifferentiated phobic disorder to its present status as an independent diagnosis, as detailed in the current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Revised (DSM-IV-TR).10 A discussion of the nature, core features, and phenomenology of SAD follows. Issues concerning the assessment of SAD in the clinical and research settings are reviewed, and an overview of current empirically supported psychopharmacologic and psychotherapeutic treatments is provided. Finally, the article underscores the necessity of integrating biologically based and psychosocial therapies to maximize long-term treatment effectiveness of SAD.


History: From a Neglected Anxiety Disorder to a Social Anxiety Spectrum

Descriptions of social phobic states appeared in the empirical psychiatric literature nearly 4 decades ago. Marks and Gelder1 reported that in a subgroup of patients in their series of phobic adults, social anxiety manifested variably as “shyness, fears of blushing in public, of eating meals in restaurants, of meeting men or women, of going to dances or parties, or of shaking when the center of attention.” Of note, these symptoms could be distinguished from other phobic disorders including agoraphobia, specific animate phobias, and situational phobia, on the basis of both the nature of the phobic stimulus (ie, social situations), and a consistent age of onset, primarily in the late adolescent years. Marks2 later described a variety of social phobias, including “fears of eating, drinking, shaking, blushing, speaking, writing, or vomiting in the presence of other people.” Central to these phobic states were excessive concerns over one’s appearance or performance being judged, scrutinized, or negatively evaluated by others.3   

As the boundaries and core features of the syndrome were being discerned, behaviorally oriented clinicians were simultaneously laying the groundwork for both reliable measurement and behavioral and cognitive treatments of social anxiety-related difficulties. Techniques including social skills training, relaxation training, systematic desensitization, and rational/cognitive restructuring were being applied to problems that were variably referred to as social phobia, social-evaluative anxiety, performance anxiety, interpersonal anxiety, heterosexual anxiety, social failure, and social inadequacy.11-17 An apparent strength of the behavioral approaches was the targeting of discrete patterns of socially anxious experience and/or maladaptive avoidance behavior, rather than a specific diagnostic entity. In contrast, early pharmacologic treatment approaches may have been somewhat hindered, as SAD had yet to be formally recognized as an autonomous syndrome requiring independent investigation. Thus, much of the early psychopharmacologic work was conducted with heterogeneous diagnostic groups and analogue samples.18 Nonetheless, preliminary evidence suggested the potential efficacy of monoamine oxidase inhibitors (MAOIs) and β-adrenergic blockers.18

With the publication of the DSM–III,19 SAD was formally acknowledged as an independent diagnosis in its own right. It was viewed as distinct, along with agoraphobia and simple phobias, from the former diffuse class of phobic reactions or phobic neuroses in earlier versions of the DSM as illustrated in the Figure.20-23 Research clearly supported the validity of the distinction, indicating that persons with social phobia could be empirically differentiated from other phobic disorders on the basis of several sociodemographic, clinical, and psychobiological correlates.1-3,18 Despite these advances, however, some argued that social phobia remained under-recognized and understudied relative to other anxiety disorders.18 In their seminal paper, Liebowitz and colleagues18 comprehensively surveyed the literature on SAD, advocated for increased systematic efforts in clinical and psychobiological investigation, and laid the groundwork for a research agenda that has largely guided subsequent empirical inquiry into SAD for nearly 20 years.

As a consequence of these key developments, the past 2 decades have been characterized by substantial progress in understanding the origins, nature, and treatment of SAD. Nearly 3,000 empirical studies, review papers, and book chapters, and more than 30 scientific and self-help books on SAD have been published. Importantly, as the empirical knowledge base continues to expand, new and alternative theoretical conceptualizations of SAD have emerged. For example, Schneier and colleagues24 have cogently argued for the recognition and study of a social anxiety spectrum, which would encompass clinical social phobic states, as well as subsyndromal manifestations, associated symptoms, behaviors, and underlying variations in temperament and personality traits, (eg, shyness, behavioral inhibition). Among the advantages of a dimensional approach, Schneier and colleagues24 suggest that a social anxiety spectrum has utility in understanding the associations among SAD and diverse comorbid clinical syndromes, identifying underlying trait-like psychological constructs, and candidate neurobiological and neurochemical substrates. Similarly, McNeil25 has proposed a continuum model of social anxiety and its disorders in which these anxieties and fears exist along a continuum, normally distributed in the general population. The most severe manifestations reside at the high end, labeled variably as social phobia, SAD, and/or avoidant personality disorder.


Diagnosis and Definition

While spectrum or continuum approaches hold promise and can guide further systematic investigation, the current and most widely accepted definition of SAD derives from the DSM-IV-TR.10

To qualify for the diagnosis of SAD, an individual must have a marked or persistent fear of one or more social situations wherein there is exposure to unfamiliar people or possible scrutiny by others. The core fears center on behaving in a way or showing symptoms of anxious arousal (eg, blushing, sweating, trembling, stuttering, etc.) that would be humiliating or embarrassing (Criterion A). Exposure to these phobic situations consistently evokes an anxiety response, which in some cases may be in the form of a panic attack (Criterion B). The individual has some insight that the fear is excessive or unreasonable, though this is not necessarily true in children (Criterion C). There must also be prominent avoidance of the phobic performance or situation and, if not, it is typically endured with great anxiety or distress (Criterion D). The criteria also require clinically significant social and/or occupational functional impairment, or the individual experiences marked distress over having the phobia (Criterion E). If the person is <18 years of age, the anxiety and/or avoidance must have endured for at least 6 months at the time of diagnosis (Criterion F). Finally, the effects of a substance, general medical condition, or the presence of other psychiatric disorders must be ruled out as causative (Criterion G), or in the case of comorbid disorders, the fear, anxiety and avoidance of SAD are not better accounted for by the co-occurring condition (Criterion H).10


The Generalized Subtype

When the diagnostic criteria for SAD were first published in the DSM-III,19 it was noted that generally, an individual has only one social phobia. Moreover, the criteria stated that unless the disorder is severe, it is rarely incapacitating. Subsequent research has provided evidence quite contrary to this early view. A significant and consequential revision of the DSM-III-R22 was the inclusion of a generalized subtype specifier, which has been retained in subsequent revisions (Figure).10,22,23 The generalized subtype encompasses a variant of SAD in which there is fear of most if not all social situations.10 Research has shown that the generalized subtype is far more common than previously thought and significantly more impairing than a more specific or circumscribed SAD (eg, a public speaking phobia). Up to two thirds of the community appears to represent the generalized subtype.26

It is widely acknowledged that generalized SAD bears close resemblance to avoidant personality disorder (APD), which is diagnosed as an Axis II disorder in the DSM-IV-TR.10 The two conditions frequently co-occur, with an average comorbidity rate of 56% based on one quantitative review of 13 studies reporting overlap.27 At present, the DSM-IV-TR allows for the diagnosis of the generalized SAD subtype on Axis I, and APD on Axis II.10 However, definitive conclusions on the nature of the underlying relationship between generalized SAD and APD have yet to be reached. One possible interpretation of the available empirical evidence is that generalized SAD and APD are not actually qualitatively independent disorders.27 An alternative conceptualization holds that APD represents the most severe form of the generalized subtype of SAD, thus suggesting a quantitative distinction.25 Whether this matter will be resolved with the publication of the DSM-V remains to be seen.



As currently defined, SAD encompasses excessive fears and resultant avoidance of one or more social or performance situations in which there is the potential for scrutiny by others and the possibility of embarrassment or humiliation.

One of the most common forms this fear takes is that of public speaking in both large and small groups. Public speaking may be an unpleasant and somewhat distressing prospect for a significant proportion of the general population. Individuals with SAD experience such incapacitating anxiety that it can actually have the untoward effect of undermining their public speaking performance, consequently reinforcing many of the fearful and maladaptive core beliefs driving the anxiety. Public speaking situations may be avoided to the extent that one’s social success and occupational advancement are compromised, (eg, turning down a promotion for fear of conducting presentations, or speaking to and managing subordinates). Interestingly, research has shown that persons with SAD consistently overestimate the anxiety that audiences perceive, and appraise their own performances as significantly poorer than observers do.28

Excessive anxiety over interacting with strangers, such as approaching someone and engaging in “small talk” at a social gathering, or speaking over the telephone, is quite common for people with SAD. These individuals will frequently complain of worries that they “won’t be able to think of anything to say.” They may also have substantial difficulty in engaging with people who are attractive to them (eg, approaching or asking someone for a date). This likely leads to lower marriage rates among people with SAD patients. Communicating with authority figures such as supervisors or managers can be problematic, as well.

Socially phobic people may also fear situations such as eating or drinking in public, as one may spill a drink, make an awkward movement, drop a utensil, or perhaps even choke or vomit. Writing in public or signing one’s name may be problematic due to the fear that one’s hand may tremble. People with SAD often fear that their symptoms of anxiety, (eg, blushing, perspiration, trembling, or a quivering voice) will be noticeable to others. For men in particular, using public lavatories to urinate may be avoided, as they may “freeze-up,” a problem known as paruresis, or “shy bladder syndrome.” What is universal among these diverse manifestations of SAD is that each occurs in a social milieu, wherein the potential for negative evaluation by others exists. In sharp contrast, these behaviors are typically performed quite effectively in private, with no distress or impairment.29

It should be noted that much of what is described above are predominantly modes of expression of SAD in Western-oriented societies. However, clinicians should be mindful of cultural variations in the presentation of SAD, or of social anxiety phenomena more generally. A notable example of a culturally dependent manifestation of social anxiety is a condition known as taijin kyofusho, which has been reported in some Asian cultures including Japan and Korea, and is categorized as a culturally bound syndrome in the DSM-IV-TR.10 Whereas the primary focus of fear and anxiety in SAD is the prospect of embarrassing or humiliating oneself, in taijin kyofusho the individual is exquisitely sensitive to interpersonal relations, and may be preoccupied with concerns over doing something, or presenting oneself in a manner, that would be embarrassing or offensive to others in a social context (the offensive subtype). Clinical presentations include excessive concerns about offending others by emitting an unpleasant bodily odor, staring inappropriately so as to make others feel uncomfortable, blushing, not presenting the appropriate facial expression, or having some real or perceived physical deformity.30

The exact nature of the relationship between taijin kyofusho and the DSM-IV-TR10 SAD is not fully clear at present. One plausible hypothesis is that there may be a common underlying core trait of social anxiety, the expression of which varies as a function of cultural idioms. More specifically, Western societies have historically emphasized the value of independence, individualism, and the importance of the construct of self. This is in contrast to traditional Eastern societies where greater importance is allocated to social interdependence, community, and/or the construct of other. Thus, clinicians (especially those serving diverse populations) should be cognizant of this and other potential culturally variable expressions of social anxiety.



SAD is a common disorder in both community and clinical populations. Estimates from large epidemiological studies of representative community samples indicate that 12.1% to 13.2% of the US population will experience diagnosable SAD during their lifetime, with 12-month prevalence rates of 6.8% to 7.4%.8-9 A recent cohort analysis conducted by Heimberg and colleagues31 demonstrated that the prevalence of SAD has increased over the past 4 decades. The disorder appears to be slightly more prevalent in females, with a female to male ratio of 3:2. Lifetime prevalence estimates from the National Comorbidity Survey (NCS) were 15.5% and 11.1%, for females and males, respectively.8 In most clinical settings, however, the genders are equally represented, or more males are seen.10 This ascertainment bias may be due to increased social demands resulting from traditional societal gender roles. For example, historically, men have been more likely to enter the workforce and to be the initiators of romantic relationships. Difficulties in these significant roles presumably lead to greater salience and recognition of personal functional impairment in men, and to subsequent treatment seeking.

Prevalence estimates in clinical samples range from 10% to 20%, but tend to vary widely.10 Estimates of prevalence in clinical settings should also be qualified by evidence showing that individuals with SAD have much lower rates of treatment seeking than people with other psychiatric illnesses of comparable severity.32 Specifically, findings from the NCS revealed that only 22.6% of people with the generalized subtype, and only 12.7% of people with nongeneralized SAD, ever sought treatment by a physician in their lifetime.26 Interestingly, in a recent survey of callers to the Anxiety Disorders Association of America, 1,000 participants were screened for the presence of diagnosable or subthreshold SAD. A current prevalence rate of 29.5% was found for diagnosable SAD, while another 4.1% met subthreshold criteria.33 These data speak both to the very high rates of SAD among anxiety disorder populations, and quite possibly to the means by which people with the disorder may initiate contact with the mental health specialty sector.


Onset and Course

Clinicians and epidemiologists in the research community generally agree that SAD has an early onset, often in childhood or adolescence. Onsets later in life, after a peak between the second and third decades, are relatively rare and are more likely to be cases of SAD occurring secondarily to, or as sequellae of, another mental disorder (eg, depression, psychotic disorders, eating disorders).34 Though onset is characteristically early, individuals with SAD may not recognize the fears and anxieties they experience in social situations as legitimate emotional problems in need of treatment. Rather, the symptoms may be construed or dismissed as excessive shyness, or merely as a character flaw. Equally problematic, the very nature of the core pathology in SAD, fear and avoidance of embarrassment and humiliation, leads to reduced treatment seeking. Thus, it is not surprising that analysis of NCS data revealed a median interval of 15 years between the age of first onset of SAD and the age at which people with SAD first sought professional help.26 It is arguable that the primary reason the vast majority of individuals seek mental health services is not because of their SAD per se; rather, it is the impairment resulting from secondary comorbid conditions including panic, substance abuse, depression, and suicidal ideation.26,32

Research clearly suggests a largely chronic and unremitting course, which can last for decades if left untreated. Untreated SAD, especially the generalized subtype, will almost invariably lead to increasing levels of functional impairment as major role transitions occur. Specifically, as the person with SAD attempts to progress through stages of life with increasing social demands, and requiring greater social facility, (eg, high school to college, college to employment, marriage), one’s failure to thrive and master these social challenges may lead to feelings of hopelessness and despair. In turn, such feelings may lead to attempts to self medicate. These periods are fertile grounds for secondary psychiatric illnesses to emerge (eg, depression, substance abuse).26,32



In virtually all major studies of representative community and clinical samples, SAD has shown elevated rates of comorbidity (both as a primary and secondary disorder). Among the most frequent co-occurring Axis I disorders in primary SAD are depressive illnesses (eg, MDD, dysthymia),6,35 other anxiety disorders (eg, panic disorder with or without agoraphobia, generalized anxiety disorder)35,36 and substance use/abuse disorders (eg, alcohol abuse or dependence).32,35 As already noted, among the Axis II disorders, APD is highly comorbid with SAD, especially the generalized subtype.27

While impairments in occupational and social functioning, including inability to work, attend school, socialize, or marry, are significant in SAD, these problems are compounded by the presence of comorbid psychopathology.37-40 For example, in a prospective community study, young adults with comorbid SAD and MDD who were followed for approximately 4 years were significantly more likely than those with only MDD to experience more depressive symptoms, a longer duration of major depressive disorder, more intense suicidal ideation, and greater odds of having attempted suicide during the follow-up period.41

Important in this regard, data from both cross-sectional (using retrospective report) and prospective longitudinal studies have consistently demonstrated temporal precedence of anxiety disorders in cases of comorbidity with MDD.42,43 For example, analysis of data from the Epidemiological Catchment Area Program Surveys (waves 1 and 2) revealed that individual anxiety disorders (assessed at wave 1) each appear to confer an independent risk for the onset of adult MDD within 12 months (wave 2).44 Anxiety disorders have been found to be the most common primary disorders associated with MDD, and to predict the greatest risk of subsequent MDD. Of note, secondary cases of MDD were found to be more persistent and severe than pure or primary MDD.42



Thorough assessment of SAD and social anxiety symptoms is a key part of the treatment process. Clinical observations, focused interviewing, and the use of appropriate measures can help to facilitate accurate diagnosis and effective treatment planning. Several comprehensive reviews of the methodological issues and available assessment instruments for SAD have been presented elsewhere.45-47 The authors of this article provide a brief summary of strategies and tools that have been particularly useful in the assessment of SAD and social anxiety.

The clinical interview typically serves as the point of departure in assessing for SAD and social-evaluative anxieties. A detailed inquiry concerning a range of anxiety-provoking and/or avoided social situations is requisite (see phenomenology above). Careful observation of in-session behavior and patient report of physiological reactivity is also helpful. Poor eye contact, restlessness, hand tremor, brief answers to questions, late arrival to appointments, and requests to leave early, may all be evidence of the individual’s discomfort with the interview, which itself is a type of social interaction. The individual may also have trouble tracking the course of the conversation due to the interference of anxiety with sustained attention over time.

Identification of comorbid psychopathology is an especially important part of the diagnostic process, as people with co-occurring conditions pose a more significant treatment challenge. In this regard, clinicians should be particularly vigilant for the presence of other anxiety disorders, substance use or abuse, depressive symptoms, and possible suicidal ideation. Likewise, when these frequently co-occurring conditions are the presenting complaint, accompanying symptoms of social anxiety should be carefully probed for.


Clinician Administered Instruments

A variety of structured interviews and clinician-administered measures are also valuable in the assessment process. The Structured Clinical Interview for DSM-IV (SCID-IV) is a comprehensive clinician-administered diagnostic interview, with both clinical and research versions available.48 It has been designed to be consistent with the classification of psychiatric diagnoses published in DSM-IV,24 and is organized into separate modules which evaluate classes of disorders (eg, psychotic, affective, anxiety, etc). Social phobia and its generalized subtype are assessed in the anxiety disorders module.  

The SCID-IV is broad and comprehensive in its coverage and has become an industry standard for clinical research requiring thorough diagnostic evaluations. However, it can also be time-consuming to administer, especially in more complex clinical presentations. The instrument requires adequate training and instruction to ensure appropriate administration and interpretation. Thus, it is most commonly employed in academic and/or research settings, where there is likely to be adequate staff and resources available for its use.  

Another structured interview that focuses more precisely on the diagnosis of anxiety disorders is the Anxiety Disorders Interview Schedule for the DSM-IV (ADIS-IV).49 This interview is also administered by a clinical examiner in a semi-structured format, and identifies the presence of SAD, its generalized subtype, and the various other anxiety syndromes. There are modules to detect common co-occurring disorders, (eg, affective, substance use, and somatoform disorders), as well. The ADIS-IV is also equipped with a psychotic screening module. Much like the SCID-IV, the ADIS-IV requires training and is more typically employed in clinical research settings and anxiety disorder specialty clinics.

The frequently used, 24-item, clinician-administered Liebowitz Social Anxiety Scale (LSAS) provides ratings of fear and avoidance among a wide range of social situations.50 Patients’ levels of fear and avoidance are rated separately for each of the specified social situations on a four-point Likert scale. A total score is obtained by summing the two subscales. The LSAS is both valid and reliable, and has become the standard primary outcome measure for social anxiety symptoms in clinical trials research. When readministered at later points in the treatment process, the LSAS has shown a high degree of sensitivity to change in the severity of social anxiety symptoms.51 Though not designed to be an instrument for the diagnosis of SAD per se, scoring ranges of the LSAS roughly correspond to the following diagnostic levels: With total scores of ≤30, a diagnosis of SAD is less likely; however, patients may still meet criteria for SAD in a specific circumstance, such as giving a presentation in front of others. Total scores in the range of 30–60 are more typical of those with social anxiety in a specific circumstance, such as public speaking, eating in front of others, or other performance anxiety. Total scores in the range of 60–90 commonly occur in patients with the generalized subtype of SAD. Total scores of ≥90 occur in those patients with the generalized subtype of SAD experiencing very severe social anxiety and avoidance in a variety of situations.


Self Report

The Brief Fear of Negative Evaluation Scale (BFNE)52 is a useful 12-item self-report measure based on the original 30-item scale developed by Watson and Friend.13 Whereas the LSAS focuses on the dimensions of fear and avoidance in various social situations, the BFNE assesses the degree to which patients have core components of social-evaluative anxiety, including thoughts, expectations, and associated distress over possible negative social judgments and embarrassing behaviors. Representative statements include “I am afraid that others will not approve of me,” and “I often worry that I will say or do the wrong things.” Statements are rated as true or false with endorsed items summed for a total score. The scale has been found to be reliable and valid in nonclinical samples, and was recently validated in a sample of clinically anxious individuals.53 The BFNE has also been found to be a sensitive measure of change over the course of treatment.



Historically, treatments for social-evaluative anxieties and SAD have included both psychopharmacologic and psychotherapeutic strategies. Although these two modalities have largely developed independent of one another and are reviewed individually here, good clinical practice often necessitates a judicious combination of both medication and psychosocial therapy. This is particularly important in more complex presentations, including the generalized subtype of SAD and the presence of co-occurring psychopathology.54



Although pharmacotherapy of SAD was relatively neglected early on,18 recent years have witnessed a dramatic increase in progress of medication-based treatment. Several factors have likely contributed to this shift in priorities. Foremost among these was the recognition of SAD as a formal diagnosis, one that is both highly prevalent and substantially impairing. Equally important has been the demonstrated effectiveness of specific pharmacologic agents in treating SAD as well as the recent ascendance of biological psychiatry and psychopharmacology as a clinical specialization. Widely increased research efforts have been sponsored and/or conducted by the pharmaceutical industry in efforts to obtain specific indications in the treatment of SAD for various drug products.

Several comprehensive narrative and quantitative reviews of the pharmacotherapy literature in SAD have been presented elsewhere.18,55-60 This article emphasizes fundamentally practical medication treatments that have received the greatest attention and been subjected to rigorous empirical investigation (typically through randomized, double-blinded, placebo-controlled clinical trials), and that are generally viewed by a consensus of the research community as first- or second-line treatments for SAD. These medications include MAOIs and reversible MAOIs (RIMAs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), benzodiazepines, β-adrenergic blockers, and novel therapeutic agents (eg, anticonvulsants).

As a group, these studies have been characterized by some degree of methodological heterogeneity, such as varying research designs, number and nature of comparison conditions, sample composition, duration of acute treatment, medication dosage, and follow-up intervals. However, a useful thread of continuity within the extant literature has been the relatively consistent use of specific outcome measures, namely the LSAS (as described above)50 and the Clinical Global Impressions–Improvement (CGI-I) rating scale. The CGI-I is a clinician-rated measure of improvement in which a rating of 2 equals a global judgment of “much improved,” and a rating of 1 equals “very much improved.”61 Reductions in pretreatment to posttreatment LSAS scores and specific thresholds, or cutoff scores, are also reflective of varying degrees of improvement including treatment response (sometimes arbitrarily set at a 20% to 30% reduction from baseline LSAS), and remission (LSAS <30).62 Similarly, global ratings of 1 or 2 on the CGI-I are often used as an index of treatment response. Because of their common usage in the pharmacotherapy literature, these instruments provide useful metrics for inter-study comparisons.  


Irreversible Monoamine Oxidase Inhibitors

The MAOIs were one of the first groups of medications to receive intensive systematic evaluation in the treatment of SAD via controlled clinical trials. Among this class, the irreversible MAOI phenelzine has consistently demonstrated its effectiveness in treating SAD, with supporting evidence coming from four published double-blind, placebo-controlled trials (Table 1).63-67 Rates of improvement have ranged from 64% to 91%,64,65  generally far exceeding rates of response in placebo-controlled conditions, as well as surpassing rates of improvement seen with alprazolam,63 cognitive-behavioral group therapy (on some measures),63,66 atenolol,64 and moclomebide (on the social avoidance subscale of LSAS).65 Essentially, these studies have established the methodological groundwork for subsequent pharmacotherapy studies in SAD, and phenelzine has largely set the standard of comparison for treatment efficacy in SAD.

Two other MAOIs have been examined in the treatment of SAD (Table 1). Positive results were reported in two open clinical trials of tranylcypromine.68,69 In a study by Versiani and colleagues,68 patients were followed openly for 52 weeks with 62% of patients showing marked improvement, and another 17% showing moderate improvement. In comparison, modest levels of improvement were found in a 6-week, open clinical trial of the MAOI selegilene in 16 SAD patients (12 with generalized SAD) using a fixed dose regimen of 5 mg bid. In this trial, 9 of 16 patients (56%) completed treatment with 3 of those 9 (33%) classified as markedly or moderately improved on the CGI-I.70

Despite the proven effectiveness of the irreversible MAOIs in the treatment of SAD, and of phenelzine in particular, their use has been limited by an adverse side-effect profile, including the potential danger of hypertensive crisis if dietary restrictions on tyramine-rich foods are not carefully followed. This has lead to the development and examination of RIMAs as an alternative.56  


Reversible Monoamine Oxidase Inhibitors

Moclobemide was the first RIMA to be developed, showing moderate efficacy in the treatment of MDD.56 In the treatment of SAD, four randomized, double-blind, placebo-controlled trials have been published, each reporting varying degrees of efficacy (Table 1).65,71-73 In a study by Versiani and colleagues,65 14 of 17 (82%) patients (remaining out of an initial 26) treated with moclobemide were classified as treatment responders. Additionally, moclobemide was better tolerated than phenelzine. In another study, by Katschnig and colleagues,73 a dose-response relationship was observed; patients receiving 600 mg/day achieved more improvement than those receiving 300 mg/day. Response rates were 47%, 41%, and 34% for the 600 mg/day, 300 mg/day, and placebo groups, respectively. In sharp contrast, null findings were reported in the other two controlled trials of moclobemide. Specifically, no evidence of superior clinical efficacy over placebo was found for moclobemide in an 8-week flexible-dose design,71 or in a 12-week fixed-dose design.72  

A second RIMA, brofaromine, which is similar to the SSRIs in that it inhibits reuptake of serotonin, has been subjected to three controlled trials in the treatment of SAD (Table 1).74-76 Each of these studies produced generally positive results indicating superior clinical efficacy of brofaromine over placebo on primary outcome measures, as well as superiority on secondary outcome measures in studies by van Vliet and colleagues74 and Fahlen and colleagues.75 Among completers across studies, improvement rates ranged from 50% to 78%75,76 for the groups treated with brofaromine as compared to 14% to 23% in the groups treated with placebo. In all three trials, the medication was generally well tolerated.        


Selective Serotonin and Serotonin Norepinephrine Reuptake Inhibitors

SSRIs are also well tolerated and are highly efficacious for both depressive and other anxiety disorders, which are often comorbid with SAD. SSRIs are easily managed compared to other drug classes, and have therefore been investigated extensively in the treatment of SAD and its generalized subtype. Virtually all SSRIs, including citalopram,77-79 escitalopram,80-81 fluoxetine,82-88 fluvoxamine,89-91 paroxetine,92-98 paroxetine controlled release,99 and sertraline100-104 have been subjected to randomized, double-blind, placebo-controlled clinical trials, typically demonstrating superior treatment efficacy to placebo control conditions on primary efficacy parameters (Table 1). While paroxetine was the first drug in this class to receive Food and Drug Administration approval in the US for the treatment of SAD, sertraline and the SNRI venlafaxine extended release (XR) have also secured FDA approval.

Given the preponderance of evidence in support of the SSRIs, at present these medications are widely accepted and strongly recommended as first-line treatments for SAD and its generalized subtype. Additionally, recent placebo and comparator-controlled studies of venlafaxine XR have demonstrated superior treatment efficacy over placebo-controlled conditions, as well as comparable efficacy to paroxetine in head-to-head comparisons (Table 1).105-109 Hence, venlafaxine XR should now be considered a first-line treatment for generalized SAD.   


Tricyclic Antidepressants

Despite demonstrated efficacy in treating other anxiety disorders (eg, panic disorder, obsessive-compulsive disorder [OCD]), there is little existing data to support the efficacy of tricyclic antidepressants in the treatment of SAD. Imipramine and clomipramine have been evaluated. One investigation using a randomized, placebo-controlled, flexible dose design found that only 11.1% (2 of 18) patients treated with imipramine versus 4.35% (1 of 23) patients receiving placebo, improved.110 Similarly, in a case series of 15 patients treated with a mean dose of 176.4 mg/day of imipramine, Simpson and colleagues111 reported that only 20% of patients were rated as improved or very much improved. Open clinical trials of clomipramine have generally produced mixed results.56  


Gelernter and colleagues63 compared alprazolam (on average 4.2 mg/day) to phenelzine, placebo, and Heimberg’s cognitive behavioral group therapy (CBGT).66 Only 38% of patients receiving alprazolam were classified as treatment responders compared to 69% of patients receiving phenelzine. Moreover, only 2 months after drug discontinuation, most patients reported a return to baseline levels of social anxiety symptoms. In contrast, the efficacy of the longer acting benzodiazepine, clonazepam, was tested in a 10-week, double-blind, placebo-controlled trial, revealing a treatment response rate of 78% compared to only 20% of patients receiving placebo.112 The effectiveness of clonazepam in treating SAD has also been supported by several open clinical trials, and has recently been examined in a placebo-controlled clinical trial as augmentation for partial and nonresponse to SSRI therapy. Some benefit was observed suggesting the need for further controlled investigation.113

Interestingly, Jefferson114 points out that there has been a general reluctance among clinicians to utilize benzodiazepines, especially in longer-term treatment of SAD, despite evidence suggesting long-term effectiveness and safety of agents such as clonazepam. In fact, medications such as clonazepam possess a number of desirable qualities, including its established efficacy in treating SAD, relatively rapid onset of action, good tolerability, overdose safety, and dose flexibility. On the downside, however, there are several undesirable side effects such as sedation, impairment of coordination and cognition, and possible sexual dysfunction. However, these side effects are not specific to benzodiazepines. There is also greater abuse potential, discontinuation difficulties, adverse interactions with alcohol and other substances of abuse, and ineffectiveness for comorbid conditions, particularly depression.114 At present, there are no established guidelines suggesting the use of clonazepam over SSRIs as a first-line treatment for SAD. Rather, clinicians will need to assess potential benefits and liabilities on a case-by-case basis, remaining vigilant throughout the course of therapy.   


β-adrenergic Blockers

The appeal of β-adrenergic blockers has historically been the ability of these drugs to reduce the increased autonomic arousal that commonly accompanies discrete performance situations (eg, public speaking engagements, musical performances). Thus, much of the early research with these agents focused on performance-related anxiety.18 In the controlled study by Liebowitz and colleagues,64 however, only 30% of SAD patients receiving atenolol (≥50 mg/day) were rated as improved compared to 23% of patients receiving placebo.

