Researchers Determine Rates of Self-Medication in Mood Disorders Patient

Self-medication, defined as using alcohol and/or drugs to alleviate emotional distress, is a dangerous habit for patients suffering from mood disorders. Although rates of self-medication have previously been found to be fairly high in mood disorders patients, research on this topic has been at a minimum.

James Bolton, MD, and colleagues from the University of Manitoba in Canada, studied 43,093 patients >18 years of age enrolled in the National Epidemiologic Survey on Alcohol and Related Conditions. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria was used to determine the self-medication prevalence rates for patients suffering from bipolar I disorder, bipolar II disorder, dysthymia, and major depressive disorder (MDD).

Bolton and colleagues found 2,184 patients had dysthymia, 7,822 had MDD, 1,546 had bipolar I disorder, 538 bipolar II disorder, and 8,420 had any mood disorder. Of these patients, ~24% of patients with mood disorders were self-medicated with drugs and/or alcohol. Self-medication prevalence rates by disease state were as follows: 41% of bipolar I disorder patients; ~35% of bipolar II disorders patients; ~23% of dysthymic patients; and ~23% of MDD patients.  Regarding comorbidities, the researchers found significant amounts of panic disorder and dependent personality disorder in men and high rates of generalized anxiety disorder and dependent personality disorder in women.

Due to the high rates of self-medication found in bipolar I disorder, the researchers further reviewed this subset of the overall patient population. They found that self-medication was at its highest rates during depressive episodes (~41% for bipolar I patients and ~32% for bipolar II patients). They also found patients self-medicating ~29% of the time during manic episodes and ~8% of the time during hypomanic symptoms.

 Bolton and colleagues believe that it is up to the clinician to monitor each patient’s medication misuse as well as drug and alcohol intake during treatment. They also recommend that the clinician inquire as to each patient’s reason for using drugs and alcohol during treatment.  (J Affect Disorder. 2008; epub ahead of print) –CDN

Smoking Cessation More Difficult for Patients with ADHD

For patients with attention-deficit/hyperactivity disorder (ADHD), rates of tobacco use are higher than in the general population, and smoking cessation is less likely for ADHD patients than for those without the disorder. Prior studies have shown that use of tobacco and nicotine is not only related to the presence of ADHD but may also differ in presentation depending on the increased presence of inattentive or hyperactive/impulsive symptoms, which comprise the core symptomology of ADHD. Additional studies into ADHD symptoms and smoking cessation have not been conducted. An improved understanding of the associations between ADHD subtypes, tobacco use, and smoking cessation could lead to improved smoking cessation and decreased tobacco-related mortality for patents with ADHD.

Lirio Covey, PhD, and colleagues at the Columbia University Medical Center and New York State Psychiatric Institute in New York City evaluated smoking cessation patterns of 583 adult smokers, who were treated with bupropion and nicotine patch during the 8-week study period. They sought to determine if the separate domains of ADHD—inattention or hyperactivity—affected rates of smoking cessation differently. 

All patients were evaluated for ADHD using the ADHD Current Symptom Scale. Two subtypes of ADHD were identified among all patients with the disorder: ADHD with predominate inattentive symptoms (ADHD-inattention) and ADHD with predominate hyperactive/impulsive symptoms with or without inattention (ADHD-hyperactivity/impulsivity with or without inattention). To aid smoking cessation, patients were treated with bupropion, nicotine patch, and cessation counseling. Study outcome was rate of smoking abstinence, which was measured by amount of expired carbon monoxide.

Covey and colleagues found that among all patients, 540 showed no symptoms of ADHD, 20 patients met criteria for ADHD-inattention, and 23 patients met criteria for ADHD-hyperactivity/impulsivity with or without inattention. When compared to patients without ADHD, patients with both subtypes of the disorder showed lower rates of smoking cessation. The authors also found that patients with ADHD-hyperactivity/impulsivity with or without inattention had the lowest rates of smoking cessation when compared to patients without ADHD or with ADHD-inattention. The proportion of patients without ADHD or with ADHD-inattention who abstained from smoking were also similar (55% compared to 54%).