Generally speaking, β-adrenergic blockers (eg, propranolol) should be reserved for treating the prominent physiological arousal characteristic of discrete public performance situations. When a clinical presentation suggests a circumscribed or situation-specific case of performance anxiety, a standing dose of an SSRI/SNRI or other medication is unnecessary. Clinicians should consider prescribing agents such as propranolol.


Novel Therapeutic Agents

Recent interest in the use of novel anticonvulsants as antianxiety agents has prompted investigation of these medications in the treatment of generalized SAD. One randomized, double-blind, placebo-controlled study of the novel anticonvulsant gabapentin, reported superior efficacy of this medication over placebo in generalized SAD.115 Another recent controlled investigation of the closely related compound pregabalin has reportedly shown superior clinical efficacy of over a placebo control group of generalized SAD patients.116 These medications warrant further investigation.


Pharmacotherapy Guidelines

Patients with generalized SAD who are going to receive medication treatment should first be given one of the established SSRIs or SNRIs.90-109 Treating generalized SAD effectively usually requires 8–12-week trials, and dosages tend to be on the higher side of the therapeutic range for each drug. In this regard, treating generalized SAD is more like treating OCD than MDD. Discontinuation trials suggest that ≥6 months of maintenance treatment is helpful to preserve acute treatment gains. Nonresponders should be tried on alternative drugs of proven efficacy, including drugs of a different class (eg, MAOIs63-66 or RIMAs).65,71-76

Partial responders can be maintained on their original drug, augmented by benzodiazepines such as clonazepam.113 Medication augmentation with an established psychosocial treatment seems helpful in clinical practice, and is currently under study in our lab and others.87,88

Patients with nongeneralized SAD often do well with PRN β-blocker administration used acutely before a speech or performance.18 However, β-blockers seem more helpful for symptoms such as tremor, palpitations, tachycardia, and a catch in one’s throat than for the anticipatory anxiety that often plagues such patients for days (and nights) before an important speech or performance. Benzodiazepines appear helpful for this anticipatory anxiety, and can be used in conjunction with  β-blockers. In such a situation, the benzodiazepine would be used for several days before the event, and the β-blockers would be taken approximately 1 hour before the speech or performance. Whether MAOIs, SSRIs, or SNRIs used on a maintenance basis are helpful in patients who only suffer performance anxiety is not clear. However, they do seem to help the performance anxiety that is a component of generalized SAD.


Psychosocial Therapy

SAD and social-evaluative anxiety states have been treated with a variety of behavioral, cognitive, and combined cognitive-behavioral therapies (CBT). Briefly reviewed are some methods employed to treat SAD via cognitive and behavioral therapies. The authors of this article focus on the CBT protocol developed by Heimberg and colleagues, which is currently being used in conjunction with pharmacotherapy in a collaborative research program between the Anxiety Disorders Clinic of New York State Psychiatric Institute and the Adult Anxiety Clinic of Temple University. A more comprehensive examination of the CBT literature can be found in articles by Heimberg and Juster,117 Hoffman and Barlow,29 and Turk and colleagues.118


Behavior Therapies

Behavior therapies used for SAD have been relatively problem focused, addressing the most prominent features associated with the disorder. These have included social skills training to address functional skill deficits, physiological retraining to address the physical symptoms of anxious arousal occurring in social contexts, and systematic exposure to actual anxiety-provoking social situations.117  

If skill deficits are present, social skills training focuses primarily on helping patients acquire skills necessary to relate to others more naturally and competently in social situations. These skills include developing topics for conversation and maintaining appropriate eye contact and bodily orientation. In essence, this training instructs patients in knowing what to say and how to say it. Such skills are typically rehearsed in session with the therapist and then practiced in real-life situations as homework assignments between therapy sessions.

Physiological retraining, or applied relaxation, involves teaching patients to use breathing techniques and progressive muscle relaxation when anxiety-provoking social situations are encountered. Patients are taught to identify the earliest physiological cues of anxious arousal upon entering socially anxious situations, and then to counter these sensations via rapid deployment of learned anxiety reduction skills.

Systematic exposure, either real or imagined, to a hierarchy of progressively more anxiety-provoking stimuli has been found to be a powerful component of treatment for several anxiety disorders. These disorders include panic disorder (eg, physical sensations), OCD (eg, perceived contaminants, intrusive thoughts) and posttraumatic stress disorder (eg, traumatic memories and associated environmental cues). In systematic exposure for SAD, patients engage in a feared social activity such as making small talk, public speaking, and dating, and remain in the feared situation until the anxious arousal subsides. In the continued presence of the anxiety-provoking social stimulus, the central nervous system gradually habituates, so that the stimulus situation no longer has the capacity to evoke anxious arousal. Treatments that have focused on social skills acquisition and physiological retraining have likely contained similar habituation-related mechanisms that are believed to operate in exposure-based treatments.


Cognitive Therapy

Individuals with SAD typically have persistent negative thoughts and maladaptive beliefs regarding how others perceive and evaluate them socially. These distorted cognitions generate significant anxiety and form the psychological core of the disorder. Cognitive therapy, also known as cognitive restructuring, has been used to help individuals with SAD alter or “restructure” these distorted views of their social world, in turn reducing their experience of anxiety.119  

The essential components of cognitive therapy for SAD involve learning to pay attention to the thoughts that occur automatically in anxiety-provoking social situations (eg, “They will think I am weird”), and challenging or disputing these negative cognitions. Patients are taught to treat each negative automatic thought as a hypothesis, much like a scientist, and to evaluate the available evidence via systematic logical analysis. If the hypothesis does not hold up after a careful review of available data (eg, “What is the evidence?”), then the capacity of the thought to generate further anxiety should weaken.

A set of common beliefs and errors in logic that socially anxious persons habitually make has been discerned,118 and the patient is taught to self-monitor and identify these errors in his or her automatic thoughts. For example, an anxiety provoking thought that others will think the individual is “weird” is dependent in part on the capacity of the individual to read another’s mind or to predict the future. Once these erroneous beliefs are identified, alternative interpretations of the situation are sought by structured disputing questions (eg, “Do I have a crystal ball?” or “What is another way of looking at it?”), as well as considering means to moderate the impact of negative outcomes (eg, “So what if it happens?”). This type of hypothesis testing proceeds through a Socratic-like dialogue between therapist and patient in session. Patients are trained to internalize and utilize this dialogue when working to challenge maladaptive anxiety-provoking thoughts on their own between sessions.  


Combined Cognitive-Behavioral Therapy

The authors of this article use CBT treatment protocol in their clinic, which combines psychoeducation, cognitive therapy, and in-session systematic exposures to feared social situations using planned and structure role-play techniques. Cognitive restructuring exercises and in vivo exposures are assigned for between session homework, as well. For a complete presentation of the components of the treatment, including in-session exercises and homework assignments, one may refer to the Social Anxiety Client Manual by Hope and colleagues.120

Briefly, individuals with SAD are educated about social anxiety in both its normal and pathological manifestations. The therapist works to create an atmosphere of collaboration in which data acquired through careful assessment (as discussed above) are used to create a hierarchy of feared and avoided social situations. A rating of fear is established for each item in the hierarchy using the Subjective Units of Distress Scale, a 0–100 rating scale in which higher numbers indicate increasing levels of distress and anxiety. The degree of avoidance of each situation is also estimated using a similar 0–100 rating scale. A typical fear and avoidance hierarchy is shown in Table 2. 

Clients are taught to employ cognitive restructuring techniques, as discussed above, which help them to cope with anxiety experienced during in-session role-plays with the therapist. A “rational response” to the negative content of the automatic thoughts is eventually derived from the Socratic-like dialogue between patient and therapist (eg, “Being friendly does not equal being weird”). Importantly, the rational response is not seen merely as positive thinking superimposed on the negative thoughts. Rather, it is the powerful end result of a logical and scientific disputation process.  

Role plays within session proceed by involving the patient, therapist and/or one or more therapeutic confederates, depending on the parameters of the anxiety-provoking social situation (eg, age, gender, size of group). This provides both in-session practice of cognitive restructuring skills and exposure to the distressing social situation, so that the patient can experience the process of habituation. Role plays may also provide practice with situations the patient may have very little experience with given their previous patterns of avoidance. The therapist and patient gradually work through the hierarchy beginning with situations that prompt moderate amounts of anxiety, and working up to more distressing situations as therapy progresses. Much of the critical work is also done between sessions by assigning homework in which patients practice using these skills to cope with challenging and phobic situations in their natural social environment.  


Group Cognitive-Behavioral Therapy for Social Anxiety

CBT for the treatment of SAD has frequently been conducted in a group format. This approach provides a therapeutic context in which members of the group enact and replicate some of the problematic or anxiety-provoking social situations that individuals encounter in daily life. For example, patients can practice presentations or public speaking in front of the group, role-play social encounters with members of either sex, and receive constructive feedback from co-members. This also enables group therapists to evaluate the accuracy patients have in assessing their own social behavior, as well as the degree to which their anxiety is visible to others.120

Thus far, several comprehensive meta-analytic reviews have evaluated the extant literature on controlled studies of the behavioral therapy and CBT described above.121-124 Reviewers have consistently reached the same broad conclusions. Namely, systematic exposure by itself, or combined with cognitive therapy, results in superior effect sizes (eg, mean Cohen’s d=.74)123 when compared to control conditions. Equally impressive has been the durability of therapeutic benefit achieved with these treatment modalities, and the propensity toward increasing gains over follow-up periods.122


Monotherapy Versus Combined Therapy

Effective treatment of complex presentations of SAD, including the generalized subtype and/or co-occurring psychopathology, often require a multimodal treatment approach, utilizing both evidence-based pharmacotherapy and psychosocial therapies. This assertion is predicated more on clinical experience than on existent empirical literature, which has yet to unequivocally demonstrate the superiority of combination therapy over monotherapy.   

Early studies contrasted pharmacotherapy and psychotherapy, implicitly seeking the answer to the question of which therapy is superior.63,66 Findings have been mixed, demonstrating for example, that pharmacotherapy with phenelzine is superior to CBGT in the acute phase of illness.66 However, when patients are followed-up, it appears that gains obtained from psychosocial therapy may catch up to gains achieved via pharmacotherapy, or may exceed those gains on some efficacy parameters.67 The picture may be more complex, however. Specifically, it is not clear at present that superiority of CBT in long-term follow-up is due solely to continuing accrual or consolidation of gains with CBT. Rather, differences favoring CBT may be due in part to relapse of some patients when medication is discontinued. If this were determined to be the case, it would only serve to bolster support for the conduct of sequencing and augmentation studies.

Recently, investigators have questioned whether the combination of pharmacotherapy and psychosocial therapy is superior to either therapy alone.86,87 Results have generally been equivocal. Studies by Kobak and colleagues86 and Clark and colleagues87 demonstrated that both combinations of active treatments and monotherapy are superior to placebo-controlled conditions. However, thus far there is little evidence suggesting superiority of the combined treatments over either individual treatment. It should be noted that both of these studies used fluoxetine, which generally has less support in the literature as a treatment for SAD. A recently completed study conducted by Liebowitz and Heimberg (unpublished data, 2005), however, has combined two of the most efficacious treatments known for SAD, phenelzine and Heimberg’s CBGT, contrasting their combination with each therapy individually. Data are presently being analyzed and results are forthcoming.

Equally promising, current work in the authors’ clinic, in collaboration with Heimberg and colleagues at the Adult Anxiety Disorders Clinic of Temple University (unpublished data, 2005), has taken the next logical step in this line of investigation by examining whether the “sequencing” or “augmentation” of pharmacotherapy with individual CBT provides superior treatment outcome as compared to pharmacotherapy alone. To our knowledge this is the first study of its kind. Large scale, multicenter, clinical trial research of this nature is by necessity painstaking and somewhat lengthy. However, designs employing sequencing and augmentation strategies for partial and/or nonresponders should help discern optimal combinations and/or sequences of treatment, thus informing clinical practice and maximizing long-term treatment effectiveness.



SAD has clearly evolved from a once neglected anxiety disorder to an increasingly recognized, highly prevalent, and impairing psychiatric condition with considerable public health significance. The distinguishing of a generalized subtype, which bears close resemblance to APD, has had important implications for assessment and treatment of SAD. Optimal assessment of SAD can be achieved via careful clinical interviewing and in-session behavioral observation, the use of semi-structured interview procedures, and/or symptom-specific clinician-administered and self-report questionnaires. Probing for co-occurring conditions, especially other anxiety, affective, and substance use disorders, is equally critical in evaluating patients with suspected or probable SAD. Several medications including MAOIs, RIMAs, SSRIs, benzodiazepines, and b-blockers have shown acute phase treatment efficacy in randomized, double-blind, placebo-controlled trials. CBT, combining cognitive restructuring techniques and systematic graded exposure, has also shown treatment efficacy, typically with maintenance of gains enduring beyond the acute phase of therapy. As of yet, the combination of pharmacotherapy and psychotherapy has not been established empirically to be more effective than either therapy alone. However, clinical experience continues to suggest the utility of multimodal treatment approaches in maximizing long-term effectiveness. Systematic research efforts are presently underway to discern optimal treatment strategies and to provide a solid empirical foundation for current clinical practice.  PP



1. Marks IM, Gelder MG. Different ages of onset in varieties of phobia. Am J Psychiatry. 1966;123(2):218-221.

2. Marks IM. The classification of phobic disorders. Br J Psychiatry. 1970;116(533):377-386.

3. Amies PL, Gelder MG, Shaw PM. Social phobia: a comparative clinical study. Br J Psychiatry. 1983;142:174-179.

4. Schneier FR, Johnson J, Hornig CD, Liebowitz MR, Weissman MM. Social phobia. Comorbidity and morbidity in an epidemiologic sample. Arch Gen Psychiatry. 1992;49(4):282-288.

5. Schneier FR, Heckelman LR, Garfinkel R, et al. Functional impairment in social phobia. J Clin Psychiatry. 1994;55(8):322-331.

6. Kessler RC, Stang P, Wittchen HU, Stein M, Walters EE. Lifetime co-morbidities between social phobia and mood disorders in the U.S National Comorbidity Survey. Psychol Med. 1999;29(3):555-567.

7. Stein MB, Fuetsch M, Müller N, Höfler M, Lieb R, Wittchen HU. Social anxiety disorder and the risk of depression: a prospective community study of adolescents and young adults. Arch Gen Psychiatry. 2001;58(3):251-256.

8. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51(1):8-19.

9. Kessler RC, Berglund P, Demler O, Jin R, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):593-602.

10. Diagnostic and Statistical Manual of Mental Disorders. 4th ed text rev. Washington, DC: American Psychiatric Association; 2000.

11. Paul G. Insight Versus Desensitization in Psychotherapy: An Experiment in Anxiety Reduction. Stanford, CA: Stanford University Press; 1966.

12. D’Zurilla TJ. Reducing heterosexual anxiety. In: Krumboltz JD, Thoresen CE, eds. Behavioral Counseling: Cases and Techniques. New York, NY: Holt, Rinehart and Winston; 1969.

13. Watson D, Friend R. Measurement of social-evaluative anxiety. J Consult Clin Psychol. 1969;33(4):448-457.

14. Marzillier JS, Lambert C, Kellett J. A controlled evaluation of systematic desensitization and social skills training for socially inadequate psychiatric patients. Behav Res Ther.1976;14(3):225-238.

15. Trower P, Yardley K, Bryant B, Shaw P. The treatment of social failure: A comparison of anxiety-reduction and skills acquisition procedures on two social problems. Behav Mod. 1978;2(1):41-60.

16. Kanter NJ, Goldfried MR. Relative effectiveness of rational restructuring and self-control desensitization in the reduction of interpersonal anxiety. Behav Res Ther. 1979;14(4):472-490.

17. Öst LG, Jerremalm A, Johansson J. Individual response patterns and the effects of different behavioral methods in the treatment of social phobia. Behav Res Ther. 1981;19(1):1-16.

18. Liebowitz MR, Gorman JM, Fyer AJ, Klein DF. Social phobia: Review of a neglected anxiety disorder. Arch Gen Psychiatry. 1985;42(7):729-736.

19. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Washington, DC: American Psychiatric Association; 1980.

20. Diagnostic and Statistical Manual of Mental Disorders. Washington, DC: American Psychiatric Association; 1952.

21. Diagnostic and Statistical Manual of Mental Disorders. 2nd ed. Washington, DC: American Psychiatric Association; 1968.

22. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed rev. Washington, DC: American Psychiatric Association; 1987.

23. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.

24. Schneier FR, Blanco C, Antia SX, Liebowitz MR. The social anxiety spectrum. Psych Clin North Am. 2002;25(4):757-774.

25. McNeil DW. Terminology and evolution of the constructs. In: Hofmann SG, DiBartolo PM, eds. From Social Anxiety to Social Phobia: Multiple Perspectives. Needham Heights, MA: Allyn & Bacon; 2000.

26. Kessler RC, Stein MB, Berglund P. Social phobia subtypes in the national comorbidity survey. Am J Psychiatry. 1998;155(5):613-619.

27. Reich J. The relationship of social phobia to avoidant personality disorder. In: Hoffman SG, DiBartolo PM, eds. From Social Anxiety to Social Phobia: Multiple Perspectives. Needham Heights, MA: Allyn & Bacon; 2000:148-161.

28. Rapee RM, Lim L. Discrepancy between self- and observer ratings of performance in social phobics. J Abnorm Psychol. 1992;101(4):728-731.

29. Hoffman SG, Barlow DH. Social phobia (Social Anxiety Disorder). In: Barlow DH, ed. Anxiety and Its Disorders: The Nature and Treatment of Anxiety and Panic. New York, NY: Guilford Press; 2002:454-476.

30. Clarvit SR, Schneier FR, Liebowitz MR. The offensive subtype of Taijin-kyofu-sho in New York City: The phenomenology and treatment of a social anxiety disorder. J Clin Psychiatry. 1996;57(11):523-527.

31. Heimberg RG, Stein MB, Hiripi E, Kessler RC. Trends in the prevalence of social phobia in the United States: a synthetic cohort analysis of changes over four decades. Eur Psychiatry. 2000;15(1):29-37.

32. Kessler RC. The impairments caused by social phobia in the general population: Implications for intervention. Acta Psychiatr Scand Suppl. 2003;(417):19-27.    

33. Zhang W, Ross J, Davidson JR. Social anxiety disorder in callers to the Anxiety Disorders Association of America. Depress Anxiety. 2004;20(3):101-106.

34. Wittchen HU, Fehm L. Epidemiology and natural course of social fears and social phobia. Acta Psychiatr Scand Suppl. 2003;( 417):4-18.

35. Brown TA, Campbell LA, Lehman CL, Grisham JR, Mancill RB. Current and lifetime comorbidity of the DSM-IV anxiety and mood disorders in a large clinical sample. J Abnorm Psychol. 2001;110(4):585-599.

36. Wittchen HU, Zhao S, Kessler RC, Eaton WW. DSM-III-R generalized anxiety disorder in the national comorbidity survey. Arch Gen Psychiatry. 1994;51(5):355-365.

37. Schneier FR, Johnson J, Hornig CD, Liebowitz MR, Weissman MM. Social phobia. Comorbidity and morbidity in an epidemiologic sample. Arch Gen Psychiatry. 1992;49(4):282–8.

38. Davidson JR, Hughes DL, George LK, Blazer DG. The epidemiology of social phobia: Findings from the Duke Epidemiological Catchment Area study. Psychol Med. 1993;23(3):709-718.

39. Schneier FR, Heckelman LR, Garfinkel R, et al. Functional impairment in social phobia. J Clin Psychiatry. 1994;55(8):322-331.

40. Wittchen HU, Beloch E. The impact of social phobia on quality of life. Int Clin Psychopharmacol. 1996;11(suppl 3):15-23.

41. Stein MB, Fuetsch M, Muller N, Hofler M, Lieb R, Wittchen HU. Social anxiety disorder and the risk of depression: A prospective community study of adolescents and young adults. Arch Gen Psychiatry. 2001;58(3):251-256.

42. Kessler RC, Nelson CB, McGonagle KA, Liu J, Swartz M, Blazer DG. Comorbidity of DSM-III-R major depressive disorder in the general population: results from the US National Comorbidity Survey. Br J Psychiatry Suppl. 1996;(30):17-30.

43. Wittchen HU, Beesdo K, Bittner A, Goodwin RD. Depressive episodes—evidence for a causal role of primary anxiety disorders? Eur Psychiatry. 2004;18(8):384-393.

44. Goodwin RD. Anxiety disorders and the onset of depression among adults in the community. Psychol Med. 2002;32(6):1121–1124.   

45. Orsillo SM, Hammond C. Social phobia: A brief overview and guide to assessment. In: Antony MM, Orsillo SM, Roemer L, eds. AABT Clinical Assessment Series: Practitioner’s Guide to Empirically Based Measures of Anxiety. New York, NY: Kluwer Academic/Plenum Publishers; 2001:159-164.

46. Orsillo SM. Measures for social phobia. In: Antony MM, Orsillo SM, Roemer L, eds. AABT Clinical Assessment Series: Practitioner’s Guide to Empirically Based Measures of Anxiety. New York, NY: Kluwer Academic/Plenum Publishers; 2001:165-187.

47. Herbert, JD, Rheingold AA, Brandsma, LL. Assessment of social anxiety and social phobia. In: Hofmann SG, DiBartolo PM, eds. From Social Anxiety to Social Phobia: Multiple Perspectives. Needham Heights, MA: Allyn & Bacon, 2001:20-45.

48. First MB, Spitzer RL, Gibbon M. Structured Clinical Interview for DSM-IV Axis I Disorders. New York, NY: New York State Psychiatric Institute, Biometrics Research Unit, 1995.

49. Dinardo PA, Brown TA, Barlow DH. Anxiety Disorders Interview Schedule for DSM-IV: Lifetime Version. San Antonio, TX: Psychological Corp; 1994.

50. Liebowitz MR. Social phobia. Mod Probl  Pharmacopsychiatry. 1987;22:141-173.

51. Heimberg RG, Horner KJ, Juster HR, et al. Psychometric properties of the Liebowitz Social Anxiety Scale. Psychol Med. 1999;29(1):199-211.

52. Leary MR. A brief version of the Fear of Negative Evaluation Scale. Pers Soc Psychol Bull. 1983;9(3):371-375.

53. Collins KA, Westra HA, Dozois DJ, Stewart SH. The validity of the brief version of the Fear of Negative Evaluation Scale. J Anxiety Disord. 2005;19(3):345-359.

54. Belzer K, Schneier FR. Comorbidity of anxiety and depressive disorders: issues in conceptualization, assessment and treatment. J Psychiatr Pract. 2004;10(5):296–306.

55. van der Linden GJ, Stein DJ, van Balkom AJ. The efficacy of selective serotonin reuptake inhibitors for social anxiety disorder (social phobia): A meta-analysis of randomized controlled trials. Int Clin Psychopharmacol. 2000;15(suppl 2):S15-S23.

56. Blanco, C, Schneier, FR, Liebowitz, MR. Psychopharmacology. In: SG Hoffman SG, DiBartolo PM, eds. From Social Anxiety to Social Phobia: Multiple Perspectives. Needham Heights, MA: Allyn & Bacon, 2001:335-353.

57. Fedoroff IC, Taylor S. Psychological and pharmacological treatments of social phobia: A meta-analysis. J Clin Psychopharmacol. 2001;21(3):311-324.

58. Blanco C, Raza MS, Schneier FR, Liebowitz MR. The evidence-based pharmacological treatment of social anxiety disorder. Intl J Neoropsychopharmacol. 2003;6(4):427-442.

59. Davidson, JR. Pharmacotherapy of social phobia. Acta Psychiatr Scand Suppl. 2003;(417):65-71.

60. Blanco C, Schneier FR, Schmidt A, et al. Pharmacological treatment of social anxiety disorder: A meta-analysis. Depress Anxiety. 2003;18(1):29-40

61. Guy W. 1976. ECDEU assessment manual for psychopharmacology: Publication adm 76-338. Washington, DC: US Department of Health, Education, and Welfare; 1976.

62.    Liebowitz MR. Medications: Achieving remission in the anxiety disorders. Symposium presented at the 25th Annual Meeting of the Anxiety Disorders Association of America. March 17-20, 2005. Seattle, Washington.

63. Gelernter CS, Uhde TW, Cimbolic P, et al. Cognitive-behavioral and pharmacological treatments of social phobia: a controlled study. Arch Gen Psychiatry. 1991;48(10):938-945.

64. Liebowitz MR Schneier F, Campeas R, et al. Phenelzine vs atenolol in social phobia. A placebo-controlled comparison. Arch Gen Psychiatry. 1992. 49(4):290-300.

65. Versiani M, Nardi AE, Mundim FD, Alves AB, Liebowitz MR, Amrein R. Pharmacotherapy of social phoba: a controlled study with moclobemide and phenelzine. Br J Psychiatry. 1992. 161:353–360.

66. Heimberg RG, Liebowitz MR, Hope DA, et al. Cognitive behavioral group therapy vs phenelzine therapy for social phobia: 12-week outcome. Arch Gen Psychiatry. 1998;55(12):1133-1141.

67. Liebowitz MR, Heimberg RG, Schneier FR, Hope DA, et al. Cognitive-behavioral group therapy versus phenelzine in social phobia: long-term outcome. Depress Anxiety.1999:10(3):89-98.

68. Versiani M, Mundim FD, Nardi AE, Liebowitz MR. Tranylcypromine in social phobia. J Clin Psychopharmacol. 1988;8(4):279–283.

69.    Versiani M, Nardi AE, Mundim FD. Fobia social. J Brasileiro dePsiquiatria. 1989;38(5):251-256.

70. Simpson HB, Schneier FR, Marshall RD. et al. Low dose selegilene (L-Deprenyl) in social phobia. Depress Anxiety.1998;7(3):126–129.

71.    Schneier FR, Goetz D, Campeas R, Fallon B, Marshall R, Liebowitz MR. Placebo-controlled trial of moclobemide in social phobia. Br J Psychiatry. 1998;172:70-77.

72. Noyes R Jr, Moroz G, Davidson JR, et al. Moclobemide in social phobia: A controlled dose-response trial. J Clin Psychopharmacol. 1997;17(4):247-254.

73. Katschnig H, Stein MB,  Buller R. The International Multicenter Clinical Trial Group on Moclobemide in Social Phobia.Moclobemide in social phobia: a double-blind, placebo-controlled clinical study. Eur Arch Psychiatry Clin Neurosci. 1997;247(2):71-80.  

74. van Vliet IM, den Boer JA, Westenberg HJM. Psychopharmacological treatment of social phobia: clinical and biochemical effects of brofaromine, a selective MAO-A inhibitor. Eur Neuropsychopharmacol. 1992;2(1):21-29

75. Fahlen T, Nilsson HL, Borg K, Humble M, Pauli U. Social phobia: the clinical efficacy of and tolerability of  the monoamine oxidase-A and serotonin uptake inhibitor brofaromine: A double-blind placebo-controlled study. Acta Psychiatr Scand. 1995;92(5):351–58.

76. Lott M, Greist JH, Jefferson JW, et al. Brofaromine for social phobia: a multicenter, placebo-controlled, double-blind study. J Clin Psychopharmacol. 1997;17(4):255-260.

77. Furmark T, Tillfors M, Marteinsdottir I, et al. Common changes in cerebral blood flow in patients with social phobia treated with citalopram or cognitive-behavioral therapy. Arch Gen Psychiatry. 2002;59(5):425-433.

78. Atmaca M. Kuloglu M. Tezcan E, Unal A. Efficacy of citalopram and moclobemide in patients with social phobia: some preliminary findings. Hum Psychopharmacol. 2002;17(8):401-405.

79. Schneier FR, Blanco C, Campeas R, et al. Citalopram treatment of social anxiety disorder with comorbid major depression. Depress Anxiety. 2003;17(4):191-196.  

80. Lader M, Stender K, Burger V, Nil R. Efficacy and tolerability of escitalopram in 12- and 24-week treatment of social anxiety disorder: randomised, double-blind, placebo-controlled, fixed-dose study. Depress Anxiety. 2004;19(4):241-248.

81. Kasper S, Stein DJ, Loft H, Nil R. Escitalopram in the treatment of social anxiety disorder: randomised, placebo-controlled, flexible-dosage study. Br J Psychiatry. 2005;186:222-226.

82. Sternbach H. Fluoxetine treatment of social phobia. J Clin Psychopharmacol. 1990;10(3):230-231.

83. Schneier FR, Chin SJ, Hollander E, Liebowitz MR. Fluoxetine in social phobia. J Clin Psychopharmacol. 1992;12(1):62-64.

84. Black B, Uhde TW, Tancer ME. Fluoxetine for the treatment of social phobia. J Clin Psychopharmacol. 1992;12(4):293-295.

85. Van Ameringen M,  Mancini C, Streiner DL. Fluoxetine efficacy in social phobia. J Clin Psychiatry.1993;54(1):27-32.

86. Kobak KA, Griest JH, Jefferson JW, Katzelnick DJ. Fluoxetine in social phobia: a double-blind, placebo-controlled pilot study. J Clin Psychopharmacol. 2002;22(3):257-262.

87. Clark DM, Ehlers A, McManus F, et al. Cognitive therapy versus fluoxetine in generalized social phobia: a randomized placebo-controlled trial. J Consult Clin Psychol. 2003;71(6):1058-1067.

88. Davidson JR, Foa EB, Huppert JD, et al. Fluoxetine, comprehensive cognitive behavioral therapy, and placebo in generalized social phobia. Arch Gen Psychiatry. 2004;61(10):1005-1013.  

89. van Vliet IM, den Boer JA, Westenberg HG. Psychopharmacological treatment of social phobia; a double blind placebo controlled study with fluvoxamine. Psychopharmacology (Berl). 1994;115(1-2):128-134.

90. Stein MB, Fyer AJ, Davidson JR, Pollack MH, Wiita B. Fluvoxamine treatment of social phobia (social anxiety disorder): a double-blind, placebo-controlled study. Am J Psychiatry. 1999;156(5):756-760.