In addition, the treatment approach of bupropion and nicotine patch was more helpful for patients with ADHD-inattention than those with ADHD-hyperactivity/impulsivity with or without inattention. Study data also found that the frequency of past major depressive disorder was highest in patients with ADHD-inattention, and the frequency of past alcohol dependence was highest in patients with ADHD-hyperactivity/impulsivity with or without inattention.

They concluded that more research is necessary for an improved understanding of ADHD, particularly the ADHD-hyperactivity/impulsivity with or without inattention subtype, and tobacco use, which could lead to early prevention of one or both of these conditions. Prior studies have shown that nicotine improves attentiveness and other performance deficits for patients with ADHD and may be used as a form of self-medication for patients, although more data in needed to understand the mechanism behind ADHD and tobacco use.  

Funding for this research was provided by the National Institute on Drug Abuse. (Nicotine Tob Res. 2008;10(12):1717-1725.) –CP

Psychiatric Diagnoses and Treatment Seeking in College Students: Findings from the NESARC

Psychiatric disorders are not uncommon among young, college-aged adults. Those attending college, however, are less likely to seek psychiatric treatment than their non-college-attending peers. This finding was reported in a recent study that assessed the differences in 1-year prevalence of psychiatric disorders, sociodemograhic correlates, and rates of treatment in United States college students, compared to peers not attending college for at least the previous year. Carlos Blanco, MD, PhD, at Columbia University Medical Center in New York City, and colleagues used data from the large (N=43,093) National Epidemiologic Survey on Alcohol and Related Conditions to conduct their subsample analyses.

The subsample comprised 2,188 college attending, and 2,904 non-college-attending adults 19–25 years of age. Approximately 50% of the subsample had at least one Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition psychiatric disorder in the previous year. The unadjusted risk for alcohol use disorders was significantly greater for college students (odds ratio=1.25; 95% CI, 1.04–1.50) than non-college-attending peers, but not after adjusting for sociodemographic characteristics (adjusted odds ratio=1.19; 95% CI, 0.98–1.44).

Diagnosis of a drug use disorder, nicotine dependence, or tobacco use were all significantly less likely to occur in those attending college, although non-college-attending subjects were more likely to receive relevant psychiatric treatment—especially regarding alcohol-use disorders.

The authors note that, overall, <25% of those with a psychiatric disorder sought treatment within the year preceding the survey. This statistic suggests that a more centralized mental healthcare structure may be helpful for college and university campuses.

This study is supported by grants from the American Foundation for Suicide  Prevention, the National Institutes of Health, and the New York State Psychiatric Institute. (Arch Gen Psychiatry. 2008;65(12):1429-1437). –LS

Association Between MDD and Adverse Cardiovascular Events May Be Due to Changes in Patient Behavior

Despite lacking data on causality, researchers have long established that major depressive disorder (MDD) and other depressive disorders increase the risk of cardiovascular disease for physically healthy patients as well as increase the likelihood of recurring adverse cardiac events for patients with existing cardiovascular disease. Understanding the causality of the relationship between MDD and adverse cardiovascular symptoms would allow for primary care physicians (PCPs), psychiatrists, and other healthcare professionals to develop treatments that would slow or stop the progression of cardiovascular disease in patients with MDD.

Mary A. Whooley, MD, of the Veteran’s Affairs Medical Center in San Francisco, California, and colleagues, evaluated 1,017 patients with stable coronary heart disease to determine why depressive symptoms are associated with an increased risk of cardiovascular events in patients with cardiovascular disease. All patients were gathered from area hospitals and followed by researchers for an average of 4.8 years after study beginning.

Depressive symptoms were assessed using the Patient Health Questionnaire (PHQ), and presence of depressive symptoms was defined as a PHQ score of ≥10. Various analyses were used to determine the rate of cardiovascular events in patients with MDD symptoms as compared to patients without MDD. Recorded cardiovascular events included heart failure, heart attack, stroke, transient ischemic attack—a temporary reduction of blood supply to the brain—or death.

Whooley and colleagues found that 341 cardiovascular events occurred during the study period. Patients with MDD symptoms had an ~50% increased risk of cardiovascular events than patients without MDD. The annual rate of cardiovascular events was 10% for the 199 patients with MDD when adjusted for age. For the 818 patients without MDD, the annual rate of cardiovascular events was 6.7% during the study period. When adjusted for the severity of cardiac disease and other factors, the authors found that patients with MDD symptoms were at a 31% increased risk of experiencing adverse cardiac events as compared to patients with depression.

In addition, after adjusting findings for particular health behaviors, including lack of physical activity, Whooley and colleagues found that there was no significant difference between patients with or without MDD and subsequent development of adverse cardiac events. However, lack of physical exercise was associated with a 44% increase in cardiovascular events for all patients. The authors concluded that although depressive symptoms are associated with cardiovascular events, this association may be due to changes in behavior—particularly lack of exercise—due to MDD symptoms.

Whooley and colleagues said that the relationship between MDD and cardiovascular events may be caused when patients with MDD symptoms do not adhere to exercise, dietary, and other recommendations by PCPs and other medical professionals, which leads to cardiovascular events. Medication adherence for this group may also be reduced when compared to patients without MDD. The authors added that these findings are useful for PCPs as they illustrate that adverse cardiovascular events could potentially be prevented if depressed patients modify certain health behaviors, such as increasing amount of exercise. (JAMA. 2008;300(20):2379-2388.) –CP

Psychiatric dispatches is written by Christopher Naccari, Carlos Perkins, Jr, and Lonnie Stoltzfoos.


Dr. Pasic is associate professor of psychiatry in the Department of Psychiatry and Behavioral Sciences at the University of Washington School of Medicine and medical director of the Psychiatric Emergency Services at Harborview Medical Center in Seattle, Washington. Dr. Combs is clinical assistant professor and Dr. Romm is clinical associate professor in the Department of Psychiatry at Harborview Medical Center at the University of Washington.

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: Jagoda Pasic, MD, PhD, Associate Professor of Psychiatry, Department of Psychiatry and Behavioral Sciences, Harborview Medical Center, 325 Ninth Ave, Box 359896, Seattle, WA 98104-2499; Tel: 206-744-2377; Fax: 206-744-8615; E-mail:


Focus Points

• The hallmark of factitious disorder is motivation to assume a sick role.
• Deception is an integral part of factitious disorder.
• Care providers must be attentive to their own responses to patients who might have the diagnosis of factitious disorder.



Factitious disorders can represent diagnostic and treatment dilemmas for all clinicians who come in contact with these perplexing patients. Presentations are unusual; symptoms may be incongruent with known diagnoses or match textbook descriptions. As demanding as it may be to care for such patients in the long term, it is equally challenging to assess a case in the initial emergency department where patients can present without historic data, demonstrate the ability to deceive, have unclear motivation, and exhibit puzzling symptoms. Missing a serious condition can be disastrous but there can also be sequelae of inadvertently ordered expensive and potentially harmful treatment. This article presents two patients who sought care in the psychiatric emergency services of a large, county hospital and discusses diagnostic and treatment issues. The authors propose psychological explanations for staff and clinicians’ reactions and suggest interventions useful in the emergency setting. The article emphasizes the necessity of caring for the patient in an ethical and appropriate manner and raises issues of risk management.


Factitious disorders, classified as major mental illnesses by the American Psychiatric Association (APA),1 can represent diagnostic and treatment dilemmas for all who come in contact with these perplexing patients. Psychiatrists and medical practitioners are confronted with individuals whose presentations are unusual, with symptoms either incongruent with known diagnostic categories or that match textbook descriptions with surprising precision. As demanding as it may be to care for such patients in the long term, it is equally challenging to assess a case in the initial, emergency treatment setting.