91. Stein DJ, Westenberg HG, Yang H, et al. Fluvoxamine CR in the long-term treatment of social anxiety disorder: the 12- to 24-week extension phase of a multicentre, randomized, placebo-controlled trial. Int J Neuropsychopharmacol. 2003;6(4):317-323.

92. Stein DJ, Westenberg HG, Yang H, Li D, Barbato LM. Paroxetine treatment of generalized social phobia (social anxiety disorder): a randomized controlled trial. JAMA. 1998;26;280(8):708-713.

93. Baldwin D, Bobes J, Stein DJ, Scharwachter I, Faure M. Paroxetine in social phobia/social anxiety disorder. Randomised, double-blind, placebo-controlled study. Paroxetine Study Group. Br J Psychiatry. 1999;175:120-126.

94. Allgulander C. Paroxetine in social anxiety disorder: a randomized placebo-controlled study. Acta Psychiatr Scand. 1999;100(3):193-198.

95. Stein DJ, Berk M, Els C, et al. A double-blind placebo-controlled trial of paroxetine in the management of social phobia (social anxiety disorder) in South Africa. S Afr Med J. 1999;89(4):402-406.

96. Allgulander C, Nilsson B. A prospective study of 86 new patients with social anxiety disorder. Acta Psychiatr Scand. 2001;103(6):447-452.

97. Stein DJ, Versiani M, Hair T, Kumar R. Efficacy of paroxetine for relapse prevention in social anxiety disorder: a 24-week study. Arch Gen Psychiatry. 2002;59(12):1111-1118.

98. Wagner KD, Berard R, Stein MB, et al. A multicenter, randomized, double-blind, placebo-controlled trial of paroxetine in children and adolescents with social anxiety disorder. Arch Gen Psychiatry. 2004;61(11):1153-1162.

99. Lepola U, Bergtholdt B, St Lambert J, Davy KL, Ruggiero L. Controlled-release paroxetine in the treatment of patients with social anxiety disorder. J Clin Psychiatry. 2004;65(2):222-229.

100. Katzelnick DJ, Kobak KA, Greist JH, et al. Sertraline for social phobia: a double-blind, placebo-controlled crossover study. Am J Psychiatry. 1995;152(9):1368-1371.

101. Blomhoff S, Haug TT, Hellstrom K, et al. Randomised controlled general practice trial of sertraline, exposure therapy and combined treatment in generalised social phobia. Br J Psychiatry. 2001;179:23-30.

102. Haug TT, Blomhoff S, Hellstrom K, et al. Exposure therapy and sertraline in social phobia: I-year follow-up of a randomised controlled trial. Br J Psychiatry. 2003;182:312-318

103. Van Ameringen M, Oakman J, Mancini C, Pipe B, Chung H. Predictors of response in generalized social phobia: effect of age of onset. J Clin Psychopharmacol. 2004;24(1):42-48.

104. Liebowitz MR, DeMartinis NA, Weihs K, et al. Efficacy of sertraline in severe generalized social anxiety disorder: results of a double-blind, placebo-controlled study. J Clin Psychiatry. 2003;64(7):785-792.

105. Rickels K, Mangano R, Khan A. A double-blind, placebo-controlled study of a flexible dose of venlafaxine ER in adult outpatients with generalized social anxiety disorder. J Clin Psychopharmacol. 2004;24(5):488-496.

106. Allgulander C, Mangano R, Zhang J, et al. Efficacy of venlafaxine ER in patients with social anxiety disorder: a double-blind, placebo-controlled, parallel-group comparison with paroxetine. Hum Psychopharmacol. 2004;19(6):387-396.

107. Stein MB, Pollack MH, Bystritsky A, et al. Efficacy of low and higher dose extended-release venlafaxine in generalized social anxiety disorder: a 6-month randomized controlled trial. Psychopharmacology (Berl). 2005;177(3):280-288.

108. Liebowitz MR, Gelenberg AJ, Munjack D. Venlafaxine extended release vs placebo and paroxetine in social anxiety disorder. Arch Gen Psychiatry. 2005;62(2):190-198.

109. Liebowitz MR, Mangano RM, Bradwejn J, Asnis G. A randomized controlled trial of venlafaxine extended release in generalized social anxiety disorder. J Clin Psychiatry. 2005;66(2):238-247.  

110. Emmanuel NP, Johnson M, Villareal G. Imipramine in the treatment of social phobia A double blind study. Poster presented at: the 37th Annual Meeting of the American College of Neuropsychopharmacology. December 1998; Puerto Rico.

111. Simpson HB, Schneier FR, Campeas R, et al. Imipramine in the treatment of social phobia. J Clin Psychopharmacol. 1998;18(2):132-135.  

112. Davidson JR, Potts N, Richichi E, et al. Treatment of social phobia with clonazepam and placebo. J Clin Psychopharmacol. 1993;13(6):423-428.

113. Seedat S, Stein MB. Double-blind, placebo-controlled assessment of combined clonazepam with paroxetine compared with paroxetine monotherapy for generalized social anxiety disorder. J Clin Psychiatry. 2004;65(2):244-248.

114. Jefferson JW. Benzodiazepines and anticonvulsants for social phobia (social anxiety disorder). J Clin Psychiatry. 2001;62(suppl 1):50-53.

115. Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol. 1999;19(4):341-348.

116. Pande AC, Feltner DE, Jefferson JW, et al. Efficacy of the novel anxiolytic pregabalin in social anxiety disorder: a placebo-controlled, multicenter study. J Clin Psychopharmacol. 2004;24(2):141-149.

117. Heimberg RG, Juster HR. Cognitive-behavioral treatments: literature review. In: Heimberg RG, Liebowitz MR, Hope DA, Schneier FR, eds. Social Phobia: Diagnosis, Assessment and Treatment. New York, NY: Guilford Press; 1995:261-309.

118. Turk C, Heimberg R, Hope D. Social anxiety disorder. In: Barlow DH, ed. Clinical Handbook of Psychological Disorders. 3rd ed. New York, NY: The Guilford Press; 2001:114-153.

119. Beck AT, Emery G, Greenberg RL. Anxiety Disorders and Phobias: A Cognitive Perspective.  New York, NY: Basic Books; 1985.

120. Hope DA, Heimberg RG, Juster HA, Turk CL. Managing Social Anxiety: A Cognitive Behavioral Therapy Approach (Client Manual). New York, NY: Oxford University Press; 2000.

121. Feske U, Chambless D. Cognitve behavioral versus exposure only treatment for social phobia: A meta-analysis. Behav Ther. 1995;26(4)695-720.

122. Taylor S. Meta-analysis of cognitive-behavioral treatments for social phobia. J Behav Ther Exp Psychiatry. 1996;27(1):1-9.

123. Gould RA, Buckminster S, Pollack MH, et al. Cognitive-behavioral and pharmacological treatment for social phobia: A meta-analysis. Clin Psychol Science Prac. 1997;4(4):291-306.

124. Fedoroff IC, Taylor S. Psychological and pharmacological treatments of social phobia: a meta-analysis. J Clin Psychopharmacol. 2001;21(3):311-324.


Potential New Alzheimer’s Disease Diagnostic Criteria Determined

Data presented at the Alzheimer’s Association’s  International Conference on Alzheimer’s Disease 2010 hopes to change the way physicians diagnose Alzheimer’s disease as well as provide a diagnosis well before symptoms are evident.  The Alzheimer’s Association wants to develop new diagnostic criteria based on the current theory that Alzheimer’s disease occurs before patients become symptomatic. Earlier detection means earlier, effective risk reduction methods and better treatment options for all patients.

The workgroups focused on three areas: Alzheimer’s disease dementia, mild cognitive impairment (MCI) with Alzheimer’s disease, and pre-clinical Alzheimer’s disease. The Alzheimer’s disease dementia group is revising the existing diagnostic criteria to include biomarkers and other assessment methods to aid diagnosis. The MCI with Alzheimer’s disease group is reviewing and refining the MCI criteria in an effort to better indicate cognitive change before dementia as well as to better differentiate between MCI and Alzheimer’s disease. The pre-clincial group is focusing on identifying the best methods of assessment to better predict a person’s risk for developing Alzheimer’s disease.

Once this criteria is validated, it needs to be flexible enough for use by health care providers that do not have access to advanced imaging, cerebrospinal fluid measures, and neuropsychological testing.

The results are only preliminary and still need to be systematically validated via incorporation of this criteria into clinical trials.

For more information on the Alzheimer’s Association, please visit www.alz.org/icad. –CN

Obesity-related Gene Increases Risk for Incident Alzheimer’s Disease

The fat mass and obesity-associated (FTO) gene, which related to obesity, affects body mass index (BMI), risk for diabetes, and leptin levels. A study by Caroline Graff, MD, PhD, at the Karolinska Institutet in Sweden, and colleagues, found that these vascular risk factors may also play a role in the development of Alzheimer’s disease and dementia. The risk for Alzheimer’s disease could be doubled when certain variants of both FTO and the Alzheimer’s disease risk gene, apolipoprotein E (APOE), are present.

The aim of the study was to examine the direct role of the FTO gene on Alzheimer’s disease and dementia risk in the elderly. BMI, diabetes, cardiovascular diseases (CVD), and physical inactivity were also reviewed as possible modifiers to the association. The researchers also assessed possible interaction with APOE, which plays a role in the development of Alzheimer’s disease as well as vascular risks.

Data was gathered from a prospective population-based study called the Kungsholmen project, which followed 1,003 dementia-free Swedish adults ≥75 years of age for 9 months to detect incident Alzheimer’s disease and dementia cases, as classified by Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised criteria. Participants were genotyped for the FTO polymorphism (rs9939609) and APOE e4 (rs429358) on DNA that was sampled at baseline.

The study found—after adjustment for age, gender, education, and APOE genotype, as well as additional adjustment for diabetes, BMI, CVD, and physical inactivity—that carriers with the AA gene variant in the FTO gene had an increased risk for developing Alzheimer’s disease (RR 1.58, 95% CI: 1.11-2.24) and dementia (RR 1.48, 95% CI: 1.09-2.02) when compared to carriers with the TT genotype. Dementia risk was increased in carriers of FTO-AA and APOE e4.

Although more research is needed to confirm these results, the study shows the importance of metabolic dysregulation on the development of Alzheimer’s disease and dementia. Greater understanding of the genetics and other causes of Alzheimer’s disease will provide additional targets for therapies and prevention strategies.

Funding for this research was provided by Anslag forskning och utveckling (FAS, Stockholms läns landsting), Forskningsrådet för Arbetsliv och Socialvetenskap (Sweden), the Gamla tjänarinnor Foundation, the Gun & Bertil Stohne’s Foundation, the Karolinska Institutet’s Faculty funding for postgraduate students, the Swedish Brain Power Initiative, the Swedish Research Council in Medicine, the Marianne and Marcus Wallenberg Foundation, and the Swedish Alzheimer Foundation. (AAICAD 2010. Presentation #O2-06-06). –DC

Alzheimer’s Patients Have Greater Risk for Seizures, Anemia

The findings of two separate studies suggest that an Alzheimer’s disease diagnosis is associated with health conditions such as seizures and anemia.

H. Michael Arrighi, PhD, at Janssen Alzheimer Immunotherapy Research & Development, and Nicole Baker, MPH, at Pfizer, and colleagues, used medical records from ~400 primary practices in England to estimate the incidence rate of seizures in Alzheimer’s disease patients. The Alzheimer’s disease population in this analysis numbered 14,838 people ≥50 years of age. The Alzheimer’s disease cohort was compared to a randomly selected age- and sex-matched non-Alzheimer’s disease cohort.

Over an average period of 2.3 years for Alzheimer’s disease patients and 3.4 years for non-Alzheimer’s disease comparisons, the rate of seizures per 1,000 people numbered 9.1 and 1.4, respectively, an incidence rate 6.4 times higher for the Alzheimer’s disease group.

In a second study, Noel Faux, PhD, at the Mental Health Research Institute in Parkville, Australia, and colleagues, took a closer look at the hypothesis stating that iron accumulates in the tau tangles in the brains of Alzheimer’s disease and mild cognitive impairment (MCI) patients. They examined whether elevated iron levels in the brains of Alzheimer’s disease patients could appear in plasma iron level analyses. The researchers took hemoglobin and iron measurements, among other blood-based assessments, in 1,112 subjects comprising 211 Alzheimer’s disease patients, 133 MCI patients, and 768 healthy controls. Diet, medications, short- and long-term memory status, and global cognition were also assessed.

Compared to age- and sex-matched controls, Alzheimer’s disease patients had significantly lower levels of hemoglobin, mean cell hemoglobin concentration, and packed cell volume. These data concurred with a significantly higher erythrocyte sedimentation rate in the Alzheimer’s disease group. Anemic patients also stood a greater risk of Alzheimer’s disease (OR 2.56), and Alzheimer’s disease patients had an increased risk of anemia (OR 2.61), although iron intake did not vary between these two groups. (AAICAD 2010. Arrighi Presentation #O2-06-04; Faux Poster #P3-261). –LS

Outpatient Healthcare Costs May Be Reduced Following Screening and Diagnosis of Cognitive Impairment

Dementia is a common, costly, and underrecognized problem in the elderly. As severe loss of memory and other mental abilities interfere with daily life, it is important to more adequately detect and diagnose dementia as well as to provide necessary care management.

A study by J. Riley McCarten, MD, at the VA Medical Center in Minneapolis, Minnesota, and colleagues, analyzed results from the Dementia Demonstration Project (DPP), an interdisciplinary effort led by the Geriatric Research, Education and Clinic Center at the Minneapolis VA Medical Center. The aim of the project was to identify, evaluate, diagnose, and manage cognitive impairment (CI) in primary care, and to provide information, support, and care coordination for veterans newly diagnosed with dementia. Advanced practice registered nurses specially trained in dementia acted as Dementia Care Coordinators in primary care clinics at seven VA Medical Centers.

Veterans ≥70 years of age who were medically stable, able to comply, and without a prior diagnosis of CI or other dementia were screened uing the Mini-Cog memory test during each routine primary care clinic appointment. Of the 8,278 veterans screened, 26% failed; 34% of those who failed the test returned for a comprehensive evaluation, and of them 95% were diagnosed with CI, including 76% with dementia.

Data from 1 year prior to and 1 year after CI diagnosis were analyzed in 347 DDP patients and 1,261 non-DDP patients. Median DDP outpatient care costs saw a decline of >54% (-$5,519), compared with a 25% decline (-$1,759) of those diagnosed in non-DDP clinics. Median number of line-item outpatient costs declined by 53% (-54) in DDP patients compared with 32% (-21) in non-DDP patients.

The program aimed at providing family members with information about dementia, at ensuring that patients were physically active and socially engaged, and at providing caregivers with all necessary support. The study demonstrated that diagnosing CI was associated with a decrease in total and line-item healthcare costs in the year after diagnosis compared to the year prior. More dramatic decreases were seen in patients who were identified through cognitive screening and had subsequent case management available by a dementia care team.

Funding for this research was provided by the Strategic Initiative and the Veterans Integrated Service Network 23. (AAICAD 2010. Presentation #O4-04-04). –DC

Psychiatric dispatches is written by Dena Croog, Christopher Naccari, and Lonnie Stoltzfoos.


Needs Assessment: Although suicide in Micronesia is unique in cross-cultural comparison, relatively little research has systematically investigated suicidal behavior in this area. Limited knowledge of suicidal behavior prohibits the development of suicide prevention. Researchers and clinicians should have the knowledge for development of more culturally responsive suicide prevention and intervention strategies.

Learning Objectives:
• Recognize the characteristics of suicide in the Micronesia area.
• Understand the relationship between mental disorders and suicide.
• Understand the importance of cultural factors on suicidal behavior.

Target Audience: Primary care physicians and psychiatrists.

CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: October 16, 2007.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by November 1, 2009 to be eligible for credit. Release date: November 1, 2007. Termination date: November 30, 2009. The estimated time to complete all three articles and the posttest is 3 hours.


Dr. Ran is associate professor at the School of Nursing and Health Sciences at the University of Guam in Mangilao, Guam.

Acknowledgments: The author thanks Professor Yeates Conwell, MD, of Department of Psychiatry at the University of Rochester for his advisory and editorial support, and Professor Donald H. Rubinstein, PhD, of the University of Guam for his support.

Disclosures: Dr. Ran is a lead consultant for the Suicide Research and Prevention Project at the Department of Mental Health and Substance Abuse in Guam.

Please direct all correspondence to: Mao-Sheng Ran, MD, PhD, School of Nursing and Health Sciences, University of Guam, Mangilao, Guam 96923; Tel: 671-735-2655; Fax: 671-734-1203; E-mail: ranmaosh@yahoo.com.




Introduction: What are the characteristics of suicide in Micronesia? Limited knowledge of suicidal behavior prohibits the development of culturally responsive suicide prevention in Micronesia. This study explores the status of suicide and provides recommendations for further research and prevention programs.
Methods: All the available studies on suicidal behavior in Micronesia were reviewed.
Results: Since the late 1960s, the number of suicides through Micronesia has risen sharply. There is a strong preponderance of male over female suicides (male versus female=10–16:1). The victims are generally young males between 15 and 24 years of age. The suicide rates, especially among youths, are amongst the highest in the world. The most common scenario leading to suicide is an incident of intergenerational conflict. Less than 40% of suicides occur in people with mental disorder.
Discussion: Suicide in Micronesia is unique in cross-cultural comparison. However, relatively little research has systematically investigated suicidal behavior in this area.
Conclusion: Further studies should focus on the risk and protective factors—especially sociocultural factors—of suicidal behavior using standardized instruments and diagnostic criteria. Suicide prevention might focus on improving public education, mental health services, and crisis intervention.



Suicide is a significant public health issue and a leading cause of death in the world, claiming approximately 1 million people  annually worldwide.1 In 2004, the suicide rate in the United States was 11.05 per 100,000, equaling 32,439 people.2 Although many studies on suicide have been conducted in the US, many previous studies of suicide incorporated Micronesian populations into the broad category of Asian Americans and Pacific Islanders. Consequently, the ability to make important distinctions between Micronesians and others and among subgroups in the Micronesian population were lost.3-5 The categorization of Pacific Islanders ignores that this group may actually reflect many diverse ethnic groups (eg, Hawaiians, Samoans, Micronesian). Existing evidence indicates that Asian groups have been found to have substantially lower rates of completed suicide than those of white people, whereas rates of completed suicide among Pacific Islanders including Micronesian populations are some of the highest in the world.6,7 Disaggregated suicide data on US Pacific Islander populations, especially Micronesian populations, are limited.5

Suicide is a significant public health issue and has long been a feature of Micronesian cultures.8 Micronesian adolescent suicide in particular has received notice since 1976.9 Currently, within some island nations of the Pacific region, suicide is the leading cause of death for young adults, and youth rates are among the highest in the world.7 Although culture may play a role in suicidal behaviors, cross-cultural research is lacking in suicidology.10,11 As limited research on suicidal behavior, especially among different islanders, has been conducted in Micronesia, the characteristics of suicide among Micronesian people are still unclear, preventing the development of evidence-based approaches to suicide prevention.

The aim of this article is to explore the characteristics of suicidal behavior in this specific area and to make recommendations for further research and prevention among Micronesian populations. This will provide researchers and clinicians with knowledge necessary for development of more culturally responsive prevention and intervention strategies.


Micronesian Populations

There is considerable linguistic and cultural diversity throughout Micronesia.12 Significant cultural differences exist from one main island group to another. Politically, the region is also very diverse, resulting from the successive eras of foreign colonial activity in the Western Pacific.13 The Micronesian region of Western Pacific generally includes one unincorporated American territory (Guam); one US Commonwealth of Northern Mariana Islands (CNMI); and the Pacific Island Nations of Micronesia, which include the Federated States of Micronesia (FSM), the Republic of Belau (Palau), and the Republic of the Marshall Islands that have signed unique contracts of “free association” with the US.

During the past 55 years Micronesian communities have experienced rapid sociocultural transformation toward increasing reliance upon cash economy and government employment; American-style schools and health services; and modern forms of technology, consumer goods, transportation and communication. Today, Micronesians live in two worlds, including the still-intact communities of the rural and outer islands, and the increasingly Americanized urban centers.12 Within the Micronesia area, there are approximately 15 different languages spoken. English is an official language of these Pacific Islands, but proficiency levels vary immensely. Religious practices include Catholic, Protestant, and others.13

The total estimated population of the area including indigenous Micronesians and immigrants is approximately 352,472, of which almost half is located on the island of Guam (171,019 in 2006).14 Based on the 2000 US Census,15 there are 874,414 Pacific Islanders, 0.3% of the total US population (Micronesians: 13.2% of Pacific Islanders: 80.1% Chamorro; 0.5% CNMI, 1.8% FSM, 5.8% Marshallese; 3% Belauan; 8.6% non-specified Micronesian).



An electronic literature search of all articles published from 1966 to the latest publication available (2007) was conducted via MEDLINE, PsychINFO, and ScienceDirect to identify reports about suicidal behavior and suicide prevention in Micronesia. The search used the identifier “suicide” (including the subheading “suicide, attempted, ideation, prevention”) and the subheading “Micronesia and Guam.” Moreover, all other available studies reported about suicidal behavior in Micronesia were also collected, through key references from the literature already accumulated and suggestions from experts in these fields. Abstracts and full-text articles were retrieved and reviewed.



Trend of Suicide

The suicide rates in Micronesia have risen in epidemic fashion since the late 1960s. More than 500 suicides have been recorded for the US Trust Territory (exclusive of the Northern Marianas) from the early 1960s to the early 1980s.16-18 From the early 1960s to the early 1980s, suicide rates overall in Micronesia more than doubled every decade (Figure 1).9,13,16,18-21 From 1960–1967 the suicide rate for the Micronesian population overall was fairly low (4–5 per 100,000 population); the rate doubled during 1968–1975, reaching 22 per 100,000 people in 1972–1975. The most rapid increase had occurred during the 1970s. The rate continued to climb, although less rapidly, until 1980–1983, when it reached 30 per 100,000 people. During 1984–1987, the suicide rate leveled and declined significantly to 26 per 100,000 people.13 The suicide rate in Micronesia is one of the highest rates in the world.7,21 However, the trend in suicide rates from 1990s to the present in Micronesia is unclear due to the paucity of research data.


The rate of suicide on Guam increased sharply since the end of 1980s, peaking at 28.2 per 100,000 people in 1999 (Figure 1).22 However, there has been a sharp decline after 2000 on Guam.21 Rates have fallen back to 10.7 per 100,000 people in 2004.

The relative frequency of suicide on Guam differs by ethnic group.21 Indigenous Micronesians are considerably overrepresented among Guam suicide cases. They account for 27% of Guam suicides, although they constitute only 8% of Guam’s 2000 population. Filipinos have a relatively low suicide rate. Although the results indicate that ethnic differences appear striking, there are insufficient data on the ethnic subgroups to lend further insight into the issue.


Gender Distribution

There is a strong preponderance of male suicides over female suicides in Micronesia (Figure 1).7,13,20,23 The male-to-female suicide ratio was 3:1 during the years 1922–1939, 5.3:1 pre-1960, and 11.5:1 post 1960. The suicide rate of Micronesian males increased eight-fold during the 2 decades (1960–1979).16 In a study of 13 Pacific Island nations (excluding Hawaii), Booth7 reported that the differences in rates increased dramatically when youths (15–24 years of age) were disaggregated and examined by gender for Western Samoa (64 males, 70 females), Guam (49 males, 10 females), Chuuk State (182 males, 12 females), and Micronesia (91 males, 8 females). On Guam, male suicides outnumber female suicides by a factor of five (83.5 versus 16.5 percent) from 1998 to 2000.21


Age Distribution

During the past four decades, suicide has become the primary cause of death for Micronesian youths.9,24 During the period from 1960–1987, 57% of suicides in Micronesia overall were in the 15–24 years of age group (Figure 2).13,20,22,25 Suicides in Micronesia display an essentially unique age distribution, peaking in the age bracket from 20–24 years for males (with a suicide rate of 110 per 100,000 people annually), and peaking in the age bracket from 15–19 for females (with a suicide rate slightly over 10 per 100,000 people annually).9,16 The median age of suicide is younger for females than for males.7 The suicide rates in youths in Micronesia, especially for men between 15 and 24 years of age, have achieved the tragic distinction of being among the highest in the world (Figure 3).7,9,13,22,25




Although Micronesian populations showed an age distribution where male suicides rose sharply from adolescence and peaked at ages 20–24, the age distributions after this peak differed for each subpopulation. Chuukese and Marshall Islanders had a dramatic decrease followed by a smaller peak at 60–65 years of age, while Belauan, Pohnpeans, and Yapese showed steady decreases after 39 years of age without a bimodal increase among elders.5 Similar to Hawaiians, indigenous Pacific Islanders from Micronesia and Guam have rates of completed suicide that increase sharply from adolescence to young adulthood, with rates dropping at 30 years of age and continuing to drop for middle-aged and elderly people.7,9

On Guam, suicide was the first leading cause of death for 20–34-years-old people, and the second leading cause of death for people 10–19 and 35–39 years of age (1993–2000; Figure 2). During 1998–2002, the age-specific suicide rates were 48.4 per 100,000 people for those 15–24 years of age, 26.3 for people 25–34 years of age, and 19.9 for people 35–44 years of age.22 All these rates were significantly higher than in the US mainland.25 Age-adjusted suicide rates in Guam were 67% higher than in the US mainland.22


Area Distribution

Among the different Micronesian island groups, suicide rates varied from place to place, suggesting that cultural differences influence suicides.9 The peri-urban fringe areas have the highest rates of suicide.12,16,19,26 The most urbanized town areas have somewhat lower rates of suicide, while the most rural areas and outer-island communities have the lowest rates. The highest rates were found in Chuuk during the 10-year period in people 15–24 years of age, wherein 1 in 40 Chuukese boys commited suicide.


Methods of Suicide

The most common method of suicide in Micronesia among both men (86%) and women (69%) is by hanging.13,20 In Micronesia, hanging usually takes the form of leaning into a noose from a standing or sitting position. The primary method of suicide in Guam was by hanging as well, accounting for >50% of the cases during the 1980s and 1990s. On Guam, males usually employ more lethal methods than females.21 The strong preference in Micronesia for suicide by hanging may reflect the cultural patterning of the act which has not been influenced by foreign models.13


Psychiatric Diagnoses

Mental illness did not appear to be an important factor in Micronesian suicides.13 Most of the victims have had no serious delinquency problems, psychological abnormality, or psychosis. Only a small percentage of suicide victims (Micronesia, 10%; Palau, 34% to 37%) showed any evidence of psychopathology.13,20,27 No obvious patterns of physical or psychological illness were found among the suicide victims.9 Among the victims with serious mental disorders, many of them were diagnosed with schizophrenia. Most of these victims have undergone treatment at some time in their lives for their mental illness.

However, repeated studies conducted worldwide over the past 3 decades indicate that >90% of suicide victims have a psychiatric disorder at the time of death.28-30 Although some studies did not show such a high percentage of psychiatric disorder, there were still 63% of suicide victims with a psychiatric disorder at the time of death in China31 and 62% with a documented history of mental illness in Hawaii (Figure 4).5




Alcohol and Substance Abuse

Alcohol is part of the suicide motivation or method.9 Evidence indicated that 41% to 68% of suicide victims were intoxicated or drinking at the time of suicide, and 34% of suicide victims (male 41%, female 7%) had a history of heavy drinking or drug abuse.12,13 This result is higher than the rate of alcohol use in Hawaii in which 31% of suicides tested positive at autopsy for alcohol use, with heavy alcohol use more common in youths.5 The reasons need to be explored further.


Precipitating Factors for Suicide

Intergenerational conflict is the most common scenario leading to suicide.20 Suicide is consistent with the Micronesian preferences for dealing with serious interpersonal domestic problems by withdrawal rather than confrontation. Most suicides were precipitated by a quarrel, argument, or misunderstanding between the young victim and someone very close to him or her, especially family members such as parents or another older relative.13,20,26 Older victims are often offended by their children or other younger people who are expected to serve as their care takers.20 Often, the preceding event seemed oddly trivial, and the response of suicide appeared completely out of proportion to the event.8,9,13 Many of these suicides appeared to be very impulsive acts rather than premeditated or planned actions.9

Hezel8 identified three major patterns of Micronesian suicides including anger suicides (50% to 85% cases), shame suicides (4% to 27% cases), and psychotic suicides (2% to 34% cases). The dominant emotion at play in suicide in Micronesia is anger.13,16,20 Anger toward a parent or other authority figure in the immediate family is often the cause for the suicide act.13 The definition of “anger” was similar to the way Americans describe depression.5


Suicide Attempts and Suicidal Ideation

Official data on suicide attempts in Micronesia are nearly nonexistent.13 Evidence indicates that only 20% to 25% of the suicide cases might reveal any prior intentions toward suicide by indirect statements or acts that could be interpreted as communication of suicidal ideation.13,16 The ratio of parasuicides to suicide is likely to be much higher (eg, 5 to 1 in Truk Lagoon).13 The sample of suicide attempts appears somewhat different (eg, age distribution, gender ratio, preferred method) from the completed suicide cases. Although males have higher rates of suicide, females have higher rates of suicidal ideation and attempts.21 Among the sample of suicide attempt cases, the preferred methods tend to be less lethal than among the completed suicide cases.13

Although suicidal ideation among adolescents appears widespread in certain Micronesian communities, there is no systematic survey to explore this issue. Only one study documents suicidal thoughts and attempts in Guam’s Asian/Pacific Islander adolescents with a probability sample.32 Results of one survey of high school students in Guam indicated that adolescents who reported suffering physical abuse in the context of a romantic relationship, engaging in binge drinking, and experiencing feelings of hopelessness were at greater risk for suicidal ideation and attempts.32 Girls were more likely than boys to indicate that they had attempted suicide during the past 12 months (28.2% versus 14.5%, respectively).

Race and ethnicity is related to suicide risk among adolescents.32 Among boys, risk for suicidal ideation is higher for Micronesians than for members of all other races and ethnicities. Compared with Micronesian girls, the risk of female suicidal ideation is reduced both for whites and for other races and ethnicities (ie, Hispanic, African American, other Pacific Islanders), whereas the risk of female suicide attempt is reduced only for other races and ethnicities. Given suicide attempts are more common among Micronesian boys,33 these results may actually understate the effect of Micronesian race or ethnicity for boys.