Identifying factitious disorder is difficult in the emergency department where patients may present without available historic data, unclear motivation, and puzzling symptoms. The literature is a less helpful diagnostic aid than with other conditions. Because deception is integral, accurate epidemiologic data is unavailable2 and causes are equally puzzling.3 Missing a serious condition can be disastrous but there can also be sequelae of inadvertently ordered expensive and potentially harmful treatment.4

This article presents two patients, one with chiefly psychological symptoms and the second whose symptoms were predominantly physical, who sought care in the psychiatric emergency services of a large, county hospital. The authors discuss diagnostic and treatment issues, propose psychological explanations for staff and clinicians’ emotional reactions,5-7 and suggest interventions useful in the emergency setting.8 The authors also emphasize the necessity of caring for the patient in an ethical and appropriate manner and raise issues of risk management.9,10

Clinical Case Reports

Case Report 1

Mr. X is a 28-year-old male who presented multiple times to the psychiatric emergency services of Seattle, Washington’s Harborview Medical Center; he had also sought care at local emergency rooms. He presented with bizarre behavior and confusion, though he showed no signs of internal preoccupation or responding to internal stimuli which would have be indicative of a true psychotic state. He was noted to be uncooperative during prior visits. Disorganized, he had been brought by ambulance at the request of the police. Medical and psychiatric history was unknown except for indication that in the past he had “lived in an institution.” Mr. X remained mute on questioning so, for considerations of safety, he was referred to the County Designated Mental Health Professionals for involuntary psychiatric admission; however, he was not detained due to insufficient evidence as required by Washington State Mental Health Law.

Although discharged, the patient declined to leave the area. He also refused to walk although he had been previously observed to ambulate. When he left the hospital, he did so with the assistance of security officers. He yelled and spat throughout the discharge process, insisting there was “something seriously wrong.” A similar scenario had occurred in previous visits; on reluctant discharge from emergency services, he publicly disrobed, walked in front of a moving car, and jumped into a construction site, dangerous and bizarre behaviors that caused the police to return him to the emergency room.

Case Report 2

Mr. Y is a 38-year-old male with an esophageal stricture previously dilated on several occasions. He presented to the emergency department because he was experiencing difficulty swallowing. His history included ingestion of objects such as tacks and safety pins, behaviors which lacked obvious external incentives. On the current occasion, a computed axial tomography scan showed the presence of a coin in his esophagus which was subsequently removed by endoscopy. His post-operative course was complicated by intentional ingestion of a pulse oximeter which had lodged in his cervical esophagus and caused respiratory difficulty. Surgeons removed this with a rigid endoscope. After evaluation by psychiatry, he was deemed neither suicidal nor homicidal and was discharged. Within 24 hours, he presented to an affiliated hospital with a razor blade in his esophagus. Psychiatric evaluation was repeated and this time he was detained by the County Designated Mental Professionals as a danger to himself.


Factitious disorder is classified as a major mental illness by the APA.1 The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, offers three diagnostic criteria for this condition (Table 1), including the intentional production of physical or psychological symptoms; the motivation to assume the sick role; and the absence of external incentives for this behavior. The condition can present with either physical or psychological symptoms by themselves or by a combination of the two. Variants exist and are classified as factitious disorder not otherwise specified. Munchausen’s syndrome, a chronic variant, most often presents with numerous physical symptoms. It was first described by Asher2 in 1951, who identified patients traveling from hospital to hospital to dramatically offer their complaints. Munchausen’s syndrome by proxy3 is another version of the disease in which a person, typically a parent, intentionally creates symptoms in their child so enabling the adult to identify with the sick role.