The rates of suicide in Pacific Islanders including Micronesian populations are among the highest in the world.7 The reasons for a high suicide rate observed in this area may include the following. First, the changes following World War II in family structure or parent-adolescent relations may be the underlying cause of the increase in adolescent suicide between the 1960s and 1980s.9,13,20 The expansion of a cash economy in Micronesia and the decreasing reliance on subsistence production in favor of store-bought produce has seriously eroded the importance of lineage and clan activities. This, in turn, has undermined the wider social supports for adolescents and brought about their unaccustomed dependency upon the nuclear family, resulting in a sharp increase in parent-adolescent conflict. Second, the acceptance of suicide is one of the reasons for a high suicide rate.20 The suicide act is seen as resolving characteristic social problems that individuals face in society.13 As suicide has gained familiarity among youths, the act itself has become more acceptable or even expected.9 Micronesian beliefs in spirit communication may also be an important factor for contagious influence from one suicide to another.13

Suicide rates and patterns between Micronesian populations with other indigenous populations in the US, Canada, and New Zealand are similar to some extent.5 For all, the highest rates of suicide are found among males 15–24 years of age, peaking at 20–25 years of age. The patterns of suicide rates declining after 20–25 years of age and then increasing at 60–65 years of age were found in the US, Canada, and Chuukese, and Marshalles.6,34 The bimodal second spike among the elderly is commonly seen in US and many other nations.5,7,31,35,36 The similar pattern of suicide rates steadily decreasing after 20–25 years of age without a later peak for elderly males was found in New Zealand Maori, Hawaiians, Belauans, Pohnpeans, and Guam.5,22,37 The “Pacific pattern” may reflect the influence of culture. As in Hawaii,5 the steady decline after 40 years of age and the absence of the second smaller spike at 60–65 years of age among Micronesians may be due to the more structured role designations that occur for men, who have a more respected role with age.

Youth suicide is a significant phenomenon among Pacific islanders.5,7 Though time differences exist between Micronesian and current US rates, this comparison is considered valid and useful since current US levels provide a recognized benchmark. Youth suicide in the US has also nearly tripled from 1952–1996, and from 1980–1996 suicide rates among youths 15–19 years of age increased by 14%.38 Similar patterns and trends exist among Micronesian populations. The rate of suicide among youths in Micronesia have remained at epidemic levels for nearly 3 decades and have been reported as being as much as 10–13 times the rates for similarly aged youths in the US and other industrial nations.24,26

Micronesian young men are at significantly greater risk for suicide than are young men of other races and ethnicities. Although men commit suicide more frequently than women in most countries in the world, the differences in rates are usually not so extreme as in Micronesia.5,39 Several factors may help explain the relatively greater risk for suicide among young Micronesian men. First, the traditional status of women in these matrilineal island societies provides women with a much more stable residential and support network than it does men, as men marry and live with women from another village or island.13 Second, family structure and adolescent socialization practices changed in Micronesia following World War II.13 A rapid socioeconomic change or societal transition from traditional to modern creates cultural dislocation for young people. The role changes have undermined adolescent male roles and social supports. The predicament appears to affect the quality of the relationship between parents and their adolescent sons much more than between parents and daughters. Third, young men may face more intergenerational conflicts and pressures than young women.13,26,40 Fourth, young men are at significantly higher risk for substance and alcohol abuse and mental illnesses than young women.13,18,19

Compared with other countries of the world where rapid economic transformation has been taking place, such as China and other Asian or Pacific islands, the suicide patterns in Micronesia are similar in higher youth suicide rates. The author suggests that the youth suicide rates may be affected mostly in countries where the elderly are commonly respected. Female youth suicide may be influenced mostly in traditional patrilineal societies (eg, rural China) and male youth suicide may be mainly affected in traditional matrilineal societies (eg, Micronesia area). Further studies need to explore the assumptions.

The particular form of a suicide method can be culturally determined.41,42 Lethality of hanging may be one reason for high suicide rates of Micronesian men. The lethality of the preferred method (eg, paraquat) may also be one reason for a higher female suicide rate on some Pacific Islands.7,21 The rate of female suicide may be high if women commonly use a highly toxic means (eg, paraquat, pesticide) for suicide, such as in the Fijian islands7 and many other nations (eg, rural China).31

Why did Micronesian studies report much lower prevalence of psychiatric disorders among suicides than other studies in Hawaii, China, the US mainland, and other nations? This may be related to the unstandardized diagnosis process (eg, not using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–Text Revision [DSM-IV-TR],43 or International Classification of Diseases, Tenth Revision [ICD-10]44 criteria) used in Micronesian studies, which may severely underreport the percentage of mental disorders. For example, anger suicide may sometimes be regarded as pathologic using medical diagnosis criteria.20 Diagnoses in most previous studies in Micronesia were based on local mental health office records as well as the author’s own assessment of the individual’s behavior and from interviews with family and acquaintances.13,20 However, the standard DSM-IV-TR and ICD-10 criteria were not used in diagnoses in these Micronesian studies as in other studies.30,31 In a 2007 National Violent Injury Statistics System pilot,45 the results indicated that youths (46%) were less likely than adults (64%) to have had a mental health or substance abuse problems noted in the death investigation reports written by police, medical examiners, or coroners. The lower rates of mental illness among the Micronesian suicides may also be due to the higher percentage of suicide in youths. The lower rate of mental disorders among Micronesian suicides may reflect the influence of cultural factors on suicidal behavior. This may also indicate that the role of mental disorders in suicidal behavior may vary among various ethnic groups. However, further studies need to explore the relationship between suicide and mental disorders in this specific area.

The study was limited in a few ways. First, there is limited literature on suicide, attempted suicide, and suicidal ideation for Pacific Islanders, especially the Micronesian populations. Second, there are relatively few studies and only small samples of cases in specific subgroups (eg, older age group). Third, when comparing existing studies, there is the problem of differing instruments, wording of questionnaires, and time span (eg, lifetime, 1 year, 1 week).5 Many previous studies were based on the available reports or records (eg, hospital and medical records, death certificates, police records and statistics, pertinent church records).9,16 Suicide statistics which are based on death certificates and hospitalization reports may potentially underestimate rates of completed and attempted suicide.5 The degree of underreporting and unreliability of suicide cases in the official reports and publications may be severe.7 Fourth, many cases with mental disorders might not be diagnosed without the standardized instruments and diagnosis criteria (eg, DSM-IV-TR or ICD-10). Given the limitations of previous studies, the basis on which to draw conclusions may be weak.



The suicide phenomenon in Micronesia is unique in cross-cultural comparison, owing to the extremely high incidence among adolescent males; a pattern of extremely high peaks of suicide in young Micronesian Islanders without bimodal distribution; the enormous disproportion of male suicides over female suicides; rapid onset of high suicide rates that occurred in the 1970s, becoming alarmingly high by the 1980s; and the tight cultural patterning in method and motive of suicide. The difference in age distribution may be due to social-cultural influences in family system and role designations for youths, adults, and elders.5 Suicide behaviors among Micronesian populations should be understood in specific culture and acculturation. As there are discordant results in drawing conclusions on the role of ethnicity in suicidal behavior,42 further studies should explore the role of culture in suicide.

Given the limitation of previous studies, various suggestions may be offered for future studies. First, a suicide surveillance system should be set up to monitor the suicidal behavior in this area. Second, more independent research (eg, Psychological Autopsy study, epidemiological survey) on suicidal behavior should be conducted to explore the trend of suicide, especially after 1990, and risk and protective factors of suicide in Micronesia. Third, the impact of ethnicity and culture on suicide should be explored in a deeper way using qualitative and quantitative methods. The effect of social and economic shifts on suicide, especially suicide by male youths, should be explored in detail using longitudinal methods. Fourth, it is crucial to explore the relationship between the mental disorders and suicide in this specific area. The differences between local perceptions and standardized instruments and diagnosis criteria should be investigated. Fifth, standard or comparable instruments and procedures should be used in studies. Sixth, different ethnic groups (eg, Chamorro, Marshallese, Filipino) should be explored separately. Seventh, given the very limited professional personnel (eg, psychiatrist, psychologist, social worker) available in Micronesia, more professionals should be trained. Finally, culturally responsive suicide prevention should be conducted to reduce the suicidal behavior, especially male youth suicide, in this area. PP



1. World Health Report 2002. Geneva, Switzerland: World Health Organization; 2002.
2. CDC. WISQARS Fatal Injuries: Mortality Reports, 1999-2004. Available at: http://webappa.cdc.gov/sasweb/ncipc/mortrate.html. Accessed October 1, 2007.
3. Grunbaum JA, Lowry R, Kann L, Pateman B. Prevalence of health risk behaviors among Asian American/Pacific Islander high school students. J Adol Health. 2000;27(5):322-330.
4. Arias E, MacDorman MF, Strobino DM, Guyer B. Annual summary of vital statistics–2002. Pediatrics. 2003;112(6 Pt 1):1215-1230.
5. Else IR, Andrade NN, Nahulu LB. Suicide and suicidal-related behaviors among indigenous Pacific Islanders in the United States. Death Stud. 2007;31(5):479-501.
6. Department of Health and Human Services. Mental Health: A Report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services; 1999.
7. Booth H. Pacific Island suicide in comparative perspective. J Biosoc Sci. 1999;31(4):433-448.
8. Hezel FX. Cultural patterns in Trukese suicide. Ethnology. 1984;23(3):193-206.
9. Rubinstein DH. Youth suicide and social change in Micronesia. Paper presented at: the 26th Kyushu Regional Meeting of the Japanese Society of Tropical Medicine; Kagoshima University Research Center, Japan; 2002.
10. Colucci E. The cultural facet of suicidal behaviour: its importance and neglect. AeJAMH. 2006;5(3). Available at: www.auseinet.com/journal/vol5iss3/colucci.pdf. Accessed October 1, 2007.
11. Leenaars AA, Haines J, Wenckstern S, Williams CL, Lester D. Suicide notes from Australia and the United States. Percept Mot Skills. 2003;96(3 Pt 2):1281-1282.
12. Rubinstein DH. Changes in the Micronesian family structure leading to alcoholism, suicide, and child abuse and neglect. Micronesian Seminar-FSM Mental Health Program. Occasional Papers. 1994;15:1-8.
13. Rubinstein DH. Suicidal behaviour in Micronesia. In: Peng KL, Tseng WS, eds. Suicidal Behaviour in the Asia-Pacific Region. Kent Ridge, Singapore: Singapore University Press; 1992:199-230.
14. Guam Bureau of Statistics and Plans. Ethnic Origin and Race Projections: 2001 to 2010. Guam:  2000 Census of Population and Housing; 2005.
15. U.S. Census Bureau. The native Hawaiian and other Pacific Islander population: 2000. Census 2000 Brief. Available at: www.census.gov/prod/2001pubs/c2kbr01-14.pdf. Accessed October 1, 2007.
16. Rubinstein DH. Epidemic suicide among Micronesian adolescents. Soc Sci Med. 1983;17(10):657-665.
17. Rubinstein DH. Suicide in Micronesia. In: Hezel FX, Rubinstein DH, White GM eds. Culture, Youth and Suicide in the Pacific: Paper from an East-West Center Conference. Honolulu, Hawaii: Pacific Islands Studies Program, University of Hawaii; 1985:88-111.
18. Hezel FX. In search of the social roots of mental health pathology in Micronesia. In: Robillard AB, Marsella AJ, eds. Contemporary Issues in Mental Health Research in the Pacific Islands. Honolulu, HI: University of Hawaii Press; 1987:12-31.
19. Rubinstein DH. Cultural patterns and contagion: epidemic suicide among Micronesian youth. In: Robillard AB, A.J. Marsella AJ, eds. Contemporary Issues in Mental Health Research in the Pacific Islands. Honolulu, HI: University of Hawaii Press; 1987:127-148.
20. Hezel FX. Suicide and the Micronesian family. The Contemporary Pacific. 1989;1(1):43-74.
21. Workman RL, Rubinstein DH. Suicide in Micronesia: Guam’s historical trends and patterns. Guam Pedia. In press.
22. Haddock RL, Naval CL. Health on Guam: Age-specific and age-adjusted mortality data-derived from Guam and U.S. death certificates and the Guam cancer registry. Paper presented at: the 2nd Annual Micronesian Medical Symposium; October 2005; Guam.
23. Hezel FX. Trukese Suicide. In: Hezel FX, Rubinstein DH, White GM, eds. Culture, Youth and Suicide in the Pacific: Paper from an East-West Center Conference. University of Hawaii, Honolulu: Pacific Islands Studies Program; 1985:112-124.
24. Rubinstein DH. Love and suffering: adolescent socialization and suicide in Micronesia. Contemporary Pacific. 1995;7(1):21-53.
25. National Center for Injury Prevention and Control (CDC).  WISQARS Injury Mortality Reports, 1999-2004. Available at: http://webappa.cdc.gov/sasweb/ncipc/mortrate10_sy.html
26. Hezel FX. Truk suicide epidemic and social change. Hum Organ. 1987;46(4):283-291.
27. Dale PW. Prevalence of schizophrenia in the Pacific Island populations of Micronesia. J Psychiatr Res. 1981;16(2):103-111.
28. Cheng AT. Mental illness and suicide. A case-control study in East Taiwan. Arch Gen Psychiatry. 1995;52(7):594-603.
29. Conwell Y, Duberstein PR, Cox C, Herrmann JH, Forbes NT, Caine ED. Relationships of age and axis I diagnoses in victims of completed suicide: a psychological autopsy study. Am J Psychiatry. 1996;153(8):1001-1008.
30. Mann JJ, Waternaux C, Haas GL, Malone KM. Toward a clinical model of suicidal behavior in psychiatric patients. Am J Psychiatry. 1999;156(2):181-189.
31. Phillips MR, Li XY, Zhang YP. Suicide rates in China, 1995-99. Lancet. 2002;359(9309):835-840. Erratum in: Lancet. 2002;360(9329):344.
32. Pinhey TK, Millman SR. Asian/Pacific islander adolescent sexual orientation and suicide risk in Guam. Am J Public Health. 2004;94(7):1204-1206.
33. Rubinstein DH. Suicide in Micronesia and Samoa: a critique of explanations. Pacific Studies. 1992;15(1):51-75.
34. Tsuang MT, Simpson JC, Fleming JA. Epidemiology of suicide. Intern Rev Psychiatry. 1992;4(2):117-129.
35. Galanis D. Overview of suicides in Hawaii. Honolulu: Injury Prevention and Control Program. Hilo, HI: Hawaii State Department of Health; 2006.
36. Hunter E, Harvey D. Indigenous suicide in Australia, New Zealand, Canada, and the United States. Emerg Med (Fremantle). 2002;14(1):14-23.
37. Beautrais A. Risk factor for suicide and attempted suicide among young people. Aust N Z J Psychiatry. 2000;34(3):420-436.
38. U.S. Public Health Service. The Surgeon General’s Call to Action to Prevent Suicide. Washington, DC: Department of Health and Human Services, U.S. Public Health Service; 1999.
39. State of Hawaii Department of Health. Fatal Injuries in Hawaii: 1996-2000. Honolulu, HI: Injury and Prevention Control Program; 2004.
40. Lowe ED. Identity, activity, and the well-being of adolescents and youths: lessons from young people in a Micronesian society. Cult Med Psychiatry. 2003;27(2):187-219.
41. Shiang J, Blinn R, Bongar B, Stephens B, Allison D, Schatzberg A. Suicide in San Francisco, CA: A comparison of Caucasian and Asian groups, 1987-1994. Suicide Life Threat Behav. 1997;27(1):80-91.
42. Colucci E, Martin G. Ethnocultural aspects of suicide in young people: A systematic literature review. Part 1: Rates and methods of youth suicide. Suicide Life Threat Behav. 2007;37(2):197-221.
43. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
44. The International Statistical Classification of Diseases and Health Related Problems. Geneva, Switzerland: World Health Organization; 2004.
45. NVISS Fact Sheet. Youth Suicide: Findings from a Pilot for the National Violent Death Reporting System. Available at: www.sprc.org/library/YouthSuicideFactSheet.pdf. Accessed October 1, 2007.



Dr. Dhossche is professor and Dr. Wilson is resident in the Department of Psychiatry at the University of Mississippi Medical Center in Jackson. Dr. Wachtel is assistant professor in the Department of Psychiatry at Johns Hopkins University School of Medicine, Kennedy Krieger Institute, in Baltimore, Maryland.

Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Dirk M. Dhossche, MD, PhD, Professor, Department of Psychiatry, University of Mississippi Medical Center, 2500 N State St, Jackson, Mississippi 39216; Tel: 601-984-5805; Fax: 601-984-6965; E-mail: dr6340451@pol.net.



The study of catatonia in children and adolescents shows that its presentation is similar as in adults and, as such, is readily diagnosable. Catatonia occurs in children and adolescents with affective, psychotic, autistic, developmental, drug-induced, and medical disorders. Benzodiazepines and electroconvulsive therapy, the treatments that have historically proven to be effective in adults with catatonia, also improve catatonia in children and adolescents. These findings shed new light on the importance of catatonia in psychiatric impairments across the lifespan by loosening the purported link between catatonia and schizophrenia, and thereby supporting an independent category of catatonia in psychiatric classification. Catatonia, a treatable syndrome, occurs in children and adolescents, and warrants prompt identification and treatment.

Focus Points

• Catatonia occurs in children and adolescents with affective, psychotic, autistic, developmental, drug-induced, and medical disorders, but its prevalence is unknown due to lack of systematic studies.
• The symptoms of catatonia in youths are the same as in adults.
• Catatonia in youths is a treatable syndrome, regardless of any underlying disorders; its primary treatments, also effective in adults, are benzodiazepines and electroconvulsive therapy.
• Child psychiatrists and other pediatric specialists should be attentive to the diagnosis of catatonia in their patients given that effective treatment is available.
• The study of catatonia in youths supports an independent category of catatonia in psychiatric classification.



Systematic controlled studies of catatonia in childhood and adolescence are lacking in modern literature. Findings in this area are based on case reports and smaller studies1-8 supporting the occurrence of catatonia in children and adolescents diagnosed with affective, psychotic, autistic, developmental, drug-induced, and medical-neurologic disorders.

An overview of associated conditions of catatonia in children and adolescents is provided in Table 1.7-22 The frequencies of the most common catatonic symptoms in children and adolescents are shown in Table 2.8 Rates for urinary and fecal incontinence as a feature of catatonia are only available for pediatric patients.

These findings in pediatric patients mostly parallel findings of catatonia in adult patients. Between 10% and 15% of adult patients with catatonia meet the criteria for schizophrenia. Various neurologic, medical, and drug-related etiologies23 are also found in adult patients with catatonia. Although there are no controlled treatment studies in catatonia, the literature consistently shows positive effects of benzodiazepines and barbiturates, and of electroconvulsive therapy (ECT), regardless of the severity or etiology of catatonia24-26 or age of the patient.7,27-32

On a historic note, catatonia was originally described in 1874 by Kahlbaum33 as a separate brain disorder with a cyclic, alternating, and progressive course. It was incorporated as a type of dementia praecox or schizophrenia by Kraepelin34 in 1896. In the 1970s, various authors described catatonia to be a feature in affective disorders in adults, particularly mania.35-37

Recent reports contradict the rarity of pediatric catatonia. Approximately 33% (12 of 38) of children with schizophrenia exhibited catatonic signs in one report,38 although no formal diagnoses of catatonia were made. Another study13 of 198 child and adolescent psychiatric outpatients showed a 5% prevalence of catatonia, and 17% prevalence in the subgroup with psychotic disorders. Catatonia has been increasingly recognized as a comorbid syndrome of autism.11 Two systematic studies39,40 show catatonia to occur in 12% to 17% of adolescents and young adults with autism. A caveat in these studies is that medication status was not fully described. This should be addressed in future studies given the overlap between antipsychotic-induced parkinsonism and catatonia in some cases.

Is catatonia underdiagnosed in children and adolescents? In the early 1980s, catatonia was thought to be almost extinct. However, recent studies report prevalence rates of catatonia between 7% to 17% in acute adult psychiatric inpatients23,41 and show that, although its symptoms are easily recognized, catatonia is underdiagnosed42,43 in adults with affective and psychotic disorders, leaving specific anti-catatonic treatments like benzodiazepines and ECT underused. Underdiagnosis of catatonia may be due to the historic decision to classify catatonia as a type of schizophrenia, the segregation of severely ill psychiatric patients and patients with developmental disorders in long-term facilities, the perceived lack of anti-catatonic treatments, and the disparagement of physical and neurologic examination by psychiatrists.23

Diagnostic and therapeutic errors of omission may also be instrumental in poor recognition of catatonia in children and adolescents given the considerable stigma and ambivalence surrounding pediatric ECT in the general and medical community. While errors of commission, such as operating on the wrong knee, may be more visible and anxiety provoking, errors of omission undoubtedly have an enormous cumulative impact on patient outcomes including or especially in psychiatry in the United States and in other countries.44,45 Such errors in pediatric patients concern the failure to diagnose or avoidance of perceived high-risk diagnoses (ie, severe or lethal catatonia), or not providing appropriate perceived high-risk or controversial treatments (ie, high-dose benzodiazepines or ECT), leading to undertreatment or no treatment at all.

Catatonia should be considered in any pediatric patients when there is a marked deterioration in psychomotor function and overall responsiveness. Infectious, metabolic, endocrine, neurologic, toxic, and autoimmune conditions have been associated with catatonia and must therefore be ruled out. A drug screen to detect common illicit and prescribed substances is necessary. All prescribed medications should be evaluated for their potential to induce catatonic symptoms since many medical and psychiatric medications can cause catatonia or catatonia-like conditions.23,46 Antipsychotic agents should be discontinued as they are contraindicated in patients who exhibit the signs of catatonia because of the reported increased incidence of malignant catatonia or neuroleptic malignant syndrome (NMS) in patients with incipient signs of catatonia.

Although different criteria for a diagnosis of catatonia are used in clinical practice and research, the authors of this article find the criteria proposed by Fink and Taylor23 most relevant based on experience in pediatric populations. Diagnosis is based on the presence of immobility, mutism, or stupor of at least 1 hour duration, associated with at least one of the following: catalepsy, automatic obedience, or posturing, observed or elicited on two or more occasions. Alternatively, in the absence of immobility, mutism, or stupor, the diagnosis is based on at least two of the following, which can be observed or elicited on two or more occasions: stereotypy, echolalia/echopraxia, waxy flexibility, automatic obedience, posturing, negativism, or ambitendency.

The proposed medical treatment Algorithm for catatonia reflects the cumulative experience in this area,11,23,26 and features the lorazepam test (by mouth, intravenous, or intramuscular administration of lorazepam 1–2 mg) for the rapid resolution of acute catatonia. If improvement is seen after the challenge test, treatment with increasing doses of lorazepam is recommended. The reports cite doses up to 30 mg as necessary in adults. The authors’ experience shows that in some adolescents with catatonia, doses up to 24 mg are tolerated without ensuing sedation and result in marked reduction of catatonic symptoms. This suggests that in some cases, catatonia may be associated with high tolerance to benzodiazepines. However, careful monitoring in a medical setting for excessive sedation, respiratory compromise, and other side effects is mandatory.


ECT is indicated in catatonia when increased dosages of lorazepam do not bring rapid relief. The efficacy of bilateral (bitemporal or bifrontal) electrode placement is better documented than is unilateral placement. The concurrent use of lorazepam and ECT is a useful treatment variant when lorazepam treatment brings benefits but not complete remission or return to baseline function. Intravenous administration of flumazenil, a benzodiazepine antagonist, can be used if lorazepam interferes with eliciting seizures during ECT. In a case series, synergy of lorazepam and ECT treatment using flumazenil was observed.47

The relief of catatonia requires more frequent seizures than does the relief of major depression. In severe or malignant catatonia, daily “en bloc” treatment for 3–5 days may be needed. The number of sessions needed before substantial improvement or remission occurs varies greatly per case.

Continuation treatment after an effective ECT course with lorazepam or maintenance ECT (M-ECT) is essential as relapse after short courses of treatment is common. A flexible approach to the frequency of treatments in M-ECT is preferable and should be guided by patient tolerability and clinical status. Several pediatric patients have maintained stable improvements with M-ECT but relapse if the intensity of M-ECT is decreased.


Case Vignette Of Adolescent Catatonia

M is a 16-year-old adolescent who was in a good state of physical and mental health until he became preoccupied with food and the sinfulness of eating. These obsessions increased for several months, and one morning, M was found rigid in front of his computer with his arms extended outwards above his lap. Parents were initially unable to move M at all. With much prompting he was able to ambulate with physical assistance, but moved very slowly with ongoing staring, mutism, unresponsiveness, and frequent posturing. M was admitted to a psychiatric facility, diagnosed with catatonia and psychosis, and started on olanzapine and lorazepam, but then developed food refusal with resultant need for intravenous hydration. Olanzapine was discontinued and risperidone was begun with lorazepam ordered only on a PRN basis. Catatonic symptoms worsened rapidly, including posturing, mutism, stupor, rigidity, food refusal, and incontinence. Risperidone was discontinued with improvement lasting for a few days only. M then presented again to the emergence room with reduced responsiveness and speech other than utterances, prominent waxy flexibility, and posturing, and was re-admitted.

During this admission, a neurologic work-up was conducted and found to be negative. magnetic resonance imaging and electroencephalogram were both within normal limits. The urine toxicology screen was negative. Catatonic symptoms in M waxed and waned during the next 6 weeks when he continued to be treated with various low doses of lorazepam and risperidone. Typically, when doses of lorazepam were increased, catatonic symptoms quickly resolved and M requested several food items and ate them, moved readily around his room, and was able to engage in normal conversation. M reported feeling “really weird” and remembering wanting to move his limbs but being unable to do such. He also reported remembering thinking that he “could not and should not eat.” Risperidone and lithium carbonate were also prescribed to target psychosis as evidenced by ongoing discussions of demons and auditory hallucinations telling M not to eat, and to target potential underlying mania. When catatonic symptoms remained absent for 2 weeks, lorazepam was decreased to 1 mg TID; within days, M became unresponsive and mute, with posturing and waxy flexibility, incontinence, and food refusal, laying in bed immobile and purring all day. Agitation, incoherent yelling, aggression and self-barricading in the bathroom followed, as well as ongoing posturing episodes and sudden bursts of self-slapping behavior.

At this juncture, ECT was finally pursued due to the severity of impairment and clear lack of efficacy of psychotropics. All psychotropics were stopped. M received seven bilateral ECT treatments over the course of 14 days, resulting in complete remission of all catatonic, psychotic, and affective symptoms. ECT was terminated after seven treatments, yet within 4 days M began again to report vivid thoughts of religious character, delusions related to devils, and disturbed sleep. Parents refused further antipsychotic trials based on past poor response, and elected to return to ECT. The patient received a second course of five ECT treatments, with complete resolution of symptoms. M was discharged and continued with four outpatient ECT treatments once weekly followed by an additional four ECT treatments every other week. M has remained without psychiatric symptoms since stopping ECT 6 months ago, and was able to return to school.



The case vignette is fictitious and intended to illustrate the convoluted diagnostic and treatment trajectory that follows when unequivocal catatonia currently presents in children and adolescents, as treatments targeting psychosis or depression are usually pursued more often and more vigorously than the treatment specifically targeting catatonia.

Typically, after considerable delay and ineffective trials of different classes of psychotropic medications, ECT is pursued and proves to be the definitive treatment for catatonia whose symptoms are clearly present in the early stages of illness. Continuation ECT consolidates the resolution of catatonia, and no further treatment is needed. Other patients need longer courses of maintenance treatment to avoid relapses, or treatment of symptoms that are independent of catatonia.

Lorazepam, sometimes prescribed as a PRN agent for “agitation” and not for catatonia, is found to improve catatonia allowing the patient to start communicating, eating, and drinking for a few hours. However, lorazepam is usually prescribed at low doses and is not continued, leaving catatonia only partially resolved and prone to relapse. Although antipsychotics should not be used or should be discontinued as there is a risk for precipitating malignant catatonia or NMS in patients with incipient signs of catatonia, trials of antipsychotics and antidepressants in patients with catatonia are a common strategy in an attempt to improve latent or possible underlying affective or psychotic disorders. However, catatonia often then remains the primary source of psychiatric impairment and is left untreated. Unfortunately, specific anticatatonic treatments are often not considered until catatonia worsens or only after considerable delay.


Catatonia In the DSM-5

One of the most important changes for clinical practice debated in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,48 work group responsible for psychotic disorders concerns the further separation of catatonia from schizophrenia. Catatonia is currently found in several categories of the DSM-IV,49 and this may add to diagnostic confusion and poor selection of effective treatment for catatonia. First, catatonia due to a general medical condition (code 293.89) is listed as a distinct entity in the section on medical conditions. Second, the catatonia subtype of schizophrenia (code 295.20) is one of the original Kraepelinian forms of schizophrenia listed since the DSM-I50 in 1952. Third, catatonia is an episode specifier for depressive disorder and bipolar disorder but without separate diagnostic codes. Fourth, the diagnosis of NMS, which some consider a form of malignant catatonia,51,52 is listed separately as a medication-induced movement disorder.

The degree of independence that catatonia should be allotted in DSM-5 is actively debated. Fink and colleagues53 and Rosebush and Mazurek54 believe that catatonia deserves a home of its own in psychiatric classification,23,53,55 and that catatonia’s divorce from schizophrenia and its recognition as an independent syndrome, akin to delirium, are needed in the next psychiatric classification. Independence of catatonia would increase timely recognition of its frequent comorbidity with affective disorders and general medical disorders, and increase attention to specific diagnostic and therapeutic measures (specifically high-dose benzodiazepines and ECT) that are commonly overlooked. Catatonia research would also benefit from greater convergence with the existing body of research on repetitive behavior disorders.

Ungvari and colleagues56 warn against completely severing catatonia from the major psychotic and mood disorders as this may lead to continued neglect of catatonia as a valid syndrome and to continued exclusion from vital research on the significance of psychomotor phenomena as a symptom dimension of psychotic and mood disorders. Heckers and colleagues57 ponder the use of specifiers to diagnose catatonia in three different patients groups (ie, schizophrenia, mood disorder, and general medical condition) versus the creation of an independent category of catatonia:

“The crucial step is a divorce of catatonia from schizophrenia. As divorces go, this is a nasty one… It appears problematic for catatonia to become a completely independent diagnostic class as it is not a single condition but an expression of several different disorders and because of the particular difficulties it would create for the nosology of schizophrenia… It may be justified to give catatonia more prominence in the next edition of the DSM, by consolidating catatonia across different diagnoses into one section. If such a consolidation does occur, it should likely be in the section on Psychotic Disorders because catatonia is a dimension of psychosis.”57



Despite warnings that a complete divorce between catatonia and psychosis would be nasty,57 the authors of this article believe it should be done, not only for the reasons already mentioned but also “for the sake of the children”. Separating catatonia from psychosis and schizophrenia would improve early diagnosis and treatment of catatonia in children and adolescents, especially those with autistic or developmental disorders, outweighing any negative or unintended consequences. The occurrence of catatonia in adolescents with a non-psychotic disorder like autism is an important finding that further loosens the historic link between catatonia and psychosis/schizophrenia. Systematic studies and treatment trials of catatonia are warranted in children and adolescents with affective, psychotic, autistic, developmental, drug-induced, and medical conditions.

ECT is likely to remain an essential component in the treatment of catatonia. Wider recognition of the benefits of ECT in pediatric catatonia will help to reduce stigma of ECT that is widespread when recommended for children and adolescents or patients with developmental disorders. To a lesser extent, this would also apply to the application of benzodiazepines that are frowned upon when prescribed in high doses, but often critical for treatment.  PP



1.    Cohen D, Flament M, Dubos PF, Basquin M. Case-series: catatonic syndrome in young people. J Am Acad Child Adolesc Psychiatry. 1999;38(8):1040-1046.
2.     Dhossche D. Catatonia in autistic disorders. J Autism Dev Disord. 1998;28(4):329-331.
3.    Rosebush P, MacQueen G, Clarke J, Callahan J, Strasberg P, Mazurek M. Late-onset Tays-Sachs disease presenting as catatonic schizophrenia: diagnostic and treatment issues. J Clin Psychiatry. 1995;56(8):347-353.
4.    Takaoka K, Takaoka T. Catatonia in childhood and adolescence. Psychiatry Clin Neurosci. 2003;57(2):129-137.
5.    Zaw F. ECT and the youth: catatonia in context. Int Rev Neurobiology. 2006;72:207-231.
6.    Dhossche D, Shettar S, Kumar T, Burt L. ECT for malignant catatonia in adolescence. South Med J. 2009;102(11):1170-1172.
7.    Dhossche D, Bouman N. Catatonia in children and adolescents. J Am Acad Child Adolesc Psychiatry. 1997;36(7):870-871.
8.    Dhossche D, Bouman N. Catatonia in an adolescent with Prader-Willi Syndrome. Ann Clin Psychiatry. 1997;9(4):247-253.
9.    Wing L, Attwood A. Syndromes of autism and atypical development. In: Cohen D, Donnellan A, eds. Handbook of Autism and Pervasive Developmental Disorders. New York, NY: Wiley-Interscience; 1987:3-19.
10.    Realmuto G, August G. Catatonia in autistic disorder: a sign of comorbidity or variable expression. J Autism Dev Disord. 1991;21(4):517-528.
11.    Dhossche D, Wing L, Ohta M, Neumärker KJ, eds. Catatonia in Autism Spectrum Disorders. San Diego, CA: Elsevier Academic Press; 2006.
12.    Wachtel L, Kahng S, Dhossche D, Cascella N, Reti I. Electroconvulsive therapy for catatonia in an autistic girl. Am J Psychiatry. 2008;165(3):329-333.
13.    Thakur A, Jagadheesan K, Dutta S, Sinha V. Incidence of catatonia in children and adolescents in a pediatric psychiatric clinic. Austr NZ J Psychiatry. 2003;37(2):200-203.
14.    Sullivan B, Dickerman J. Steroid-associated catatonia: report of a case. Pediatrics. 1979;63:677-679.
15.    Elia J, Dell M, Friedman D, et al. PANDAS with catatonia: a case-report. Therapeutic response to lorazepam and plasmapheresis. J Am Acad Child Adolesc Psychiatry. 2005;44(11):1145-1150.
16.    Davis E, Borde M. Wilson’s disease and catatonia. Br J Psychiatry. 1993;162:256-259.
17.    Perisse D, Amoura z, Cohen D, et al. Case study: effectiveness of plasma exchange in an adolescent with systemic lupus erythematosus and catatonia. J Am Acad Child Adolesc Psychiatry. 2003;42(4):497-499.
18.    Wang HY, Huang TL. Benzodiazepines in catatonia associated with systemic lupus erythematosus. Psychiatry Clin Neurosci. 2006;60:768-770.
19.    Cavanna A, Robertson M, Critchley H. Catatonic signs in Gilles de la Tourette syndrome. Cogn Behav Neurol. 2008;21(1):34-37.
20.    Dhossche D, Reti I, Shettar S, Wachtel L. Tics as signs of catatonia. Journal of ECT. In press.
21.    Woodbury M, Woodbury M. Neuroleptic-induced catatonia as a stage in the progression toward neuroleptic malignant syndrome. J Am Acad Child Adolesc Psychiatry. 1992;31(6):1161-1164.
22.    Revuelta E, Bordet R, Piquet T, Ghawche F, Destee A, Goudemand M. Acute catatonia and neuroleptic malignant syndrome. A case of infantile psychosis. Encephale. 1999;20(3):351-354.
23.    Fink M, Taylor MA. Catatonia: A Clinician’s Guide to Diagnosis and Treatment. New York, NY: Cambridge University Press; 2006.
24.    Fricchione G, Cassem N, Hooberman D, Hobson D. Intravenous lorazepam in neuroleptic-induced catatonia. J Clin Psychopharmacol. 1983;3(6):338-342.
25.    Rohland B, Carroll B, Jacoby R. ECT in the treatment of the catatonic syndrome. J Affect Disord. 1993;29(4):255-261.
26.    Caroff S, Mann S, Francis A, Fricchione G. Catatonia: From Psychopathology to Neurobiology. Washington, DC: American Psychiatric Publishing; 2004.
27.    Carr V, Dorrington C, Schrader G, Wale J. The use of ECT for mania in childhood bipolar disorder. Br J Psychiatry. 1983;143:411-415.
28.    Black D, Wilcox J, Stewart M. The use of ECT in children: case-report. J Clin Psychiatry. 1985;46(3):98-99.
29.    Cizadlo B, Wheaton A. Case study: ECT treatment of a young girl with catatonia. J Am Acad Child Adolesc Psychiatry. 1995;34(3):332-335.
30.    Slooter A, Braun K, Balk F, van Nieuwenhuizen O, van der Hoeven J. Electroconvulsive therapy of malignant catatonia in childhood. Pediatr Neurol. 2005;32(3):190-192.
31.    Lee A, Glick D, Dinwiddie S. Electroconvulsive therapy in a pediatric patient with malignant catatonia and paraneoplastic limbic encephalitis. J ECT. 2006;22(2):267-270.
32.    Esmaili T, Malek A. Electroconvulsive therapy (ECT) in a six-year-old girl suffering from major depressive disorder with catatonic features. Eur Child Adolesc Psychiatry. 2007;1691):58-60.
33.    Kahlbaum K. Catatonia or the Tension Insanity. Berlin: Verlag August Hirshwald; 1874.
34.    Kraepelin E. Textbook for Students and Physicians. 5th ed. Leipzig: Barth; 1896.
35.    Morrison J. Catatonia: retarded and excited types. Arch Gen Psychiatry. 1973;28(1):39-41.
36.    Abrams R, Taylor M. Catatonia: a prospective clinical study. Arch Gen Psychiatry. 1976;33(5):579-581.
37.    Gelenberg A. The catatonic syndrome. Lancet. 1976;1(7973):1339-1341.
38.    Green W, Padron-Gayol M, Hardesty A, Bassiri M. Schizophrenia with childhood onset: a phenomenological study of 38 cases. J Am Acad Child Adolesc Psychiatry. 1992;31(5):968-976.
39.    Wing L, Shah A. Catatonia in autistic spectrum disorders. Br J Psychiatry. 2000;176:357-362.
40.    Billstedt E, Gilberg C, Gilberg C. Autism after adolescence: population-based 13- to 22-year follow-up study of 120 individuals with autism diagnosed in childhood. J Autism Dev Disord. 2005;35(3):351-360.
41.    Chalasani P, Healy D, Morriss R. Presentation and frequency of catatonia in new admissions to two acute psychiatric admission units in India and Wales. Psychol Med. 2005;35(11):1667-1675.
42.    Ungvari G, Leung S, Shing F, Cheung HK, Leung T. Schizophrenia with prominent catatonic features (“catatonic schizophrenia”). I. Demographic and clinical correlates in the chronic phase. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29(1):27-38.
43.    van der Heijden F, Tuinier S, Arts N, Hoogendoorn M, Kahn R, Verhoeven W. Catatonia: disappeared or under-diagnosed? Psychopathol. 2005;15(1):3-8.
44.    Passmore K, Leung WC. Defensive practice among psychiatrists: a questionnaire survey. Postgrad Med J. 2002;78(925):671-673.
45.    Tellefsen C. Commentary: lawyer phobia. J Am Acad Psychiatry Law. 2009;37(2):162-164.
46.    Lopez-Canino A, Francis A. Drug-induced catatonia. In: Caroff S, Mann S, Francis A, Fricchione G, eds. Catatonia: From Psychopathology to Neurobiology. Washington, DC: American Psychiatric Publishing; 2004.
47.    Petrides G, Divadeenam KM, Bush G, Francis A. Synergism of lorazepam and electroconvulsive therapy in the treatment of catatonia. Biol Psychiatry. 1997;42(5):375-381.
48.    Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; In Press.
49.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
50.    Diagnostic and Statistical Manual of Mental Disorders. 1st ed. Washington, DC: American Psychiatric Association; 1952.
51.    White D. Catatonia and the neuroleptic malignant syndrome – a single entity? Br J Psychiatry. 1992;161:558-560.
52.    Fink M, Taylor M. Neuroleptic malignant syndrome is malignant catatonia, warranting treatments efficacious for catatonia. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30(6):1182-1183.
53.    Fink M, Shorter E, Taylor MA. Catatonia is not schizophrenia: Kraepelin’s error and the need to recognize catatonia as an independent syndrome in medical nomenclature. Schizophr Bull. Jul 8, 2009 [Epub ahead of print].
54.    Rosebush PI, Mazurek MF. Catatonia and its treatment. Schizophr Bull. Dec 7, 2009 [Epub ahead of print].
55.    Taylor M, Fink M. Catatonia in psychiatric classification: a home of its own. Am J Psychiatry. 2003;160(7):1-9.
56.    Ungvari GS, Caroff SN, Gerevich J. The Catatonia Conundrum: Evidence of Psychomotor Phenomena as a Symptom Dimension in Psychotic Disorders. Schizophr Bull. Sep 23, 2009. [Epub ahead of print].
57.    Heckers S, Tandon R, Bustillo J. Editorial: catatonia in the DSM—shall we move or not? Schizophr Bull. Feb 22, 2010. [Epub ahead of print].


Dr. Valuck is associate professor in the Department of Clinical Pharmacy and Dr. Libby is assistant professor in the Department of Psychiatry, both at the University of Colorado School of Pharmacy in Denver. Dr. Benton is assistant professor in the Department of Psychiatry at the University of Pennsylvania Medical School in Philadelphia and an adult, child, and adolescent psychiatrist at The Children’s Hospital of Philadelphia. Dr. Evans is the Ruth Meltzer professor and chairman of the Department of Psychiatry and professor of Psychiatry, Medicine, and Neuroscience at the University of Pennsylvania School of Medicine.

Disclosures: Dr. Valuck receives grant support from the Agency for Healthcare Research and Quality, the American Foundation for Suicide Prevention, Eli Lilly, Forest, Janssen, and Pfizer. Dr. Libby receives grant support from Eli Lilly. Dr. Benton receives grant support from the National Institute of Mental Health (NIMH). Dr. Evans is consultant to Abbott, AstraZeneca, Bristol-Myers Squibb/Otsuka, Eli Lilly, Forest, Johnson & Johnson Pharmaceutical Research and Development, Neuronetics, Pamlab, and Wyeth; and receives grant support from the NIMH.

Please direct all correspondence to: Robert J. Valuck, PhD, RPh, Associate Professor, Department of Clinical Pharmacy, University of Colorado at Denver and Health Sciences Center, 4200 E Ninth Ave, C-238, Denver, CO 80262-0238; Tel: 303-315-3841; Fax: 303-315-1797; E-mail: Robert.Valuck@UCHSC.EDU.



Focus Points

• A retrospective study examined the annual rates of suicide attempts among managed care enrollees.
• The study found that 50% of suicide attempters were adults 25–64 of age, 38% were youths 10–19 years of age, and 55% had a psychiatric diagnosis 90 days prior to the attempt.



Introduction: Depression is a risk factor for suicide and is prevalent among adult and pediatric populations. Associations between antidepressant use and suicidal behaviors have resulted in a black box warning about antidepressant use. This study examines annual rates of suicide attempts among managed-care enrollees and describes their demographics, diagnoses, and prior treatments.
Methods: A retrospective case series was compiled from the PharMetrics Integrated Outcomes Database, representing 47 million covered lives from 1998–2005. Suicide attempts were identified from paid claims data using the
International Classification of Diseases, Ninth Revision, Clinical Modification, and Tenth Revision diagnostic codes. Numbers of suicide attempters and population-based rates were measured annually. Demographic data, chronic disease, psychiatric diagnoses, and antidepressant use were described.
Results: Among 10,914 attempters, subjects with one suicide attempt increased from .04% in 1998 to .13% in 2005. Most were female (72%), adult (63%), and lived in the Midwest (57%). The most frequent (38%) age group was 10–19 years of age. Over 50% had a diagnosis of depression (38%), anxiety (14%), or substance abuse (14%). Fifty-three percent were receiving antidepressants.
Discussion: The findings in this study support the large body of evidence reporting higher risks of suicide attempts or completion among children and adolescents. The findings are also consistent with reports of lack of recognition and undertreatment of psychiatric illness, since 47% of suicide attempters in the present study were not receiving antidepressants at the time of the attempt.
Conclusion: While suicide attempters varied significantly in their demographic characteristics, psychiatric diagnosis and antidepressant use were similar in the majority of cases. Further studies should identify shared risk factors for suicide among those treated with antidepressants.


Major depressive disorder (MDD) has been shown to be a prevalent disorder in both adult and pediatric populations. The most recent estimate based on the National Comorbidity Study Replication for the adult United States population is 16.2% for lifetime prevalence of MDD.1 Estimates of 1-year prevalence are as high as 2.5% in childhood and 8.3% in adolescence.2,3 Important from a public health perspective and for this study, a four-fold increased likelihood of suicide attempt associated with pediatric depression has been reported,4,5 and those with MDD are at especially high risk compared to those with other emotional disorders.6 Studies report higher risk for suicide attempts among adolescents, particularly among those with depression.7,8

Concern over a possible link between antidepressant use and “suicidality” (a term that encompasses a large range of behaviors, including completed suicide, suicide attempt, planning or other preparatory action, suicidal ideation, and self-injury with lethal intent)9 has led the US Food and Drug Administration to take regulatory action in the form of a black box warning for this class of drugs for children and adolescents (up to 18 years of age) in 2004,10 and for young adults (ages 19–24 years) in 2007,11 despite the existence of very few cases of suicide attempt and no reports of completed suicide(s) in antidepressant clinical trials.12 Given the rarity of reported suicidal behaviors in clinical trials and the difficulty in accurately classifying such behaviors from case report forms9 little is known about the demographic or clinical characteristics of subjects who attempt suicide or how often such attempts occur in large, “real-world” populations.

The purpose of this study is to quantify the crude incidence rate of suicide attempt in US managed healthcare plans and to provide descriptive information on demographic and clinical characteristics of suicide attempt cases. Such information will lay the groundwork for further, comparative studies of suicide attempters and other subjects to further our understanding of the possible link between patient factors, prescribed medication use, and suicide attempt.




Data for this study come from a commercially available claims database provided by PharMetrics, Inc., a unit of Intercontinental Marketing Services (presently known as IMS), the largest national patient-centric database of longitudinal, integrated medical, facility, and pharmacy claims data. These integrated data include paid claims from 85 managed-care plans nationally, representing 47 million covered lives from 1998 to 2005. The majority of subjects in this database (92%) were covered by commercial insurance plans, and 8% were insured by Medicaid. Descriptive statistics suggest that these integrated data describe a population that is regionally representative and comparable to US Census distributions on age and gender. In fact, the 0–65 years age distribution within the database is not statistically different than the 2000 US Census distribution.13


Base Population

Information on the number of managed-care enrollees covered by participating health plans and stratified by age, gender, and in total, was provided by PharMetrics for the purpose of calculating crude incidence rates of suicide attempt. Blinded, individual patient-level medical claims data (consisting of all paid physician, facility, and pharmacy claims records) were obtained for those subjects with at least one suicide attempt, as defined below, and with at least 360 days of prior enrollment and claims history. This restriction was employed to enable accurate description of demographic and clinical characteristics of identified case subjects in the year prior to as well as at the time of the suicide attempt.


Suicide Attempt Cases

Suicide attempt cases were identified from insurance claims coded for a suicide attempt associated with any visit to a medical provider or facility. The National Center on Health Statistics reports that most states use the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM)14 to code injuries resulting from suicide attempts; ICD-10 codes are also in use and all states use these codes for suicide deaths.15 These external cause codes describe manner and mechanism of injury, but do not differentiate suicide attempt from self-inflicted injury, ie, an injury not intended to cause death. We followed the Centers for Disease Control and Prevention guidelines in defining suicide attempts as claims with ICD-9-CM codes E950-E959 and ICD-10 codes X60-X84 and Y87.0.16 For each suicide attempt case, the date of the attempt was labeled the “index date” (in the case of multiple attempts per subject, the date of the first attempt was labeled the “index date” and subsequent descriptive analyses focused only on the initial attempt).



Several measures were determined or calculated for each suicide attempt case. For all measures, descriptive statistics were used where appropriate (Statistical Analysis System v9.0, Cary, North Carolina). No inferential statistical tests were performed. The study received exemption from institutional review board-approval by the Colorado Multiple Institutional Review Board (Aurora, Colorado).


Suicide Attempt Rate

The crude annual incidence rate of suicide attempt in the base population was calculated as the percent of enrolled subjects with at least one attempt in a given calendar year (1998–2005). The number of attempts per subject as well as the minimum, maximum, mean, median, and modal number of attempts per subject were also determined to fully characterize the distribution of attempts in the population.


Demographic Characteristics

For each suicide attempt case, the authors of this article determined subject age in years at time of first attempt (mean, standard deviation, median, and interquartile range), and broken down further by age groupings (pediatric, <18 years of age; young adult, 18–24 years of age; adult, 25–64 years of age; or elderly, ≥65 years of age) and age decades (0–9, 10–19, etc., up to 90–99). The authors also determined subject gender (male or female), region (East, Midwest, South, or West), and payer type (commercial insurance, Medicaid, Medicare Risk, Self-insured, or Medicare Gap).


Diagnostic Characteristics

For each suicide attempt case, the presence of numerous diagnoses of interest were identified using ICD-9-CM codes, both at the time of initial suicide attempt (within 90 days of, or on, the “index” date) or previous diagnoses (>90 days prior to the initial attempt). Mental health disorders of interest included: MDD, anxiety, schizophrenia, substance use disorder, bipolar disorder, any other mental health disorder (not previously listed), the presence of multiple mental health disorders, and the presence of any mental health disorder. Terminal disorders of interest included: HIV/AIDS, or malignant neoplasm. The 10 most frequently occurring “other” (ie, non-mental health, non-terminal) diagnoses among suicide attempt cases were identified as well. The level of chronic medical comorbidity and healthcare service utilization for each suicide attempt case at the time of initial suicide attempt were measured using the Chronic Disease Indicator (CDI) score, which indicates the total number of chronic diseases a subject has according to medical and pharmacy claims data,17 and the subject’s prior year total healthcare costs (paid by their managed health plan; expressed as mean, standard deviation, median, and interquartile range). Also noted for each case subject was the location at which the suicide attempt was coded (ie, the type of medical facility where the suicide attempt diagnosis was made).


Treatment History

For each suicide attempt case, several parameters indicative of prior medical treatment were determined. Antidepressant use prior to the first suicide attempt was identified using pharmacy claims data and was classified as any use of an antidepressant (yes/no); class of antidepressant used (ie, selective serotonin reuptake inhibitor [SSRI] monotherapy, serotonin norepinephrine reuptake inhibitor [SNRI] monotherapy, tricyclic antidepressant monotherapy, other antidepressant monotherapy, or multiple antidepressant use—either consecutively or concurrently); recent use (within 90 days or not); and use at the time of the suicide attempt (overlapping the “index date” or not). Use of other psychotropic medications of interest was measured as “yes” (indicative of any use in the 360 days prior to first suicide attempt) or “no” (no recorded use) for the following classes of drugs: conventional antipsychotics, atypical antipsychotics, anxiolytics, mood stabilizers, or other psychotropic medications (not previously listed). Lastly, prior receipt of psychotherapy services was also determined, using the Current Procedural Terminology, 4th Edition.18 Psychotherapy service use was classified as any prior psychotherapy claim(s) (yes/no); if yes, number of psychotherapy visits prior to first suicide attempt (one or >1); and the mean, standard deviation, median, mode, and range of number of psychotherapy visits per case were determined.



Suicide attempt cases from a national managed-care population were identified and rates of attempt were measured annually for the years 1998–2005 (Table 1). The percent of subjects with at least one attempt out of all managed-care enrollees increased from .04% (4 cases per 10,000 enrollees) in 1998 to .13% (13 cases per 10,000 enrollees) in 2005. Although the number of attempts per case ranged from 1–17, the average number of attempts per case was 1.1 and the median and modal number of attempts per case was one.



Demographic characteristics of suicide attempts subjects are described in Table 2. The average age at first suicide attempt was 29 years, with a median age of 25 years. Half of attempters were adults 25–64 years of age; older adults accounted for <1% of all attempts. Youths <18 years of age accounted for 28%, and young adults 18–24 years of age accounted for 22% of attempts. The most frequent age group (in decades) were youths 10–19 years of age at 38% of all attempts. Most attempters were female (72%). Suicide attempt cases were prominent in the Midwestern health plans (57%) and health plans in the West (28%). A majority of cases came from commercial insurance plans (64%). Cases from Medicaid plans (22% of suicide attempts) were proportionally higher than overall representation in the manage care patient population (9% of all enrollees).



Diagnostic history is reported for time periods within 90 days prior to the first suicide attempt (if there is more than one) and >90 days (91–360 days, at least as long as the 1 year minimum window preceding the attempt, and possibly longer than 1 year; Table 3). In the 90 days prior to the attempt, 50% of cases had either a diagnosis of depression (38%) or anxiety (12%). Fourteen percent had a diagnosis of substance abuse disorders. Thirty percent of cases had multiple mental health or substance abuse disorders. In the period >90 days prior to the attempt, 75% of attempters had been given a diagnosis of depression (52%) or anxiety (23%). Approximately 24% were assigned a substance abuse diagnosis on a medical claim. Forty-seven percent of attempters had multiple mental health or substance abuse diagnoses. Overall, 70% of cases had some type of psychiatric diagnosis on a paid claim >90 days prior to the suicide attempt.


Terminal diagnoses were uncommon. The most common non-psychiatric diagnoses in the 90 days prior to the attempt were headache (6%), abdominal pain (6%), pharyngitis (6%), lumbago (5%), and poisoning (5%). Chronic disease indicator CDI scores ranged from 0–20, with a median of two and mode of zero, indicating that these attempters did not represent complex severely chronically medically ill patients. Nearly 40% of attempts were reported in hospital emergency rooms, followed by inpatient settings (21%).

Psychiatric treatment history is described for any period in 360 days prior to the first suicide attempt (Table 4). Among cases, 60% had some record of filled antidepressant prescriptions. Among those, 35% of cases used SSRIs and >50% used multiple antidepressants of any class. Among antidepressant users, 72% was within 90 days prior to the suicide attempt and 53% was at the time of the attempt. A history of other mental health medications was reported for cases in the 360-day period prior to the attempt and included atypical antipsychotics (17%), anxiolytics (14%), mood stabilizers (4%) and other psychotropic drugs (37%).



Prior to the suicide attempt, 56% had at least one record coded for psychotherapy from any type of healthcare provider. Only 10% had only one claim for psychotherapy. The average number of psychotherapy visits was 17, with a median of 9, ranging from 1–274; the modal number of psychotherapy visits was one.



This study provides crude incidence rates as well as demographic and clinical characteristics of suicide attempters in a large representative sample of US managed-healthcare plans.

The authors of this article found trends toward increasing rates of the total number of suicide attempts per 10,000 enrollees from 1998 (0.04%) to 2005 (0.13%). Significant differences between the demographic characteristics of suicide attempters were also found. In this sample, females were the majority of first-time suicide attempters (71.8%), consistent with findings from epidemiologic surveys suggesting increased rates of suicide attempts among females.19,20 First suicide attempts spanned a wide age range but occurred with much greater frequencies among individuals <20 years of age.

The finding that the highest rates for first-time suicide attempts were among the 10–19-year-old age group (38%) is similar to the findings of other large epidemiologic surveys of suicide attempts.19,20  These surveys suggest that higher risks for initial suicidal ideation, plans, and attempts occur during the late teen years and early twenties and the median ages of onset for all of these outcomes occur during the mid-twenties. Consistent with these findings, this study described found a mean age at first suicide attempt of 29 years with a median of 25 years. Young adults 18–24 years of age accounted for 22% of all attempts and youths <18 years of age accounted for 28% of all attempts. The other 50% were accounted for by adults 25–64 years of age.

The findings in this study support the large body of evidence reporting higher risks for suicide attempts or suicide completion among children and adolescents. This increased risk among youths has recently received a great deal of attention in the psychiatric literature and public media. The FDA’s black box warning in 2004, suggesting that this population may be more vulnerable to increased suicidality when SSRIs or SNRIs are prescribed, has resulted in substantial declines in prescription rates for these agents in this age group and some decreased prescribing in adults up to 60 years of age as well. A study by Gibbons and colleagues21 assessed whether these warnings led to changes in prescription patterns and changes in suicide rates. They noted a 22% decrease in prescriptions for young people in 2003 and 2004 in the US and Netherlands and a subsequent increase in the rate of completed suicide in the US (14%) and the Netherlands (49%). The largest decreases in prescriptions were observed in the population <20 years of age, one group most vulnerable to suicide. An inverse relationship was noted between the SSRI prescription rates and the rates of completed suicides for the period 1998–2005. The trend toward increased prescription rates and decreased suicide rates for children and adolescents observed between 1998–2003 has been reversed with increased suicide rates noted in 2004. These data raise questions about current trends for treatments of psychiatric disorders associated with suicide. The decline in prescriptions may suggest trends toward undertreatment or underrecognition of depression. Evidence from the pediatric and adult populations suggests that diagnoses for depression and treatments have declined since 2004.22,23

The most recent population-based estimates of the 1-year prevalence of trends for suicide attempts describe rates of .6% from 2001–2003. These studies also show higher rates of psychiatric symptoms meeting criteria for a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR),24 disorder among suicide attempters. In the National Comorbidity Survey–Replication (NCS-R) studies, MDD (51%) was the most common individual disorder among people with suicide-related behaviors, and anxiety disorders (81%) were the most common class of disorders.19 Similar to the attempters, >90% of completed suicides in the US are associated with psychiatric illness, most commonly mood disorders (60%).25-29 Another result of the study was that most attempters had a psychiatric or substance use diagnosis at 90 days prior to the attempt and at >90 days prior to their attempt, and many had more than one diagnosis in the time period 90 days prior to an attempt or >90 days prior to attempt. Most attempters in the sample were diagnosed with an MDD (38% to 52%), anxiety disorder (12% to 23%), or substance use disorder (55% to 70%) prior to their suicide attempt. Higher rates of attempted suicide were associated with the presence of MDD, anxiety disorder, or substance use disorders within the 90 days prior to an attempt, and the highest rates occurred at >90 days prior to the attempt. Any mental health or substance use disorder was associated with higher rates of attempted suicide (55.3%) when compared to no psychiatric diagnosis (16.8%).

An important finding in the described study is that nearly 50% of the attempters in this population were not receiving antidepressants for any psychiatric disorder. Among those receiving medication treatment for depression, only 53% were using medications at the time of the attempt. Of those attempters receiving antidepressants, 38% were receiving SSRI or SNRI monotherapy and 51% were receiving multiple antidepressants. In addition, slightly more than 50% of the population had received some form of psychotherapy. Recent data for antidepressant prescribing patterns suggest that of 9,911,743 antidepressant prescriptions written for the population <20 years of age, 65% of those prescriptions were SSRIs and 20% were for non-serotonin–specific agents.21 The 51% rate of multiple antidepressant prescribing in the present study might be related to the severity of depression among attempters and/or prior poor response to antidepressants, suggesting treatment refractory disorders.

The evidence suggests that the majority of depressed individuals who die from suicide seek professional help within the month prior to their deaths.30 Nonetheless, the majority of these individuals are not being treated with antidepressants at the time of their suicide.31-33 These findings are consistent with the lack of recognition and undertreatment of psychiatric illness in general34 and mood disorder in particular.35 The data from the present study of suicide attempters also suggest underrecognition and lack of treatment since approximately 47% of suicide attempters were not receiving antidepressants at the time of the attempt. The trend toward increasing incidence rates for suicide attempts between 1998 and 2005 in the authors’ preliminary data cannot fully be explained. While suicide attempts are a risk factor for completed suicides, there is not a direct correlation between rates of attempts and rates of completion, making it difficult to provide correlations between data from the authors of this study and data on completed suicides.