Prevalence and Etiology

Because of difficulty in diagnosing the disorder and deception is a prominent componant, accurate epidemiologic data is absent and long-term follow-up is almost impossible to obtain.4 Estimated prevalence rates vary from 0.1% in an Italian community study5 of 2,363 people to 9.3% of referrals of fever of unknown origin to the National Institute for Allergy and Infectious Disease. Causes are equally puzzling. One theory is that the condition develops as a result of stressful life events such as early loss and abandonment. The resulting use of the medical arena to enact life’s dramas allows them to gain control over situations where previously there was none.6


The majority presenting with what ultimately proves to be factitious disorder are women 20–40 years of age, often employed in the medical field as nurses, medical technicians, or other health-related jobs. Common presenting conditions are self-induced wounds or infections and simulated disease states.7,8

Making the Correct Diagnosis

Accurate diagnosis is difficult. There are no specific tests to aid in assessment. Clinical acumen is vital. The patient may tell a story that seems almost unbelievable; laboratory finding may be inconsistent; and there may be inexplicable gaps in the record or the patient may refuse to allow gathering of historic data. In spite of the impulse to collect as much information as possible, regulations regarding privacy and confidentiality must be respected.9

Differential diagnosis can be perplexing. Diagnostic boundaries blur between factitious disorder, the somatoform disorders where symptoms are unconsciously generated, and malingering with its accompanying external incentives. Foremost, a genuine organic etiology of the condition must be eliminated.10

Unlike the outpatient setting where patients, after exhaustive medical work-up, are referred to a psychiatrist who diagnoses factitious disorder, several visits to an emergency department may take place before this occurs. According to one study11 of psychiatrists providing emergency services at an urban general hospital, 13% of patients were suspected of feigning symptoms.

Emergency room providers are familiar with homeless or substance-abusing patients who produce symptoms to obtain food and shelter. These individuals evoke frustration and negative reactions from the staff. However, malingerers, unlike those with factitious disorder, intentionally produce or feign symptoms by which to benefit such as economic gain in the form of disability payment or the avoidance of legal responsibility.1 Assumption of the sick role is benefit enough for those with factitious disorder. Because factitious disorders are often diagnoses of exclusion, an individual presenting in the emergency setting with physical complaints is entitled to medical screening for acute illness and stabilization. Similarly, a thorough psychiatric evaluation is warranted for a patient with psychological symptoms.

Psychodynamics Associated with Diagnosis and Treatment

Countertransference, or feelings evoked in the treator, poses problems for both patient and provider. Patients who feign illness to gain privileges afforded those in the sick role stir up strong negative reactions. Clinicians and staff respond with despair, anger, and frustration. Patients are pejoratively labeled “chronic complainers,” “difficult,” and “frequent flyers,” because they repeatedly seek healthcare services. Staff reaction may be so strong that they lose ability to respond with empathy.12

Countertransference complicates treatment. Clinicians may harbor a conviction that all patients with factitious disorder are untreatable, causing the patient to feel not only incurable but worthless. Anger, fear, aversion or disgust undermines a therapeutic alliance. The inherent drama of factitious behaviors can create inappropriate levity, titillation, or gossip, reflecting the provider’s underlying rage caused by the patient’s manipulation of his peers and practitioners. Providers, in turn, may treat the patient or referring physician with undue harshness.13 If feelings go unrecognized, there is the potential danger of missing a diagnosis of an accompanying condition or that the care provider’s anger or resignation will mobilize the patient’s resistance.13,14 Furthermore, clinicians may over-identify with the patients, who often are healthcare providers themselves, which can interfere with diagnosis and appropriate treatment.

Groves12 identified four subtypes of difficult patients. (Table 2) These descriptions can promote insight into patient behavior and clinician response. Case Report 1 may, at first, be seen as a malingerer, but on closer scrutiny can be identified as a “manipulative help-rejecter.” Case Report 2 is identified as “self-destructive denier” in combination with “dependant clinger.”