Advances in the evidence-based treatments for depressive disorders should predict decreased suicide attempts in this population. Findings in this study, suggesting increased rates of first-time attempts, are in line with some epidemiologic studies that suggest that suicide-related behaviors have not changed over time, although evidence-based treatments have increased significantly.19,20 Epidemiologic data examining trends for suicidal behaviors from the 1990–1992 NCS and the follow up 2001–2003 NCS-R survey showed significant increases in treatment for depression and decreases in completed suicide rates, but no decrease in suicidal behaviors over time, suggesting potential clinical differences between attempters and completers.

These results have several limitations. ICD-9-CM codes as proxies for DSM-IV-TR psychiatric diagnoses for this study limit the ability to assess methods of diagnostic ascertainment, intent of self-injury, and severity of depression, which could impact suicidal behavior. Additionally, use of claims data to assess treatments provides limited information about adherence to treatment prior to or at the time of attempt or appropriateness, sufficient intensity, or continuity of treatment. Even with sufficient treatment, medication, and psychotherapies, recent evidence suggests that there is a phase during the treatment process during which the incidence of suicide attempts remains high. Simon and Savarino36 studied the incidence of suicide attempts among depressed patients starting psychotherapy or medications prescribed by a psychiatrist or primary care provider. While differences were found in the overall incidence of suicide attempts between these three treatment conditions, the pattern of suicide attempts did not vary. They found the highest incidence rates during the month before initiation, the second highest 1 month after initiation of medication or psychotherapy, and declines thereafter. Even with the appropriate management of these disorders, suicide attempts remain common. This is also important given the knowledge that adherence to antidepressant treatment is not great, with data suggesting that ≥33% of patients beginning antidepressants discontinue treatment within a few weeks.37 Additionally, ethnic background, SES data, and marital status, all identified risk factors for suicide attempts, were not included in this analysis. Despite the above limitations, the demographics and clinical characteristics of our population appear to be similar to available population-based estimates.



Preliminary findings from this large data set representing US managed healthcare plans provide crude incidence rates for suicide attempts and descriptive demographic and clinical data that do not differ substantially from those predicted by current epidemiologic data regarding suicide attempts. Additionally, the study presented provides preliminary descriptive data about the clinical presentations and psychiatric diagnoses and some descriptive data about antidepressant treatments and suicide attempts. These data suggest that managed-care databases could be used to further describe and understand the demographic and clinical characteristics of suicide attempters and those who will attempt suicide as well as the associations between antidepressant use and suicide attempts.

The findings that slightly <50% of the attempters had received antidepressant treatment and that slightly >50% received psychotherapy lend support to existing data that psychiatric illness remains underrecognized, untreated, or inadequately treated despite significant advances in detection and treatment.34,35 In light of these data, the black box warnings issued by the FDA could increase risks for undertreatment of depressed children, adolescents, and young adults who are very high-risk groups and should be the focus of further investigation. Future study is also needed to better understand the demographic and clinical characteristics that predispose individuals to suicidal behaviors.

Future efforts should focus on using patient-level data to further describe and characterize the population of suicide attempters. Although most of the attempters in the study provided had significant psychopathology, some attempters had no recorded psychiatric diagnosis. In addition, the frequency of suicide attempts far exceeds the number of deaths from suicide, suggesting that perhaps attempters and completers are not the same population. Comparative studies examining these two populations are needed. Finally, sufficient numbers of cases exist in the PharMetrics database for continued epidemiologic investigation into possible relationships between depression, antidepressant medication use, and suicide attempts. PP



1. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23):3095-3105.
2. Birmaher B, Ryan ND, Williamson D, et al. Childhood and adolescent depression: a review of the past 10 years. Part I. J Am Acad Child Adolesc Psychiatry. 1996;35(11):1427-1439.
3. Birmaher B, Arbelaez C, Brent D. Course and outcome of child and adolescent major depressive disorder. Child Adolesc Psychiatr Clin N Am. 2002;11(3):619-637.
4. Weissman MM, Wolk S, Wickramaratne P, et al. Children with prepubertal-onset major depressive disorder and anxiety grown up. Arch Gen Psychiatry. 1999;56(9):794-801.
5. Weissman MM, Wolk S, Goldstein RB, et al. Depressed adolescents grown up. JAMA. 1999;281(18):1707-1713.
6. Horesh N, Orbach I, Gothelf D, Efrati M, Apter A. Comparison of the suicidal behavior of adolescent inpatients with borderline personlatiy disorder and major depression. J Nerv Ment Dis. 2003;191(9):582-588.
7. Zametkin AJ, Atler MR, Yemeni T. Suicide in teenagers: assessment, management, and prevention. JAMA. 2001;286(24):3120-3125.
8. Keith CR. Adolescent suicide. JAMA. 2001;286(24):3126-3127.
9. Posner K, Oquendo M, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric suicidal risk analysis of antidepressants. Am J Psychaitry. 2007;164(7):1035-1043.
10. Food and Drug Administration. FDA Updates its review of antidepressant drugs in children. FDA Talk Paper T04-31. August 20, 2004. Available at: www.fda.gov/bbs/topics/ANSWERS/2004/ANS01306.html. Accessed October 8, 2007.
11. Food and Drug Administration. FDA Proposes New Warnings About Suicidal Thinking, Behavior in Young Adults Who Take Antidepressant Medications. FDA News. May 2, 2007. Available at: www.fda.gov/bbs/topics/NEWS/2007/NEW01624.html. Accessed October 8, 2007.
12. Hammad T, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry. 2006;63(3):332-339.
13. Valuck RJ, Libby AM, Sills MR, Giese AA, Allen RR. Antidepressant treatment and risk of suicide attempt by adolescents with major depressive disorder–A propensity-adjusted retrospective cohort study. CNS Drugs. 2004;18(15):1119-1132.
14. World Health Organization. ICD-9-CM: International Statistical Classification of Diseases and Health Related Problems. 9th rev, clinical modification. Geneva: World Health Organization; 1978.
15. World Health Organization. ICD-10: International Statistical Classification of Diseases and Health Related Problems. 10th rev. Geneva: World Health Organization; 1994.
16. Suicide Contagion and the Reporting of Suicide: Recommendations from a National Workshop. Centers for Disease Control and Prevention; 1994.
17. Malone DC, Billups SJ, Valuck RJ, Carter BL. Development of a chronic disease indicator score using a Veterans Affairs Medical Center medication database. IMPROVE Investigators. J Clin Epidemiol. 1999;52(6):551-557.
18. Current Procedural Terminology, 4th ed. Chicago, IL: American Medical Association; 2000.
19. Kessler RC, Borges G, Walters EE. Prevalence of Risk factors for lifetime suicide attempts in the National Comorbidity Survey. Arch Gen Psychiatry. 1999;56(7):617-626.
20. Kessler RC, Berglund P, Borges G, Nock M, Wang PS. Trends in suicide ideation, plans, gestures, and attempts in the United States, 1990-1992 to 2001-2003. JAMA. 2005;293(20):2487-2495.
21. Gibbons, RD, Brown HB, Hur K, et al. Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry. 2007;164(9):1356-1363.
22. Libby AM, Brent DA, Morrato EH, Orton HD, Allen R, Valuck RJ. Decline in treatment of pediatric depression after FDA advisory on risk of suicidality with SSRIs. Am J Psychiatry. 2007;164(6):884-891.
23. Valuck RJ, Libby AM, Orton HD, Morrato EH, Allen R, Baldessarini RJ. Spillover effects on treatment of adult depression in primary care after FDA advisory on risk of pediatric suicidality with SSRI’s. Am J Psychiatry. 2007;164(8):1198-1205.
24. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
25. Barraclough B, Bunch J, Nelson B, Sainsbury P. A hundred cases of suicide: clinical aspects. Br J Psychiatry. 1974:125(0):355-373.
26. Robins E, Murphy GE, Wilkinson RH Jr, Gassner S, Kayes J. Some clinical considerations in the prevention of suicide based on a study of 134 successful suicides. Am J Public Health Nations Health. 1959;49(7):888-899.
27. Rich CL, Fowler RC, Fogarty LA, Young D. San Diego suicide study, III: relationships between diagnoses and stressors. Arch Gen Psychiatry. 1988;45(6):589-592.
28. Isometsa E, Henriksson M, Marttunen M, et al. Mental disorders in young and middle aged men who commit suicide. BMJ. 1995;310(6991):1366-1367.
29. Beautrais AL, Joyce PR, Mulder RT, Fergusson DM, Deavoll BJ, Nightingale SK. Prevalence and comorbidity of mental disorders in persons making serious suicide attempts: a case control study. Am J Psychiatry. 1996;153(8):1009-1014.
30. Isacsson G, Boethius G, Bergman U. Low level of antidepressant prescription for people who later commit suicide: 15 years of experience from a population-based drug database in Sweden. Acta Psychiatr Scand. 1992;85(6):444-448.
31. Isaacson G, Holmgren P, Druid H, Bergman U. The utilization of antidepressants: a key issue in the prevention of suicide: an analysis of 5,281 suicides in Sweden during the period 1992-1994. Acta Psychiatr Scand. 1997;96:94-100.
32. Oquendo MA, Malone KM, Ellis SP, Sackeim HA, Mann JJ. Inadequacy of antidepressant treatment for patients with major depression who are at risk for suicidal behavior. Am J Psychiatry. 1999;156(2):190-194.
33. Isometsa E, Henriksson M, Heikkinen M, Aro H, Lonnqvist J. Suicide and the use of antidepressants. Drug treatment of depression is inadequate [letter]. BMJ. 1994;308(6933):915.
34. Evans DL, Foa EB, Gur RE, et al, eds. Treating and Preventing Adolescent Mental Health Disorders: What We Know and What We Don’t Know. New York, NY: Oxford University; 2005.
35. Evans DL, Charney DS, Lewis L, eds. Physician’s Guide to Depression and Bipolar Disorder. New York, NY: McGraw-Hill; 2006.
36. Simon GE, Savarino J. Suicide attempts among patients starting depression treatment with medications or psychotherapy. Am J Psychiatry. 2007;164(7):1029-1034.
37. Horvitz-Lennon M, Normand SL, Frank RG, Goldman HH. “Usual care” for major depression in the 1990s: characteristics and expert-estimated outcomes. Am J Psychiatry. 2003;160(4):720-726.


Dr. Bursztajn is associate clinical professor of psychiatry and Mr. Brodsky is senior research associate, both in the Department of Psychiatry at Harvard Medical School in Boston, MA.

Acknowledgments: The authors thank A. Stone Freedberg, MD, Patricia M.L. Illingworth, PhD, JD, and members of the Program in Psychiatry and the Law at Harvard Medical School, Massachusetts Mental Health Center, for their helpful dialogue. The authors report no financial, academic, or other support of this work.



How does managed care contribute to the psychiatric hazards of medical illness? How can primary care physicians and psychiatrists (as treaters or consultants) recognize and manage the clinical dynamics that result, together with their liability implications? For patients in managed healthcare settings, a latent subjective sense of captivity triggered by care restrictions can exacerbate feelings of helplessness and hopelessness brought on by the threat of serious illness. This sense of captivity can also intensify the patient’s feelings of alienation and betrayal when managed care constrains patient-physician decision making. These emotional dynamics, together with the rigid, defensive reactions to which physicians sometimes fall prey in the face of managed care’s restrictions on professional autonomy, can compromise the patient-physician relationship and the quality of clinical care while heightening liability risk. In the extreme, some patients will experience the escalating distress characteristic of posttraumatic stress disorder. Clinicians can prevent this emerging form of iatrogenesis by using such strategies as crisis anticipation and preparedness, intervention, and damage control, with the goals of enhancing the patient’s decision-making capacity and recovering a sense of choice in the patient-physician relationship. The introductory, ongoing, and termination phases of the treatment alliance are analyzed as focal points for particular clinical interventions.



There has been a growing recognition of the influence of managed health care on the doctor-patient relationship,1 including the forcing of primary care physicians into an alienating, ethically ambiguous, and clinically conflicting “gatekeeper” role.2,3 While financial constraints have always been a factor in clinical cases, one major consequence of managed care practices has been a concern as to the lack of meaningful healthcare choices for both doctors and patients. In this atmosphere, patients and their physicians—who face the threat or actuality of a major illness—may experience heightened feelings of helplessness and hopelessness, especially when healthcare benefits are denied. More dangerous still, some patients and physicians come to distrust each other, as when patients feel that physicians are not advocating for them, and when physicians feel that patients are “shooting the messenger” (ie, blaming the physician for managed care-initiated restrictions). In this atmosphere, physicians often avoid consideration of treatment alternatives they view as likely to be denied by a managed care reviewer, or feel compelled to focus on the catastrophic possibility in the differential diagnosis to obtain otherwise denied benefits.4 The final stage of this downward spiral of the physician-patient relationship can be a kind of mutual resignation, where the patient leaves with silent resentment while the physician acquiesces in the silence of a de facto gag clause.

The sense of virtual clinical captivity that patients and physicians can experience in the face of benefit denial need not be taken as a fait accompli. By becoming aware of the dynamics and dilemmas of the physician-patient relationship under managed care, treating physicians can create greater freedom for their patients and themselves to work together effectively. Useful clinical interventions can be implemented to recover a sense of choice in the doctor-patient relationship, while decreasing liability risk, by effectively anticipating, preparing for, identifying, and responding to the distress that is likely to accompany managed care restriction of clinical care.

There are compelling clinical and ethical considerations favoring a proactive stance by physicians who are aware of potential negative managed care influences on their patients. Given that helplessness and hopelessness have been documented to be predictors of negative patient outcomes (eg, in breast cancer),5 the undermining of the clinical process and the resulting loss of trust also undermine the potential for healing relationships and, in turn, the likelihood of positive health outcomes. Physicians who work to reverse this process are not just protecting themselves from liability, but also providing quality care by protecting patients from the consequences of helplessness, hopelessness, and distrust.

Although specialized consultation (eg, psychiatric) can be helpful in the face of a denial of healthcare benefits, it is important that primary care physicians have the tools and perspectives needed both to advocate for the patient and to support the patient when individually indicated benefits are deemed not “medically necessary.”6 An understanding of the dynamics of the physician-patient relationship in the managed care context can be helpful in adapting one’s clinical skills to the task of supporting the patient’s capacity for choice, hope, and trust.


Patient Dynamics: “Virtual Captivity”

Even as the prevalence of mental health problems such as mood and anxiety symptoms in primary care settings has come to be recognized,7 the cost containment strategies of managed health care have been found to inhibit the recognition and treatment of psychiatric disorders in medical treatment settings.8 Not only has a diagnosis of depression been found to be associated with patient dissatisfaction with medical care,9 but patients with high levels of depressive symptoms are less likely than the general population to act on their dissatisfaction by switching health plans.10 At the same time, the inability to choose one’s personal physician has been found to be a major determinant of patient dissatisfaction with their healthcare plan.11 The existing pool of trapped, frustrated, disillusioned patients also represents a potential tinderbox of litigation in the wake of tragic outcomes associated with managed care-influenced restrictions on effective treatment—in particular, restrictions on the building of therapeutic alliances in the doctor-patient relationship.

Serious illness that threatens an individual’s bodily or psychological integrity already poses a threat to a person’s sense of autonomy and control. Serious illness can heighten dependency while bringing with it feelings of helplessness, hopelessness, and distrust associated with depression. When faced first with a lack of choice of a provider, and then with restriction or even denial of care, the vulnerable patient, already feeling like a prisoner of the threat of serious illness, may now also begin to feel like a lonely captive of the healthcare system. This trapped, “nowhere to turn” feeling may persist after the illness is treated or even cured, as the patient, once burned by the denial of anticipated care or by worry over the prospect of such a denial, may come to think, “What if I get sick again? What care will I receive?” At the extreme, the patient may begin to experience, subtly but significantly, the emotional traumas associated with abandonment12 and captivity.13

Clinically, such experiences can generate cognitive distortions driven by anxiety—and depression—that may impair the patient’s capacity to temper realism with the hope necessary to tolerate uncertainty and to choose wisely from available alternatives.4,14 Moreover, the prospects for a supportive patient-physician alliance are undermined when the physician is seen by the patient as either untrustworthy or largely powerless to implement his or her own clinical recommendations and protect patient choices due to managed care pressure. The patient’s perception of physician trustworthiness may suffer, for example, when managed care drug formularies restrict the physician from prescribing a medication of choice. Even a trusting relationship, especially when it is founded on blind optimism,  can be destroyed by adversity together with perceived abandonment. As the patient’s distrust increases, responses can include such modes as “fight” (litigate), “flight” (drop out of treatment), or “freeze” (become numb, passive, demoralized, and unable to act effectively in the interest of one’s own health care). The resulting anxiety and depression can lead to a greater likelihood of dissatisfaction with medical care9 and to an impaired capacity to act on that dissatisfaction by changing health plans.10


Physician Dynamics: “False Necessity”

The human tendency toward resignation or self-deception and denial of what is too painful to see is not limited to patients. Often, the treating physician may not have freely chosen to be part of a particular managed care organization (MCO) nor to treat a particular patient, except as the best of a set of undesirable choices or the lesser of necessary evils. The physician is also likely to have experienced a substantial reduction of economic and professional autonomy in the shift to managed care. Like the patient, the physician may have few options and insufficient time to recognize, reflect upon, process, and put into perspective the feelings engendered by the managed healthcare context. Under any circumstances physicians are likely to react to a patient’s rejection by withdrawing emotionally from the patient. This reaction is especially likely, however, if the physician faces one frustrated, recalcitrant patient after another in a time-pressured managed care setting. At the same time, from the patient’s perspective, emotional withdrawal by a hurried and frustrated physician can easily be experienced as indifference to the patient’s suffering and a perceived abandonment.

Physicians are far from immune to the contagion of pessimism that can sweep through an institutional atmosphere, as in end-of-life care. Physicians who risk being penalized for caring for patients when, in the judgment of an anonymous third-party reviewer, there is no medical necessity to do so, are more likely to succumb to institutional pressures. Careful “not to raise the patient’s expectations” by effectively disclosing all possible options and advocating for the patient’s right to the best available care, they “hang crepe”15 as a prelude to premature discharge. In the extreme, some clinicians will automatically advise the patient and their family that only low-cost palliative measures be taken, not mentioning the more costly, intensive alternatives that may hold out a slim but real hope for the patient.

Such an atmosphere increases the risk that patients and families will give up prematurely while clinicians who are too distracted or time-squeezed to do the hard work of eliciting the patient’s and family’s deeper intentions go through the motions of obtaining informed consent.16,17 At the same time, some physicians react to their loss of autonomy and choice by making a premature cognitive commitment to diagnostic and treatment decision strategies designed to avoid punitive profiling practices. For example, a physician who is concerned about being identified as readily willing to hospitalize a patient for observation and evaluation will tend to avoid the risk of being deselected by the MCO. This avoidance can manifest itself in the doctor-patient encounter as a fixed, overly rigid stance or a reluctance to present alternatives to the patient other than the treatment least likely to engender MCO scrutiny. Such an attitude interferes with the informed-consent process vital to clinical care, and is often a pivot point in liability.

Of course, some denials of benefits by MCOs do represent a genuine effort to weed out unnecessary treatments and excessive costs. Nonetheless, other treatments that are medically appropriate (in that they are effective relative to individual patient values) come to be discounted as medically unnecessary by reference to an interpretation of “medical necessity” that is insensitive to individual patient values18 as well as to broader health-related social values.19

Medically appropriate care is care that is indicated based on the doctor-patient dialogue as informed by scientific research and accepted practice. Ideally, medically appropriate care considers the whole patient.20 By contrast, the term “medically necessary,” as used by third-party reviewers, is a misapplication of triage principles from military and disaster medicine to individual patients.21 Even treating physicians, when compelled to be time-pressured and hyper cost-conscious (as in many fixed-fee per subscriber capitated systems), tend to narrow their focus to overly concrete, readily measurable “necessary” benefits. Easily overlooked in such calculations are the costs of incomplete treatment22 to a patient’s freedom to live in the least restricted manner, as well as the biopsychosocial benefits of treatment that considers the patient’s overall well-being and level of independent and interdependent functioning.

Excessive reliance on managed care-driven “practice guidelines,” in the guise of being evidence-based, is also used to justify a denial of care. Such guidelines are often very selective as to the evidence they cite, as in the paucity of studies with outcome measures that reflect quality-of-life issues or the widespread neglect of many well-grounded outcome studies showing the efficacy of mental health treatment for patients with many medical and surgical conditions. In any case, decision making for patients in the aggregate is no substitute for individualized clinical decision making.


Prevention and Management of “Managed Care Side Effects”

Whether or not in conjunction with specialized consultation, a variety of clinical tools are available for prevention and management of the increasing iatrogenic harms experienced as side effects of managed care. To begin with, it is helpful for the treating clinician to keep in mind the complex interactions between medical and psychiatric disorders that are often obscured by various managed care influences, such as the lack of time to take a careful history that is objective and empathic. Although psychiatric consultation or referral is helpful in cases that present special difficulties, it is now less accessible than ever given the restrictions of managed health care.7

Thus, diagnostically, it is now more important than ever for treating physicians to be aware of psychiatric comorbidity within both acute and chronic physical illness. Patient suffering accompanying physical illness can present as depression, “sick role” adaptation, chronic pain, exacerbation of substance abuse or dependence, obsessive or dissociative reactions, and conversion reactions. In a person who has had a life-threatening illness, such suffering can sometimes rise to the level of disorders in the posttraumatic stress disorder (PTSD) spectrum.23

The flip side of the tendency to overlook psychiatric disorders exacerbated by managed care is the tendency to use psychiatric disorders as convenient labels to rationalize the denial of medical care and to neglect the existential dimensions of the patient’s suffering. Thus, it is important not to write off patients in panic as simply hypochondriacal because of time pressure associated with managed care. If a person presents with symptoms similar to those that marked a previous life-threatening illness, the physician first rules out a recurrence of that illness. When there has been a recurrence, any posttraumatic sequelae need to be attended to, even in the face of managed care constraints. These sequelae may include symptoms of depression, demoralization, dissociation, flashbacks (eg, “Oh my God, it is happening again!”), and an increased risk of panic and suicide. It is helpful for physicians to keep in mind that a patient who suffers from PTSD (or other emotional vulnerabilities) is especially susceptible to an exacerbation or recurrence of symptoms.

Even if a recurrence of the illness has been ruled out, the illness may have left a vulnerability in that the emotional memory of its painful and frightening initial presentation may be reactivated simply by the recurrence of general symptoms. There is the possibility of life-threatening complications for the patient, such as depression, panic disorder, and suicide or “suicide equivalents.” The latter may include self-medication of panic by excessive drinking or medication overdoses, or counterphobic risk-taking such as driving under the influence of alcohol. With the threat of illness recurrence, the feeling of being alone and the lack of choice in the managed care situation can increase the likelihood of such self-destructive reactions. The patient’s anxiety may also be amplified by acute somatic symptoms associated with vulnerable body image areas.24

Even when practicing in a time- and resource-restricted environment, with access to psychiatric consultation severely limited for patient and physician alike, treating physicians can be alert to make emotional contact with patients. Physicians can create provisional alliances even when they do not have the usual time and ongoing involvement required for sustained alliance building or for providing psychotherapy per se.25 In creating such alliances, it is important to convey certain understandings and attitudes, as delineated here, in whatever wording comes naturally to the individual physician.


Remedies for Each Phase of an Evolving Relationship

In the introductory phase of the relationship, the physician can make contact with the patient while observing the patient for indications of a potential (or hidden) but deep sense of helplessness and hopelessness which accompanies the experience of captivity.13 At the same time, it is helpful to initiate a meaningful dialogue as a first step toward creating a therapeutic alliance and detoxifying feelings of aloneness and abandonment. This step can include engaging in an informed-consent process (not merely a pro forma litany of risks and benefits).4,14 Such a process needs to address clinical and economic risks and potential ethical and role conflicts that might be engendered when a clinician is a dual agent (eg, both a “gatekeeper” and the primary care treating clinician in a capitated system).26 By the same token, the clinician can tactfully but effectively disclose all substantial treatment alternatives, including those not covered by the patient’s health plan.

These disclosures can enable the patient and physician to decide together how to respond to economic restrictions on treatment without the patient being overwhelmed by anxiety and pessimism. Likewise, if it is reasonably foreseeable at the outset that continuity of care will be interrupted by changes in the patient’s insurance coverage, then reminding the patient of how helpful it can be to keep abreast of possible insurance changes will be part of the economic informed-consent process. In our experience, patients can sometimes influence employers’ choice of insurance providers and managed healthcare packages. Subsequently, if a change in coverage is threatened, the physician can support the patient by actively inquiring about how any prospective benefit changes might affect continuity of care.

Given the distrust of physicians engendered by managed care policies,27,28 it is important to sensitively inform the patient of economic considerations such as provider profiling, managed care guidelines, and capitation contracts that may affect the quality of care that the patient receives. Openly acknowledging such dilemmas can enhance the possibilities for a therapeutic alliance. To provide for continuity in sharing uncertainty, it is helpful to articulate questions left open to be addressed in future visits, and to anticipate which questions may arise before the next visit. Such open communication is vital despite the fact that the “gag clauses”29 eliminated as explicit provisions in physician contracts with MCOs may still be implicitly enforced through healthcare provider profiling, economic deselection, and other often hidden rules and procedures.

In the ongoing care phase, the physician can implement treatment with as much continuity and mutual planning as possible while continuing to respond to managed care treatment restrictions in light of the patient’s evolving attitudes and preferences and changing clinical status. Treatment can proceed in a manner that respects the patient’s best interests, including autonomy interests, without being overwhelmed by considerations such as how this will affect the physician’s profile. The physician who needs or wants to apply practice guidelines, as noted above, is also faced with translating what any diagnostic or therapeutic option actually means for this particular patient given the patient’s life history and individual values.

In the event of a denial of benefits, every effort must be made to continue the relationship and avoid abandonment. While the denial of some benefits can reduce the quality of other benefits and the clinical care that the patient receives, it need not result in a catastrophic end to the doctor-patient relationship. For example, even when indicated hospitalization is denied, the physician can work with the patient on an appeal and remain available to help the patient consider the life choices that chronic illness periodically poses.

By working throughout the benefit denial and appeal processes to maintain as much patient confidentiality as possible under the circumstances, the physician can avoid feeling pressured into establishing “secret” manipulative agreements with the patient. An example of such an agreement is selecting, for billing purposes, differential diagnoses that increase the likelihood of receiving managed care benefits. Physicians who feel that their only recourse is to “spin”30 or lie for their patients31 are often expressing the underlying helplessness and hopelessness that they themselves feel. Such secrecy and misalliance based on deceiving the MCO can all too readily undermine the trust necessary for the doctor-patient relationship to be open and healing. The patient may ask, “If my doctor is willing to lie for me, might he/she also be willing to lie to me?” Moreover, a relationship built around secrecy and deception rather than confidentiality and open commitment is vulnerable to a sudden, panicked withdrawal by a guilt-ridden physician, culminating in abandonment.

The termination phase is critically important in any clinical relationship in which an emotional bond has been formed. Prior to the patient’s transferring to another care provider, it is helpful to consider what choices the physician and patient have made together, what other choices they might have made, and how managed care pressures may have influenced those decisions. The physician whose contract is terminated by an MCO can inform the patient of the MCO’s action and coordinate the transfer of care while supporting a patient’s choice to take steps to oppose involuntary termination. If involuntary termination is brought about because the patient’s employer has changed its health plan, the physician can attend actively to both the practical and emotional aspects of termination. The physician need not allow his or her own feelings of anger and frustration toward the MCO to become displaced onto the patient, leading to abandonment via failure to inform patients of the foreseeable consequences of “involuntary” abrupt termination. When the process of saying goodbye is properly attended to, even an involuntary termination can be borne without sliding into an abyss of abandonment and paralysis.



We have offered guidelines for prevention and management of observable clinical harms resulting from managed care’s control of choices made by patients and physicians, including anticipated and actual benefit denial and restrictions on care. Medical outcomes are affected not only by the quality of technical care given, but also by the process of care, including patient participation in decision making.32 Denial of choice reduces quality of care in that the patient loses both the psychological benefits of exercising choice and the medical benefits of individualized treatment. Moreover, irrespective of the structure of healthcare delivery, the physician retains a primary duty to advocate for the patient’s interests, including the right to make informed choices based on effective disclosure of treatment options.3 A considered clinical response to managed care constraints can help physicians fulfill this ethical duty to provide effective and compassionate care.

As risk management, attention to the clinical process can also help prevent malpractice liability in the event of a tragic outcome. Both bad medical outcomes, reasonably attributable to MCO-initiated distractions from a clinical focus on the patient’s best interests, and bad feelings arising from managed care restrictions on patient autonomy tend to feed malpractice risk.1 Moreover, attention to the clinical process allows physicians and patients to initiate, proceed with, and terminate relationships appropriately even when each phase of the relationship is subject to substantial external control.

Although clinical intervention is no substitute for instituting fundamental changes in healthcare financing and regulation of third-party control, even today the ethically sensitive primary care physician or psychiatrist practicing in a marketplace dominated by managed care need not feel too overwhelmed to practice effectively on the individual doctor-patient level. By identifying and then preventing or alleviating the negative biopsychosocial side effects of the restriction of available patient choices, a substantial reduction in the clinical complications and liability risks of MCO control and denial of patient choice and care can be achieved.   PP



1.    Bursztajn HJ, Brodsky A. A new resource for managing malpractice risks in managed care. Arch Intern Med. 1996;156:2057-2063.
2.    Bodenheimer T, Lo B, Casalino L. Primary care physicians should be coordinators, not gatekeepers. JAMA. 1999;281:2045-2049.
3.    Council on Ethical and Judicial Affairs, American Medical Association. Ethical issues in managed care. JAMA. 1995;273:330-335.
4.    Bursztajn HJ, Feinbloom RI, Hamm RM, Brodsky A. Medical Choices, Medical Chances: How Patients, Families, and Physicians Can Cope With Uncertainty. New York, NY: Routledge, Chapman, Hall; 1990.
5.    Watson M, Haviland JS, Greer S, Davidson J, Bliss JM. Influence of psychological response on survival in breast cancer: a population-based cohort study. Lancet. 1999;354:1331-1336.
6.    Levinson W, Gorawara-Bhat R, Dueck R, et al. Resolving disagreements in the patient-physician relationship: tools for improving communication in managed care. JAMA. 1999;282:1477-1483.
7.    Nease DE Jr., Volk RJ, Cass AR. Investigation of a severity-based classification of mood and anxiety symptoms in primary care patients. J Am Board Fam Pract. 1999;12(1):21-31.
8.    Horn SD. Overcoming obstacles to effective treatment: use of clinical practice improvement methodology. J Clin Psychiatry. 1997;58(suppl 1):15-19.
9.    Wyshak G, Barsky A. Satisfaction with and effectiveness of medical care in relation to anxiety and depression: patient and physician ratings compared. Gen Hosp Psychiatry. 1995;17:108-114.
10.    Druss B, Schlesinger M, Thomas T, Allen H. Depressive symptoms and plan switching under managed care. Am J Psychiatry. 1999;156:697-701.
11.    Schmittdiel J, Selby JV, Grumbach K, Quesenberry CP Jr. Choice of a personal physician and patient satisfaction in a health maintenance organization. JAMA. 1997;278:1596-1599.
12.    Pollock GH. Abandonment. In: Rothstein A, ed. The Reconstruction of Trauma: Its Significance in Clinical Work. Madison, Conn: International Universities Press; 1986:105-120.
13.    Bursztajn HJ, Brodsky A. Captive patients, captive doctors: clinical dilemmas and interventions in caring for patients in managed health care. Gen Hosp Psychiatry. 1999;21:239-248.
14.    Gutheil TG, Bursztajn HJ, Brodsky A. Malpractice prevention through the sharing of uncertainty: informed consent and the therapeutic alliance. N Engl J Med. 1984;311:49-51.
15.    Siegler M. Pascal’s wager and the hanging of crepe. N Engl J Med. 1975;293:853-857.
16.    Curtis JR, Rubenfeld GD. Aggressive medical care at the end of life: does capitated reimbursement encourage the right care for the wrong reason? JAMA. 1997;278:1025-1026.
17.    Bursztajn HJ, Brodsky A. Authenticity and autonomy in the managed-care era: forensic psychiatric perspectives. J Clin Ethics. 1994;5:237-242.
18.    Rosenbaum S, Frankford DM, Moore B, Borzi P. Who should determine when health care is medically necessary? N Engl J Med. 1999;340:229-232.
19.    Emanuel EJ, Emanuel LL. Four models of
the physician-patient relationship. JAMA. 1992;267:2221-2226.
20.    Tucker JB. Modification of attitudes to influence survival from breast cancer. Lancet. 1999;354:1320.
21.    Bursztajn HJ, Gutheil TG, Brodsky A. Ethics and the triage model in managed care hospital psychiatry. Psychiatr Times. 1998;15(9):33-40.
22.    Simon G, Ormel J, VonKorff M, Barlow W. Health care costs associated with depressive and anxiety disorders in primary care. Am J Psychiatry. 1995;152:352-357.
23.    Green BL, Epstein SA, Krupnick JL, Rowland JH. Trauma and medical illness: assessing trauma-related disorders in medical settings. In: Wilson JP, Keane TM, eds. Assessing Psychological Trauma and PTSD. New York, NY: Guilford Press; 1997:160-191.
24.    Meissner WW. The self and the body. I. The body self and the body image. Psychoanalysis and Contemporary Thought. 1997;20:419-448.
25.    Meissner WW. The Therapeutic Alliance. New Haven, CT: Yale University Press; 1996.
26.    Miller TE, Sage WM. Disclosing physician financial incentives. JAMA. 1999;281:1424-1430.
27.    Hillman AL. Mediators of patient trust. JAMA. 1998;280:1703-1704.
28.    Grumbach K, Selby JV, Damberg C, et al. Resolving the gatekeeper conundrum: what patients value in primary care and referrals to specialists. JAMA. 1999;282:261-266.
29.    Brody H, Bonham VL Jr. Gag rules and trade secrets in managed care contracts. Arch Intern Med. 1997;157:2037-2043.
30.    Illingworth PML. Bluffing, puffing and spinning in managed care. J Med Philosophy. 2000;25(1):62-76.
31.    Freeman VG, Rathore SS, Weinfurt KP, Schulman KA, Sulmasy DP. Lying for patients: physician deception of third-party payers. Arch Intern Med. 1999;159:2263-2270.
32.    Safran DG, Taira DA, Rogers WH, Kosinski M, Ware JE, Tarlov AR. Linking primary care performance to outcomes of care. J Fam Pract. 1998;47:213-220.



Ms. Schulz is psychiatry research project assistant, Dr. Gotto is director of consult/liaison services, and Dr. Rapaport is chairman in the Department of Psychiatry at Cedars-Sinai Medical Center in Los Angeles, CA. Dr. Rapaport is also vice chairman of the Department of Psychiatry and Behavioral Health at the David Geffen School of Medicine at the University of California—Los Angeles.

Disclosure: Ms. Schulz and Dr. Gotto report no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Rapaport is a consultant to Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Janssen, the National Institute of Mental Health (NIMH), the National Institute on Drug Abuse, Neurocrine Biosciences, Novartis, Pfizer, Roche, Sanofi-Synthelabo, Solvay, Sumitomo, and Wyeth; is on the speaker’s bureaus of Cyberonic, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Novartis, and Pfizer; has received grant support from Abbott, AstraZeneca, Corcept, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Janssen, the National Center for Complementary and Alternative Medicine, the NIMH, Novartis, Pfizer, Pharmacia Upjohn, Sanofi-Synthelabo, Solvay, the Stanley Foundation, UCB Pharma, and Wyeth; and owns stock in Forest.

Please direct all correspondence to: Julie Schulz, BA, Department of Psychiatry, Cedars-Sinai Medical Center, 8730 Alden Drive, Los Angeles, CA 90048. Tel: 323-449-1753; E-mail: runju32122@aol.com.



Generalized anxiety disorder (GAD) is characterized by excessive anxiety and worry occurring over the course of ≥6 months. GAD has a 5.7% lifetime prevalence in the general adult population, and an 8% lifetime prevalance in the primary care setting. GAD is associated with twice the amount of primary care visits compared with patients without GAD, which leads to significant healthcare costs. This is largely because GAD commonly manifests with musculoskeletal, gastrointestinal, and cardiovascular physical symptoms. The course of GAD is chronic and disabling, with a low rate of spontaneous remission. Two thirds of patients with GAD have a secondary comorbid psychiatric diagnosis, with major depressive disorder being the most frequently occurring. Aggressive treatment is necessary to maximize resolution of symptoms. Fortunately, a variety of effective pharmacotherapies and psychotherapies exist for the acute treatment of GAD. Preliminary work suggests that these benefits are maintained with time and that continued pharmacotherapy may prevent the reoccurrence of GAD.  



Anxiety disorders are the most common form of mental disorders in the United States.1 However, they are often missed because anxious patients typically approach primary care physicians (PCPs) with somatic complaints that obscure the underlying psychiatric diagnosis.2 Patients with generalized anxiety disorder (GAD) are more likely to complain of somatic symptoms than psychological symptoms. As a result, physicians often order costly diagnostic tests, unnecessary treatment trials, and referral for specialty evaluation.

GAD is characterized by excessive anxiety and worry occurring over the course of ≥6 months. Symptoms include restlessness, difficulty concentrating, irritability, muscle tension, sleep disturbance, and fatigue. Patients with GAD worry about physical illness, social and professional performance, interpersonal relations, personal safety, and the safety of people that are close to them. Somatic complaints of GAD patients typically fall into three categories: musculoskeletal, cardiovascular, or gastrointestinal.3 For example, a patient with GAD might complain of tachycardia, chest pain, diarrhea, and fatigue. The disorder is chronic, with periodic exacerbation, and causes significant distress and impairment.4 The spontaneous remission rate, or the rate at which patients recover from the disorder without treatment, is approximately 20% to 25%.5 This compares with a spontaneous remission rate of 32% for patients with major depressive disorder (MDD).6

Untreated GAD causes functional impairment similar to the disability seen in diabetes or congestive heart failure.7 In addition, people experiencing severe anxiety are at risk for suicidal ideation. According to the National Comorbidity Survey Replication (NCS-R), the adjusted odds ratio for lifetime suicidal ideation is .87 (.57-1.32, 95% CI), and the adjusted odds ratio for lifetime suicide attempts is 1.50 (.98-2.30, 95% CI).8 This article reviews the epidemiology, etiology, clinical presentation, diagnosis, clinical course, healthcare costs, and treatment of GAD, with an emphasis on its biological causes and treatment methods.



The Epidemiological Catchment Area study reported that the lifetime prevalence of GAD (according to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition [DSM-III]9) ranges from 4.1% to 6.6%.10 According to the NCS-R, which used DSM-IV11 criteria, GAD has a lifetime prevalence of 5.7% in the US adult population.2  While the age of onset of GAD peaks during the second and third decades,12 first onset of the disorder can occur at any age. Ten percent of GAD patients experience onset of the disorder at <13 years of age, and 10% experience onset of GAD at >51 years of age.12 The 12-month prevalence rates of GAD range from 0.5% to 1.5%.13,14 Women are at twice the risk of developing GAD as men.2

Recognition and treatment of GAD are especially important in the primary care setting since GAD is common and is associated with significant use of medical resources. In one study performed in a primary care setting, GAD was diagnosed in 8.0% of patients.15 In a second study performed in a primary care setting, 3.7% of adult patients met criteria for current GAD and 6.6% presented with subthreshold anxiety symptoms.16 In a third study, 5.3% of the patients seen in primary care met criteria for current GAD.17 Thus, the point prevalence rate for GAD is 3.7% to 8.0% for patients screened in primary care settings.



Only one third of people with a current diagnosis of GAD have no other comorbid psychiatric diagnosis.2,18 In fact, Noyes19 suggests that the rates of comorbid psychiatric disorders might be greatest for patients with GAD. MDD (11% to 47%) is the most common comorbid disorder.19 The National Comorbidity Survey data suggest that preexisting anxiety disorder is a risk factor for depression, and anxiety precedes the onset of depression by about 10 years.2 Social anxiety disorder (17% to 59%), specific phobia (15% to 56%), and panic disorder (11% to 27%) are the most prevalent secondary anxiety disorders diagnosed in patients with GAD.20-25  

Personality disorders are thought to coexist in approximately 60% of patients with GAD.26,27 The most common personality disorders diagnosed in patients with GAD are obsessive-compulsive personality disorder (33.5%), paranoid personality disorder (30.5%), and avoidant personality disorder (21.9%).27

The presence of psychiatric comorbidity increases the severity of GAD and complicates the treatment course for these patients.28 However, the presence of psychiatric comorbidity also increases the likelihood that patients will seek psychiatric care.29


Evolution of the Generalized Anxiety Disorder Diagnosis

The DSM-IV definition of GAD has evolved over the last 125 years. Prior to the DSM-III, the concept of anxiety was amorphous, lumping Freud’s “neurosis” together with phobias and panic attacks.30 The DSM-III-defined generalized anxiety as “uncontrollable anxiety of worry that is not due to a particular life problem,” has a duration of 1 month, cannot be diagnosed in the presence of another mental disorder, and requires the presence of autonomic symptoms. Changes in the DSM-III-R31 definition of GAD required lengthening the duration of symptoms (1 month was changed to 6 months), the presence of six physical symptoms, and the caveat that the anxiety could not be due to another anxiety disorder. In the DSM-III-R, GAD can be diagnosed in the presence of another mental disorder. The DSM-IV criteria require that only three of six physical symptoms be present, and these symptoms must be equally psychologic and somatic (Table 1).


Clinical Presentation

Core features of GAD include excessive anxiety or worry occurring more days than not, over a period of 6 months. These worries may be associated with several events or activities, including job responsibilities, finances, health of friends and family members, safety of children, household chores, car repairs, or tardiness. Patients experience impairment in social, occupational, or other important areas of functioning related to the worries. Individuals with GAD find it difficult to control such worry. The frequency, intensity, and duration of anxiety are out of proportion to the likelihood or impact of a feared event.

A list of common somatic symptoms associated with GAD is presented in Table 2. Patients with anxiety often seek initial treatment from their PCP. However, GAD is frequently not recognized in the primary care setting. In a recent study, PCPs recognized and diagnosed pure GAD in only 34% of patients with the disorder.32

Individual and cultural characteristics may influence the presentation of GAD. Some patients complain primarily of cognitive symptoms such as confusion, perceptual distortion, difficulty concentrating, and indecisiveness. Other patients may express anxiety predominantly through somatic symptoms. While it is accepted that the initial clinical presentation of anxious symptoms may range from cognitive to somatic complaints, the full effect of cultural and personality factors on both the presentation and treatment course of anxiety are not well understood. A review of the subject of cultural effect on anxiety disorders showed that in general, opinions on this topic are mixed.12,33 Cultural attitudes toward mental health, language nuances, and socioeconomic factors all have the potential of affecting a person’s experience of anxiety. This experience may affect the way in which a particular patient presents his or her ailments to the physician. There is a paucity of research on the cultural differences in the presentation of GAD, and this topic merits further study.

Although it is sometimes challenging to differentiate normal concern from pathological anxiety, a key finding about anxiety disorders is that the intensity and distress associated with the worry  far exceed any stimulus. A person with GAD is a “worry wart” with widespread, intense, and persistent anxiety that occurs without an identifiable trigger. Individuals with GAD palpably feel their anxiety, are disabled by it, and have diminished quality of life.


Clinical Course

While the median age of onset of GAD is 31 years, 10% of GAD patients first experience the disorder at <13 years of age, and 10% experience it after 58 years of age.12 Early-onset patients are more likely to develop GAD without precipitating events, and are more likely to have been exposed to domestic disturbances in childhood. These patients report heightened anxiety during childhood, childhood fears and obsessional traits, sensitivity to interpersonal relationships, and social inhibition and maladjustment.33 In contrast, late-onset GAD is associated with a precipitating adverse life experience.33 The development of a full-blown anxiety disorder often occurs when an already anxious person is subjected to great life stress, such as losing a job or taking on a second mortgage.

The severity of symptoms of GAD and impairment may fluctuate considerably over an individual’s lifetime. The symptoms are often more severe when exogenous stressors are present. In women, symptoms may be exacerbated premenstrually. It is clear that for the majority of patients, extended periods of remission are unlikely without vigorous treatment.

GAD has a chronic course. Treatment should be continued on a long-term basis in order to maximize resolution of symptoms, remediate functional disability, and increase the intervals between episodes of illness.34 The longer term spontaneous remission rate is low for GAD, with a .38 probability of remission at 5 years.35 The 12-year follow-up results from the Nottingham Study found that 59% of the patients originally diagnosed with GAD (using DSM-III criteria) were symptomatic at follow-up.36 Of the patients originally diagnosed with GAD, the most common diagnoses after 12 years were dysthymic disorder (18%) and major depressive episode (10%). Only 3% had a diagnosis of GAD. Thus, people with GAD are at significant risk for developing depressive disorders.  The Harvard-Brown Anxiety Research Program found that 60% of subjects identified with an index episode of GAD had active GAD at 2-year follow-up. At 5-year follow-up, 66% of index cohort was classified as having either GAD or GAD in partial remission.37


Disability and Healthcare Utilization

Patients with GAD have twice the rate of primary care visits compared to primary care patients without GAD.32 Patients with comorbid GAD and other Axis I disorders have greater rates of hospitalization, greater utilization of diagnostic and laboratory tests, higher pharmacy costs, and more absenteeism from work than patients with GAD without any psychiatric comorbidity.38 In fact, comorbid GAD is commonly associated with a number of physical disorders, such as irritable bowel syndrome. The prevalence of comorbid GAD ranges from 13% to 25% in patients with irritable bowel syndrome.39,40

Biological Etiology

Relatively few studies have addressed the biological aspects of GAD. The development of a sound biological basis for GAD, distinct from other anxiety or mood disorders, has been complicated by three major factors. First, while there are animal models available for stress and anxiety, there is no true animal model specific for GAD. Second, the pharmacologic probes available for investigating the neurobiology of GAD are relatively insensitive to their targets. Finally, the lack of a consistent definition for GAD makes it difficult to compile studies using the same criteria. Many studies investigating the biology of GAD use DSM-III or DSM-III-R criteria for diagnosis.

A significant portion of the biological research investigating GAD is based on the success of pharmacologic treatments. Since these interventions tend to be effective across most of the anxiety disorders, it is challenging to identify neurotransmitter abnormalities that may be specific to GAD. In fact, many clinical studies now address behavioral or symptomatic phenomena that cut across several diagnoses, rather than focusing on a single disorder.


Molecular Biology

It is generally accepted that dynamic interactions among several different neurotransmitter systems are likely to underlie different anxiety states. Evidence from animal and human studies suggests that alteration of function of the γ-aminobutyric acid (GABA) neuronal system plays a significant role in the pathophysiology of GAD. Benzodiazepine receptors (BDZ-Rs) and GABAA receptors are part of the same macromolecular complex. Animal studies suggest that GABAA receptor dysfunction plays a role in the development of GAD.41 In addition, clinical studies have shown that benzodiazepines are effective in treating patients with GAD.42 Patients with GAD have been shown to have low levels of peripheral benzodiazepine receptors (pBR) and low levels of pBR messenger ribonucleic acid in lymphocytes.43 These levels increased to normal after 2 months of treatment with a diazepam-related compound, and remained normal up to 1 month after discontinuing treatment. In this study, the level of pBR was also correlated with the amount of clinical improvement. These results suggest that the lower expression of pBR is a state-related biological abnormality in patients with GAD that can be remediated with appropriate treatment. However, the mechanism by which the levels of pBRs are normalized is still unknown and one must always be careful when extrapolating from studies of the pBRs to the function of the central BDZ-Rs.

Medications that affect serotonin and norepinephrine, neurotransmitters  thought to be central to the pathophysiology of GAD, prove efficacious. However, research investigating these neurotransmitters is inconsistent. One study found elevated plasma levels of norepinephrine and decreased α2-adrenergic function in GAD patients.44 The authors of that study concluded from these findings that norepinephrine activity is elevated in GAD, causing receptor downregulation. Other studies were unable to replicate these findings.45,46 The one investigation exploring the metabolic pathways of catecholamines failed to find a difference between GAD subjects and normal controls,47 and studies have failed to consistently demonstrate that plasma catecholamine levels of GAD subjects are higher than normal comparison subjects.45,46 Furthermore, research investigating catecholamine receptors in GAD patients are mixed and inconclusive.48-50 In summary, there is little evidence suggesting abnormalities in the catecholamine system for patients with GAD.

Studies investigating the role of serotonin in GAD are also inconclusive. Both overactivity or underactivity of the serotonergic system has been hypothesized to be involved in the pathogenesis of GAD.51,52 Some of the strongest biological evidence linking the serotonin system and GAD have been studies with the serotonin receptor agonists buspirone, ipsapirone, and gepirone. These agents decrease the firing rate of serotonergic neurons and exert anxiolytic effects in patients with GAD.53

The hypothalamic-pituitary-adrenal  axis has been implicated in other anxiety disorders and may play a role in GAD. Cortisol, the primary hormone implicated in stress, has been shown to be elevated in GAD patients.54 In normal subjects, exogenous cortisol induces an increase in the serotonin transporter gene transcription.55 However, the incubation of peripheral lymphocytes from GAD patients with cortisol failed to increase serotonin transporter gene product.55 Corticotropin-releasing factor (CRH) is associated with heightened states of anxiety in animal models. However, there is no conclusive association between CRH dysfunction and GAD.56-58



Genetic studies suggest a moderate degree of heritability for GAD. The prevalence rate for GAD is 20%59 to 22%60 for individuals who have a first-degree relative with GAD, as compared to a 4% prevalence rate in the control sample.59 Twin studies demonstrate that 21% of monozygotic twins are concordant for GAD, versus 13% of dizygotic twins.61 Candidate genes for further study include those influencing norepinephrine and serotonin neurotransmission as well as GABA and CRH. Of particular interest is the serotonin transporter gene located on chromosome 17q. One study reported that polymorphism in the second intron of this gene occurs at significantly higher rates in individuals with GAD.62


Treatment Options in Generalized Anxiety Disorder

There are evidence-based pharmacologic and psychologic treatment options for GAD (Table 3). Ideally, the physician and patient should work together to define the problem and the treatment plan. It helps to get the patient’s dedication to the treatment plan, and for the patient to understand that improvement may take months or even years. The patient should be aware that the course of GAD waxes and wanes, and that complete remission is unlikely. Treatment should be individualized for each patient, with the patient’s symptom profile and ability to tolerate side effects as the primary considerations. Other treatment factors may include history of previous treatment and response, presence of comorbid depression or other anxiety disorders, presence of Axis II disorder, presence of comorbid medical condition, and history of substance abuse. There are no clear evidence-based guidelines for determining the length of time a patient should receive a particular treatment. A review of eight long-term GAD treatment studies was inconclusive, and no drug was identified as a reference for long-term treatment.63 It is generally recommended that treatment continue for 1 year after the patient responds to it before considering cessation.64


Pharmacologic Therapies


Benzodiazepines are a well-studied class of medications with proven efficacy in the treatment of GAD.65 Approximately 75% of patients have either a marked (35%) or moderate (40%) response to treatment.66 Anxious symptoms respond to benzodiazepines rapidly, with the most dramatic improvement occurring in hypervigilance and somatic symptoms, such as muscle tension, restlessness, and insomnia. Psychological symptoms, such as worrying and fretting, are not as responsive to benzodiazepine medication, and may require additional treatment with cognitive-behavioral therapy (CBT) or another specific modality.

Mechanism of Action

Benzodiazepines exert their effect at BDZ-Rs, which are located throughout the brain in the cerebellum, limbic system, and cerebral cortex. The BDZ-R is structurally linked with the GABA receptor. When GABA is present at the GABA receptor, chloride ions pass through a channel into the neuron, which hyperpolarizes the cell membrane. This results in decreased firing, which “quiets” the cell. A benzodiazepine, when present at the BDZ-R, potentates the GABA-induced opening of the chloride channels. GABA must be present at the GABA receptor in order for benzodiazepines to work. This explains why an overdose on a benzodiazepine alone is usually not fatal; the body has a finite supply of GABA. However, if a benzodiazepine overdose is combined with a substance that opens chloride channels without needing to bind to a receptor (such as alcohol or phenobarbital), then a benzodiazepine overdose can result in central nervous system depression and death.

The main differences between benzodiazepines are their half-life and potency. Half-life is important when considering dosing; a medication with a short half-life, such as alprazolam, may require multiple daily dosing, whereas clonazepam, with a half-life of 34 hours, may be given QD or BID. Benzodiazepines with shorter half-lives are more likely to be associated with “clock watching.” This occurs when an anxious patient notices the anxiolytic effect of medication is wearing off, and watches the clock, counting the minutes until the next dose. Shorter-acting benzodiazepines are also associated with interdose rebound anxiety, greater potential for abuse, and greater risk of withdrawal syndromes.    

Absorption and the onset of action are most rapid for diazepam, lorazepam, alprazolam, triazolam, and estazolam.  The rapid-onset medications are useful in patients who use benzodiazepines on an as-needed basis for a burst of anxiety or for falling asleep.

The 2-keto benzodiazepines (Table 4) have half lives of 30–120 hours. This occurs because they are all metabolized to desmethyldiazepam, which is pharmacologically active and takes a long time to break down to oxazepam and then to a form that can undergo glucuronidation.67

The half-lives of the 3-hydroxy benzodiazepines are much shorter, at 10–30 hours. This is because they are directly metabolized by glucuronidation and have no active metabolites.  Alprazolam and triazolam are triazolobenzodiazepines that are hydroxylated prior to undergoing glucuronidation.  

Benzodiazepines are generally well tolerated. Side effects such as somnolence, fatigue, reduced concentration, and slowed psychomotor function may occur early in treatment, and can be handled either by dose reduction or changing the time the medication is taken. Patients usually develop tolerance to the sedating side effect of benzodiazepines after 7–10 days of treatment. Although patients become tolerant to the side effects of benzodiazepines, they do not develop tolerance to the anxiolytic effect of the medication.68 It is unclear how long therapy with a benzodiazepine should continue. Recent recommendations suggest a treatment trial of 6 weeks using the lowest possible effective dose, and then making an attempt to taper the medication dose. The reason for the 6-week time frame is that approximately 50% of patients do not relapse after 6 weeks of treatment with benzodiazepines.69 Given this, the clinician should instigate an initial taper after 6 weeks to see if the patient is one of the 50% of patients who tolerate early benzodiazepine discontinuation. If the patient does not tolerate the taper and experiences a relapse, then treatment resumes for a longer period of time. A second attempt at benzodiazepine discontinuation with a slower taper may be tried. If the patient still experiences relapse, that patient may require longer-term therapy, or the addition of antidepressant medication or CBT.

Even though the majority of patients do not escalate their dose or abuse their medication,70 the long-term use of benzodiazepines for anxiety remains controversial. There are several reasons for this. Physicians are concerned about the long-term side effects and the abuse potential of benzodiazepines. In reality, patients with anxiety typically are wary of becoming dependent on medication. The tolerance that occurs with chronic benzodiazepine use may be confused with the idea of drug dependence, and this may be unsettling for GAD patients. If a patient treated with twice daily alprazolam is admitted to the hospital for a medical illness, this patient is at great risk for rebound anxiety and even benzodiazepine withdrawal unless the admitting physician is aware of the patient’s anxiety disorder and specific treatment. Even then, a well-intentioned physician might schedule the alprazolam as needed when the patient has been using it regularly, thus setting the anxious patient up for potential demise. The withdrawal that occurs with the shorter-acting benzodiazepines can occur remarkably fast, as the patient’s mental state may move from anxious to agitated to psychotic to delirious within 48–72 hours of the last missed dose.

The benzodiazepines that undergo rapid metabolism and have no active metabolites (lorazepam, oxazepam) are safer choices when using benzodiazepines in the elderly or in patients with liver or respiratory disease. The elderly are at risk for confusion, falls, and becoming paradoxically agitated when exposed to benzodiazepines, so these medications should be used judiciously in these patients. Benzodiazepines should be used with caution in any medically ill patient, though they are quite useful in treating anxiety associated with procedures or anxiety due to certain medications.  



Tricyclic Antidepressants and Monoamine Oxidase Inihibitors

Over 2 decades of data demonstrate that antidepressants are effective in the treatment of GAD. Since anxiety and depression commonly coexist, this makes antidepressant pharmacology an efficient option for treating both problems. Most of the studies using tricyclic antidepressants (TCAs) in anxiety are older, and the criteria used for GAD are less strict than in the more recent DSM-IV-based studies, so it is possible that patients included in the earlier studies may have had disorders other than GAD. In any case, the TCAs are at least as effective as benzodiazepines in the short-term management of anxiety,71 and are more effective in reducing the psychic symptoms of anxiety.72

TCAs work by inhibiting the reuptake of norepinephrine (NE) and serotonin (5-HT), thereby increasing the available amount of both neurotransmitters in the synaptic cleft. The TCAs differ in their abilities to inhibit NE and 5-HT.  For example, clomipramine is considered to be a “serotonergic” tricyclic. The tricyclics, like the selective serotonin reuptake inhibitors (SSRIs), are useful in treating the patient with mixed anxiety and mood disorder, where anxiety and mood pathology coexist.

The clinical utility of the TCAs is limited by their side-effect and safety profile. The typical TCA side effects, which include dry mouth, constipation, blurred vision, passing out, or gaining weight, may be more than anxious patients want to tolerate. This class of agents has anticholinergic, antiadrenergic, and antihistaminic side effects.  The monoamine oxidase inhibitors (MAOIs), are used in the treatment of atypical depression, panic disorder, and as an alternative therapy in treatment-resistant depression. MAOIs are known to reduce anxiety when used in the treatment of depression. They work by irreversibly inhibiting monoamine oxidase, the enzyme that breaks down NE, dopamine, and 5-HT. MAOIs are infrequently prescribed. In a 1999 survey of prescribing practices, Balon and colleagues73 found that although 92% of respondents believed MAOIs are useful for atypical depression, only 2% said they would use them as a first-line treatment. MAOIs have fallen out of favor due to side effects and dietary restrictions. Moclobemide, a reversible MAOI, is an effective treatment for depression and does not carry the risk for tyramine reaction. However, it is not available in the US.


Selective Serotonin Reuptake Inhibitors

There is great deal of placebo-controlled evidence supporting the efficacy of SSRIs as a treatment for GAD. Clomipramine was the first TCA “serotonergic” agent studied for the treatment of GAD; the study was an 8-week open trial where 10 subjects were treated with doses ranging from 50–250 mg/day.74 Five subjects dropped out because of the clomipramine side effects. The remaining five subjects had a good response to the medication.  

The first controlled study of an SSRI compared the outcomes of 81 patients with DSM-IV-based GAD treated with paroxetine 20 mg/day, imipramine 75 mg/day, or 2-chlordesmethyldiazepam 4.2 mg/day.75 Two thirds of patients in all three treatment groups improved moderately or markedly (imipramine, 67%; paroxetine, 68%; 2-chlordesmethyldiazepam, 60%). In a multi-center, double-blind, placebo-controlled trial, 566 patients with DSM-IV-diagnosed GAD were treated with paroxetine 20 mg/day, paroxetine 40/day, or placebo. Paroxetine 40 mg alleviated symptoms better than paroxetine 20 mg, and both were superior to placebo.76 In another placebo-controlled study of 324 outpatients with DSM-IV-diagnosed GAD, a flexible dose of paroxetine (20–50 mg/day) was compared to placebo. The patients treated with paroxetine experienced improvement of core symptoms of GAD as early as 4 weeks, and a reduction in disability compared to patients treated with placebo.77

One double-blind, placebo-controlled study of citalopram 20–30 mg/day in 34 older (≥60 years of age) outpatients with mostly DSM-IV-diagnosed GAD found that 65% of patients responded by 8 weeks of treatment with citalopram versus 24% of patients treated with placebo. The most common side effect experienced by the treatment group was sedation.78 A study of escitalopram, the s-enantiomer of citalopram, compared 8 weeks of treatment with escitalopram 10–20 mg/day to placebo in 315 patients with GAD. Sixty-eight percent of escitalopram-treated subjects responded, compared to 41% of patients treated with placebo.79 There was one double-blind, prospective trial comparing 8 weeks of paroxetine to sertraline in the treatment of 55 patients with GAD.80 This comparison found that both SSRIs equally reduced Hamilton Rating Scale for Anxiety (HAM-A) scores (paroxetine 57%±28%, and sertraline 56%±28%) and were similarly well-tolerated.


Mechanism of Action   

SSRIs work by inhibiting the reuptake of serotonin so that more serotonin is available in the synaptic cleft. It is unclear exactly how this increase affects changes in anxiety and mood. The SSRI antidepressants are better tolerated than the TCAs, and are safer in overdose situations. Anorgasmia is a significant side effect of SSRI therapy, and occurs in both genders. There are several possibilities for dealing with this problem. Dose reduction may help in some cases. Adding a small dose of trazodone, bupropion, or buspirone may be helpful in others. Some patients respond to sildenafil therapy, as needed. If none of these interventions work, the patient and physician should weigh the benefit of treating the anxiety with the current SSRI versus adequate sexual functioning. Sometimes switching to a different SSRI medication may improve symptoms. CBT is an option for patients who decide to taper off SSRI medication.  

Other side effects of SSRI therapy include initiation activation, restlessness, nausea, and diarrhea. Starting patients on a very low dose of SSRI and increasing the dose slowly averts initiation activation. Alternatively, starting a benzodiazepine simultaneously with the SSRI may also prevent initiation anxiety. The benzodiazepine can be tapered and discontinued once the SSRI dose is within a therapeutic range.


Serotonergic Noradrenergic Reuptake Inhibitors

Venlafaxine, a serotonergic noradrenergic reuptake inhibitor, is the best studied antidepressant medication used in the treatment of GAD. In a series of placebo-controlled, randomized, short-term treatment trials comparing venlafaxine extended release (XR) to placebo, venlafaxine was consistently superior to placebo in improving both somatic and psychic symptoms of anxiety. In one study that compared venlafaxine XR 75 mg and 150 mg, buspirone 30 mg, and placebo, both venlafaxine doses improved anxious mood and tension indices by week 8, and both venlafaxine doses were better than placebo and more effective than buspirone after week 1.81 Another 8-week, randomized, placebo-controlled study evaluated fixed doses of 75 mg, 150 mg, or 225 mg venlafaxine XR against placebo and found that venlafaxine was consistently superior to placebo on all of the primary outcome measures. The most robust improvements were seen with the higher doses.82 An 8-week, double-blind, placebo-controlled study of Greek outpatients with GAD compared flexible dosing of venlafaxine XR (75–150 mg) with placebo, and found that the 62.5% of venlafaxine-treated patients achieved remission versus 9.1% in the placebo group. Remission was defined as a HAM-A score ≤7.83

The long-term studies of venlafaxine validate the clinical lore that the improvements gained in the acute treatment phase can be maintained and even enhanced over a longer period of time. The first long-term study evaluated flexible dosing of venlafaxine XR over 6 months. In this study, 251 patients were assigned to receive either venlafaxine XR at doses between 75 mg/day and 225 mg/day to control symptoms, or placebo. Venlafaxine XR was superior to placebo with a response rate of 69% from week 6 through week 28, versus placebo response rates of 42% to 46%.84 Another 6-month, fixed-dose trial comparing venlafaxine XR 37.5 mg/day, 75 mg/day, or 150 mg/day with placebo found that in the short term (8 weeks), both the 75-mg and 150-mg dose groups showed significant differences from placebo on all of the primary outcome measures. The outcome measures included the HAM-A total score, the HAM-A psychic anxiety factor, the Hospital Anxiety and Depression (HAD) anxiety subscale and the Clinical Global Impressions (CGI) Improvement rating. At 8 weeks, the 37.5-mg dose was only significantly better than placebo on the HAD anxiety subscale.  After 24 weeks of treatment, the greater efficacy for the higher venlafaxine doses was preserved over both placebo and the 37.5-mg dose. The higher doses also demonstrated improved social functioning by the Social Adjustment Rating Scale compared to placebo.85

Like the TCAs, venlafaxine works by inhibiting the reuptake of serotonin and norepinephrine. It lacks the anticholinergic, antiadrenergic, and antihistaminic effects of the TCAs, and is consequently better tolerated. Somnolence, nausea, and dry mouth are the side effects most commonly reported. Anorgasmia may also occur as a side effect of venlafaxine treatment. Venlafaxine needs to be tapered when discontinued.     


Other Antidepressants


Little evidence supports the role of trazodone for the treatment of GAD. One 8-week, randomized, placebo-controlled trial comparing imipramine, trazodone, and diazepam in 230 patients with a DSM-III diagnosis of GAD, found trazodone to be more effective than placebo. In this study, diazepam was initially the most effective, especially against somatic symptoms, but by the end of the 8 weeks a moderate-to-marked improvement was reported by 73% of imipramine-treated patients, 69% of trazodone-treated patients, 66% of diazepam-treated patients, and 47% of the placebo group. Both the imipramine and trazodone groups had a better response on measures of tension, apprehension, and worry.71 Trazodone’s mechanism of action is not well understood; it is believed to work by inhibiting the reuptake of serotonin, and by acting as an antagonist at the serotonin receptor 5-HT2A/1C.  

 Nefazodone is an antidepressant with activity similar to both SSRIs and trazodone. There is evidence to suggest that nefazodone is a reasonable treatment option for GAD. One open trial of 21 patients with DSM-IV-based GAD were treated with nefazodone for 8 weeks. Of the 15 patients who completed the trial, 80% were rated as both very much or much improved, 7% as minimally improved, and 13% as unchanged.86 Unfortunately, nefazodone is associated with an elevation in liver enzymes that has led to a black box warning. This has diminished its use. 

Mirtazapine, a noradrenergic and specific serotonergic antidepressant, has a dual mechanism of action. It binds to and inhibits the α2 autoreceptor and the α2 heteroreceptor, which prevents negative feedback of synaptic noradrenaline on 5-HT and noradrenaline receptors. This results in enhanced serotonergic and noradrenergic activity. Mirtazapine also blocks 5-HT2 and 5-HT3 receptors on the postsynaptic membrane, which results in enhanced 5-HT neurotransmission. There was one 8-week, open-label trial of mirtazapine in patients with comorbid MDD and GAD. In this study, 10 patients were initially treated with mirtazapine 15 mg, which was titrated up to a maximum of 45 mg/day. Significant improvement in HAM-A and Hamilton Rating Scale for Depression scores occurred after the first week of treatment and persisted throughout the rest of the study.87



The clinical evidence for buspirone in the treatment of GAD is fairly extensive. There are 15 double-blind, placebo-controlled trials of buspirone, most of which compare it to a benzodiazepine, placebo, or both. Buspirone was more effective than placebo in 10 of these studies, but was never more effective than benzodiazepines.30 One study reanalyzed previous study data of 735 patients with DSM-III GAD treated with either placebo, buspirone, or a benzodiazepine to determine whether or not prior treatment with benzodiazepines might predict a poorer response with buspirone.  The results showed that patients with recent benzodiazepine treatment report much less improvement with buspirone than patients who are benzodiazepine-naïve, or patients who have a remote history of benzodiazepine treatment.88

Buspirone acts by modulating the serotonergic system. It has activity as a full agonist at the presynaptic 5-HT1A, where it inhibits serotonin synthesis and firing of the raphe nucleus. It acts as a partial agonist at the postsynaptic 5-HT1A, which results in increased receptor activity.89 Buspirone provides a nonbenzodiazepine option for the treatment of GAD, and may be useful in the benzodiazepine-naïve patient. Unfortunately, the population most likely to be prescribed buspirone, patients with comorbid alcohol, personality, or substance abuse disorders, are the least likely to feel its antianxiety effects. Buspirone has a slow onset of action, and may take several weeks to demonstrate a significant clinical effect. It may be difficult for an anxious patient to wait for the anxiolytic effect. Additionally, buspirone does not improve insomnia, which is a common complaint in GAD.  


Other Medications

A few French studies demonstrate some efficacy for hydroxyzine in the treatment of GAD. Hydroxyzine works by competetively blocking the effects of histamine at H1 receptor sites. One 4-week, double-blind, placebo-controlled study compared hydroxyzine 50 mg/day to placebo in 133 patients with DSM-III GAD. The hydroxyzine group had significantly more improvement on measures of anxiety. However, 52% of the treatment group complained of sleepiness, weight gain, dry mouth, and loss of concentration, all common antihistamine-related side effects.90 A longer, 3-month, double-blind, placebo-controlled, randomized trial comparing hydroxyzine 50 mg/day, bromazepam 6 mg/day, and placebo found that hydroxyzine was as effective as bromazepam and more effective than placebo in reducing CGI severity scale scores and HAD scores.91 Finally, a European multicenter, double-blind comparison of hydroxyzine 50 mg, buspirone 20 mg, and placebo found that only hydroxyzine was significantly better than placebo on the HAM-A, which was the primary outcome measure. Both hydroxyzine and buspirone were more effective than placebo on CGI and HAD ratings. However, this study is confounded by the idiosyncratic dosing of buspirone.92

Kava kava, a compound from a plant that grows in the Pacific Islands region, is reported to have analgesic and anxiolytic properties. It is also reported to inhibit monoamine oxidase B.93 However, the evidence supporting its use in the treatment of GAD is scant. An 8-week, randomized, double-blind, German trial treated 129 GAD patients with either 400 mg Kava LI 150, buspirone 10 mg, or opipramol 100 mg. There were no significant differences between any of the outcome measures in 127 of the treated patients. Seventy-five percent of patients were classified as responders and 60% achieved remission.94 Another study that compared kava kava against placebo in 37 patients with DSM-IV GAD found that improvements occurred in both treatments, and kava did not differ significantly from placebo.95 Studies of kava kava have been discontinued because of concerns about hepatoxicity.



CBT has been demonstrated to be an effective treatment for GAD. A study comparing nondirective therapy, CBT, and applied relaxation in outpatients with GAD found that both applied relaxation and CBT were superior to nondirective therapy by the end of the study. Longer-term follow-up of the subjects determined that the nondirective therapy group had lost its treatment gains, but both CBT and applied relaxation maintained their treatment gains, with the greatest gains maintained by the CBT group.96 Another study comparing CBT, behavior therapy, and a wait-list control group found that CBT was consistently more effective than behavior therapy on measures of cognition, mood, and anxiety.97

Although psychodynamic psychotherapy was employed for years in the psychotherapeutic treatment of anxiety, there is no evidence to support its efficacy in the treatment of GAD.



GAD is a common disorder and is highly comorbid with other psychiatric syndromes. GAD alone and GAD comorbid with other psychiatric syndromes is remarkably disabling and significantly impedes on the quality of life of individuals and their loved ones. At this time, little is understood about the biology of GAD, but it is hoped that advances in neurobiology and genomics will enhance our knowledge about the pathogenesis of this syndrome. Patients with GAD commonly approach PCPs with somatic concerns such as headaches, backaches, and muscle spasms. Fortunately, there are safe and effective pharmacotherapies and psychotherapies for GAD. However, the longer-term prognosis for GAD is still troubling. This emphasizes the need for more longitudinal treatment research as well as exploration of alternative modalities of therapy.  PP



1.    DuPont RL, Rice DP, Miller LS, Shiraki SS, Rowland CR, Harwood HJ. Economic costs of  anxiety disorders. Anxiety. 1996;2(4):167-172.

2.    Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51(1):8-19.

3.    Weiner H. The psychobiology and pathophysiology of anxiety and fear. In: Tuma AH, Maser J, eds. Anxiety and the Anxiety Disorders. Hillsdale, NJ: Lawrence Erlbaum; 1985:333-345.

4.    First MB, Spitzer RL, Gibbon M, Williams J. Structured Clinical Interview for DSM-IV Axis I Disorders, Clinician Version (SCID-CV). Washington, DC: American Psychiatric Press; 1997.

5.    Ballenger JC, Davidson JR, Lecrubier Y, et al. Consensus statement on generalized anxiety disorder from the International Consensus Group on Depression and Anxiety. J Clin Psychiatry. 2001;62(suppl 11):53-58.

6.    Posternak MA, Zimmerman M. Short-term spontaneous improvement rates in depressed outpatients. J Nerv Ment Dis. 2000;188(12):799-804.

7.    Fifer SK, Mathias SD, Patrick DL, Mazonson PD, Lubeck DP, Buesching DP. Untreated anxiety among adult primary care patients in a health maintenance organization. Arch Gen Psychiatry. 1994;51(9):740-750.

8.    Sareen J, Houlahan T, Cox BJ, Asmundson GJ. Anxiety disorders associated with suicidal ideation and suicide attempts in the National Comorbidity Survey. J Nerv Ment Dis. 2005;193(7):450-454.

9.    Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. Washington, DC: American Psychiatric Association; 1980.

10.    Blazer DG, Hughes D, George LK, et al. Generalized anxiety disorder. In: Robins LN, Reiger DA, eds. Psychiatric Disorders in America: The Epidemiologic Catchment Area Study. New York, NY: The Free Press; 1990:180-203.

11.    Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association; 1994.

12.    Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):593-602.

13.    Wittchen HU, Nelson CB, Lachner G. Prevalence of mental disorders and psychological impairments in adolescents and young adults. Psychol Med. 1998;28(1):109-206.

14.    Carter RM, Wittchen HU, Pfister H, Kessler RC. One-year prevalence of subthreshold and threshold DSM-IV generalized anxiety disorder in a nationally representative sample. Depress Anxiety. 2001;13(2):78-88.

15.    Ustun TB, Sartorius N (eds). Mental Illness in General Health Care: An International Study. New York, NY: John Wiley & Sons; 1996: 18-23.

16.    Olfson M, Broadhead WE, Weissman MM, et al. Subthreshold psychiatric symptoms in a primary care group practice. Arch Gen Psychiatry. 1996;53(10):880-886.

17.    Wittchen HU, Krause P, Hoyer J, et al. Prevalence and correlates of generalized anxiety disorders in primary care. Fortschr Med Orig. 2001;1999(suppl 1):17-25.

18.    Wittchen HU, Zhao S, Kessler RC, et al. DSM-III-R generalized anxiety disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51(5):355-364.

19.    Noyes R Jr. Comorbidity in generalized anxiety disorder. Psychiatr Clin N Am. 2001;24(1):41-55.

20.    Sanderson WC, Barlow DH. A description of patients diagnosed with DSM-III-R generalized anxiety disorder. J Nerv Ment Dis. 1990;178:588-581.

21.    Brown TA, Barlow DH. Comorbidity among anxiety disorders: implications for treatment and DSM-IV. J Consult Clin Psychol. 1992;60(6):835-844.

22.    Noyes R Jr, Woodman C, Garvey MJ, et al. Generalized anxiety disorder vs. panic disorder. Distinguishing characteristics and patterns of comorbidity. J Nerv Ment Dis. 1992;180(6):369-379.

23.    Brawman-Mintzer O, Lydiard RB, Emmanuel N, et al. Psychiatric comorbidity in patients with generalized anxiety disorder. Am J Psychiatry. 1993;150(8):1216-1218.

24.    Starcevic V, Fallon S, Uhlenhuth EH, Pathak D. Comorbidity rates do not support the distinction between panic disorder and generalized anxiety disorder. Psychopathology. 1994;27(6):269-272.

25.    Goisman RM, Goldenberg I, Vasile RG, et al. Comorbidity of anxiety disorders in a multicenter anxiety study. Compr Psychiatry. 1995;36(4):303-311.

26.    Zimmerman M, Rothschild L, Chelminski I. The prevalence of DSM-IV personality disorders in psychiatric outpatients. Am J Psychiatry. 2005;162(10):1911-1918.

27.    Grant BF, Hasin DS, Stinson FS, et al. Co-occurrence of 12-month mood and anxiety disorders and personality disorders in the US: Results from the national epidemiologic survey on alcohol and related conditions. J Psychiatr Res. 2005;39(1):1-9.

28.    Kessler RC. The epidemiology of pure and comorbid generalized anxiety disorder: a review and evaluation of recent research. Acta Psychiatr Scand Suppl. 2000;406:7-13.

29.    Bland RC, Newman SC, Orn H. Help-seeking for psychiatric disorders. Can J Psychiatr. 1997;42(9):935-942.

30.    Hoge E, Oppenheimer J, Simon N.  Generalized anxiety disorder. Focus. 2004;2(3):346-358.

31.    Diagnostic and Statistical Manual of Mental Disorders, 3rd ed rev. Washington, DC: American Psychiatric Association; 1987.

32.    Wittchen HU, Kessler RC, Beesdo K, Krause P, Hofler M, Hoyer J. Generalized anxiety disorder and depression in primary care: prevalence, recognition, and management. J Clin Psychiatry. 2002;63(suppl 8):24-34.

33.    Hoehn-Saric R, Hazlett RL, McLeod DR. Generalized anxiety disorder with early and late onset of anxiety symptoms. Compr Anxiety. 1993;34(5):291-298.

34.    Keller MB. The long-term clinical course of generalized anxiety disorder. J Clin Psychiatry. 2002;63(suppl 8):11-16.

35.    Yonkers KA, Dyck IR, Warshaw M, Keller MB. Factors predicting the clinical course of generalised anxiety disorder. Br J Psychiatry. 2000;176:544-549.

36.    Tyrer P, Seivewright H, Johnson T. The Nottingham Study of Neurotic Disorder: predictors of 12-year outcome of dysthymic, panic and generalized anxiety disorder. Psychol Med. 2004;34(8):1385-1394.

37.    Yonkers KA, Warshaw MG, Massion AO, Keller MB. Phenomology and course of generalised anxiety disorder. Br J Psychiatry. 1996;168(3):308-313.

38.    Souetre E, Lozet H, Cimarosti I, et al. Cost of anxiety disorders: impact of comorbidity. J Psychosom Res. 1994;38(suppl 1):151-160.

39.    Walker EA, Roy-Byrne PP, Katon WJ, et al. Psychiatric illness and irritable bowel syndrome: a comparison with inflammatory bowel disease. Am J Psychiatry. 1990;147(12):1656-1661.

40.    Lydiard RB, Fossey MD, Marsh W, et al. Prevalence of psychiatric disorders I patients with irritable bowel syndrome. Psychosomatics. 1993;34(3):229-234.

41.    Crestani F, Lorez M, Baer K. Decreased GABAA receptor clustering results in enhanced anxiety and a bias for threat cues. Nat Neurosci. 1999;2(9):833-839.

42.    Rickels K, Case WG, Schweizer E. The drug treatment of anxiety and panic disorder. Stress Med. 1988;4(4):231-239.

43.    Rocca P, Beoni AM, Eva C, Ferrero P, Zanalda E, Ravizza L. Peripheral benzodiazepine receptor messenger RNA is decreased in lymphocytes of generalized anxiety disorder patients. Biol Psychiatry. 1998;43(10):767-773.

44.    Sevy S, Papadimitriou GN, Surmont DW, Goldman S, Mendlewicz J. Noradrenergic function in generalized anxiety disorder, major depressive disorder, and healthy subjects. Biol Psychiatry. 1989;25(2):141-152.

45.    Munjack DJ, Baltazar PL, DeQuattro V, et al. Generalized anxiety disorder: some biochemical aspects. Psychiatry Res. 1990;32(1):35-43.

46.    Mathew RJ, Ho BT, Francis DJ, Taylor DL, Weinman ML. Catecholamines and anxiety. Acta Psychiatr Scand. 1982;65(2):142-147.

47.    Khan A, Lee E, Dager S, et al. Platelet MAO-B activity in anxiety and depression. Biol Psychiatry. 1986;21(8-9):847-849.

48.    Tiihonen J, Kuikka J, Rasanen P, et al. Cerebral benzodiazepine receptor binding and distribution in generalized anxiety disorder: a fractal analysis. Mol Psychiatry. 1997;2(6):463-471.

49.    Abelson JL, Glitz D, Cameron OG, et al. Blunted growth hormone response to clonidine in patients with generalized anxiety disorder. Arch Gen Psychiatry. 1991;48(2):157-162.

50.    Charney DS, Woods SW, Heninger GR. Noradrenergic function in generalized anxiety disorder: effects of yohimbine in healthy subjects and patients with generalized anxiety disorder. Psychiatry Res. 1989;27(2):173-182.

51.    Jetty PV, Charney DS, Goddard AW. Neurobiology of generalized anxiety disorder. Psychiatr Clin North Am. 2001;24(1):75-97.

52.    Nutt DJ. Neurobiological mechanisms in generalized anxiety disorder. J Clin Psychiatry. 2001;62(suppl 11):22-27.

53.    Gray JA. The neuropsychological basis of anxiety. In: Last CG, Hersen M, eds. Handbook of Anxiety Disorders. New York, NY: Pergamon Press; 1988:10-37.

54.    Tafet GE, Idoyaga-Vargas VP, Abulafia DP, et al. Correlation between cortisol level and serotonin uptake in patients with chronic stress and depression. Cogn Affect Behav Neurosci. 2001;1(4):388-393.

55.    Tafet GE, Toister-Achituv M, Shinitzky M. Enhancement of serotonin uptake by cortisol: a possible link between stress and depression. Cogn Affect Behav Neurosci. 2001;1(1):96-104.

56.    Butler PD, Weiss JM, Stout JC, Nemeroff CB. Corticotropin-releasing factor produces fear-enhancing and behavioral activating effects following infusion into the locus coeruleus. J Neurosci. 1990;10(1):176-183.

57.    Griebel G. Is there a future for  neuropeptide receptor ligands in the treatment of anxiety disorders? Pharmacol Ther. 1999;82(1):1-61.

58.    Koob GF, Gold LH. Molecular biological approaches in the behavioural pharmacology of anxiety and depression. Behav Pharmacol. 1997;8(7):652.

59.    Noyes R Jr, Clarkson C, Crowe RR, Yates WR, McChesney CM. A family study of generalized anxiety disorder. Am J Psychiatry. 1987;144(8):1019-1024.

60.    Skre I, Onstad S, Edvardsen J, Torgersen S, Kringlen E. A family study of anxiety disorders: familial transmission and relationship to mood disorder and psychoactive substance use disorder. Acta Psychiatr Scand. 1994;90(5):366-374.

61.    Andrews G, Stewart G, Allen R, Henderson AS. The genetics of six neurotic disorders: a twin study. J Affect Disord. 1990;19(1):23-29.

62.    Ohara K, Suzuki Y, Ochiai M, Tsukamoto T, Tani K, Ohara K. A variable-number-tandem-repeat of the serotonin transporter gene and anxiety disorders. Prog Neuropsychopharmacol Biol Psychiatry. 1999;23(1):55-65.

63.    Mahe V, Balogh A. Long-term pharmacological treatment of generalized anxiety disorder. Int Clin Psychopharmacol. 2000;15(2):99-105.

64.    Pollack MH. Optimizing pharmacotherapy of generalized anxiety disorder to achieve remission. J Clin Psychiatry. 2001;62(suppl 19):20-25.

65.    Shader RI, Greenblatt DJ. Use of benzodiazepines in anxiety disorders. N Engl J Med. 1993;328(19):1398-1405.

66.    Dubovsky SL.  Generalized anxiety disorder: new concepts and psychopharmacologic therapies. J Clin  Psychiatry. 1990;51(suppl):3-10.

67.    Sadock BJ, Sadock VA. Biological therapies. In: Sadock BJ, Sadock VA, eds. Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry. Baltimore, MD: Lippincott, Williams & Wilkins; 1991:907-911.

68.    Ballenger J. Current treatment of the anxiety disorders in adults. Biol Psychiatry. 1999;46(11):1579-1594.

69.    Rickels K, Downing R, Winokur A. Long-term diazepam therapy and clinical outcome.  JAMA. 1983;250(6):767-771.

70.    Hollister LE, Conley FK, Britt RH, Shuer L. Long-term use of diazepam. JAMA.  1981;246(14):1568-1570.

71.    Rickels K, Downing R, Schweizer E, Hassman H. Antidepressants for the treatment of generalized anxiety disorder. A placebo-controlled comparison of imipramine, trazodone, and diazepam. Arch Gen Psychiatry. 1993;50(11):884-895.

72.    Hoehn-Saric R, McLeod DR, Zimmerli WD.  Differential effects of alprazolam and imipramine in generalized anxiety disorder: somatic versus psychic symptoms. J Clin Psychiatry.  1988;49(8):293-301.

73.    Balon R, Mufti R, Arfken C. A survey of prescribing practices for monoamine oxidase inhibitors. Psychiatr Serv. 1999;50(7):945-947.

74.    Wingerson D, Nguyen C, Roy-Byrne PP. Clomipramine treatment for generalized anxiety disorder. J Clin Psychopharmacol. 1992;12(3):214-215.

75.    Rocca P, Fonzo V, Scotta M, Zanalda E, Ravizza L. Paroxetine efficacy in the treatment of generalized anxiety disorder. Acta Psychiatr Scand. 1997;95(5):444-450.

76.    Bellew KM, McCafferty JP, Iyengar M, et al.  Paroxetine treatment of GAD: A double blind, placebo-controlled trial. Presented at: the 153rd Annual Meeting of the American Psychiatric Association; May 13-18, 2000; Chicago.

77.    Pollack MH, Zaninelli R, Goddard A, et al. Paroxetine in the treatment of generalized anxiety disorder: results of a placebo controlled, flexible-dosage trial. J Clin Psychiatry. 2001;62(5):350-357.

78.    Lenze EJ, Mulsant BH, Shear MK, et al. Efficacy and tolerability of citalopram in the treatment of late-life anxiety disorders: results from an 8-week randomized, placebo-controlled trial. Am J  Psychiatry. 2005;162(1):146-150.

79.    Davidson JR, Bose A, Korotzer A, Zheng H.  Escitalopram in the treatment of generalized anxiety disorder: double-blind, placebo controlled flexible-dose study. Depress Anxiety. 2004;19(4):234-240.

80.    Ball SG, Kuhn A, Wall D, Shekhar A, Goddard AW. Selective serotonin reuptake inhibitor treatment for generalized anxiety disorder: a double-blind, prospective comparison between paroxetine and sertraline. J Clin Psychiatry. 2005;66(1):94-99.

81.    Davidson JR, DuPont RL, Hedges D, Haskins JT. Efficacy, safety, and tolerability of venlafaxine extended release and buspirone in outpatients with generalized anxiety disorder.  J Clin Psychiatry. 1999;60(8):528-535.

82.    Rickels K, Pollack MH, Sheehan DV, Haskins JT. Efficacy of extended-release venlafaxine in nondepressed outpatients with generalized anxiety disorder. Am J Psychiatry. 2000;157(6):968-974.

83.    Nimatoudis I, Zissis NP, Kogeorgos J, Theodoropoulou S, Vidalis A, Kaprinis G. Remission rates with venlafaxine extended release in Greek outpatients with generalized anxiety disorder. A double-blind, randomized, placebo controlled study. Int Clin Psychopharmacol.  2004;19(6):331-336.

84.    Gelenberg A, Lydiard RB, Rudolph R, Aguiar L, Haskins JT, Salinas E. Efficacy of venlafaxine extended-release capsules in nondepressed outpatients with generalized anxiety disorder: A 6-month randomized controlled trial. JAMA. 2000;283(23):3082-3088.

85. Allgulander C, Hackett D, Salinas E.  Venlafaxine extended release (ER) in the treatment of generalised anxiety disorder: twenty-four-week placebo-controlled dose-ranging study. Br J Psychiatry. 2001;179:15-22.

86. Hedges DW, Reimherr FW, Strong RE, Halis CH, Rust C. An open trial of nefazodone in adult patients with generalized anxiety disorder. Psychopharmacol Bull. 1996;32(4):671-676.

87. Goodnick PJ, Puig A, DeVane CL, Freund BV. Mirtazapine in major depression with comorbid generalized anxiety disorder. J Clin Psychiatry. 1999;60(7):446-448.

88. DeMartinis N, Rynn M, Rickels K, Mandos L. Prior benzodiazepine use and buspirone response in the treatment of generalized anxiety disorder. J Clin Psychiatry. 2000;61(2):91-94.

89. Apter J, Allen L.  Buspirone: future directions.  J Clin Psychopharmacol. 1999;19(1):86-93.

90. Ferreri M, Hantouche EG, Billardon M.  Value of hydroxyzine in generalized anxiety disorder: controlled double blind study versus placebo. Encephale. 1994; 29(6): 785-791.

91. Llorca PM, Spadone C, Sol O, et al. Efficacy and safety of hydroxyzine in the treatment of generalized anxiety disorder: a 3-month double-blind study. J Clin Psychiatry. 2002;63(11):1020-1027.

92. Lader M, Scotto JC. A multicentre double-blind comparison of hydroxyzine, buspirone and placebo in patients with generalized anxiety disorder. Psychopharmacology (Berl). 1998;139(4):402-406.

93. Uebelhack R, Franke L, Schewe HJ. Inhibition of platelet MAO-B by kava pyrone-enriched extract from Piper methysticum Forster (kava-kava). Pharmacopsychiatry. 1998;31(5):187-92.

94. Boerner R, Sommer J, Berger W, Kuhn U, Schmidt U, Mannel M. Kava-kava extract li 150 is as effective as opipramol and buspirone in generalized anxiety disorder—an 8 week randomized, double blind multicentre clinical trial in 129 outpatients. Phytomedicine. 2003;10(suppl 4):38-49.

95. Connor KM, Davidson JR. A placebo-controlled study of kava kava in generalized anxiety disorder. Int Clin Psychopharmacol. 2002;17(4):185-188.

96. Borkovec TD, Costello E. Efficacy of applied relaxation and cognitive-behavioral therapy in the treatment of generalized anxiety disorder.  J Consult Clin Psychol. 1993;61(4):611-619.

97. Butler G, Fennell M, Robson P, Gelder M. Comparison of behavior therapy and cognitive behavior therapy in the treatment of generalized anxiety disorder. J Consult Clin Psychol.