Providing Necessary Medical or Surgical Care

Surgeons are used to operating on patients for truly emergent reasons, sometimes even without obtaining consent as an urgent intervention. However, with patients who deliberately create pathology, surgeons may feel less inclined to intervene. In such cases, psychiatry consultation can be a great resource. Helpful techniques include assessment of danger to self and/or decisional capacity, validation of the surgical team’s concerns, setting limits for the patient, and maintaining a safe setting which can include assigning a constant observer or placing the patient in a room monitored by camera.

The challenge comes with a surgical team reluctant to operate because of concern that self-injurious behavior will continue. This did not occur when Case Report 2 required urgent surgical intervention because of risk of airway obstruction.

In Case Report 2, the patient exhibited disturbing behavior necessitating the involvement of more than one discipline, ie, emergency medicine, psychiatry, and otorhinolaryngology. The initial assessment was conducted by the emergency medical physician who deemed necessary the consultation for dysphagia. Because a history of self-injury and swallowing objects was noted, referral to psychiatry was also made. The psychiatrist found the patient not suicidal so recommended neither hospitalization nor involuntary detention.

Treatment: Emergency Room Interventions Beyond Medical Interventions

The literature on reports on emergency room treatment of factitious disorder patients is limited. Outside of clear-cut emergent medical procedures or medication administration, interventions with factitious disorder patients are problematic at best and carry the risk for iatrogenic harm at worst.

The authors of this article have found recommendations in the literature for office treatment and suggest that they may be adapted for use in the emergency room. Either a confrontational or non-confrontational approach has been tried by the primary physician or in conjunction with a psychiatrist.15 Reich and Gottfried9 studied 12 patients with factitious disorder confronted with their behaviors. Although it has been reported that psychosis can occur,16 none became suicidal or psychotic using this approach yet only one patient acknowledged his conduct.9 If the patient feels humiliated and exposed by confrontation, no matter how sensitively handled, proceeding with any therapy is difficult.

Hollender and Hersh15 advocate the non-confrontational approach. They recommend that the consulting psychiatrist avoid the role of prosecutor and try to help the patient understand behaviors identified by the primary physician.

Another technique that can be employed to allow narcissistically vulnerable patients to relinquish symptoms without threat of exposure and humiliation was developed by Eisendrath.17 He originated a “double-bind” approach. The patient is informed that his failure to respond to the next offered treatment will prove the illness is faked. The patient can simultaneously make his recovery and save face. This approach is based on the hypothesis that confrontation fails because symptoms of factitious disorder serve as an important psychological defense and can be relinquished only in an atmosphere of safety.18

There is an absence of robust research supporting the effectiveness of any management technique for factitious disorder. Eastwood and Bisson5 reviewed treatment outcomes in 32 case reports and 13 case series. They found no significant difference between confrontational and non-confrontational approaches, between treatment with psychotherapy compared to treatment with none, and with the addition or avoidance of medications. They concluded that long-term management plans which include consistent care and a holistic approach are beneficial, a model difficult to achieve in an acute hospital setting. The authors5 suggest that various strategies may be helpful but there is no definitive way to help select a particular management plan. Of note is a report of two cases ending in suicide, a reminder of the necessity of vigilance.5 One management goal is to modify patient’s often unrealistic expectations of the medical profession. The clinician should offer encouragement to cope with symptoms rather than expect a cure19 and acknowledge that the patient is manifesting physical symptoms for psychic distress. It is this distress that must be identified and treated.

It is not unreasonable to refer the patient to psychotherapy, a treatment that may be interpersonal or psychoanalytically oriented.20-23 Realistically, a referral to therapy by an emergency room provider may be immediately rejected by the patient for emotional or financial reasons.

System Interventions

While there are no evidence-based studies to suggest interventions in the emergency department, in the case of suspected or presumed factitious disorder, the authors of this article recommend the creation of a care plan, the consideration of psychiatric consultation, and, if possible, the assignment of the same provider on repeated emergency room visits (Table 3).


Risk Assessment

Patients with factitious disorder engage in behaviors endangering themselves. Researchers24,25 propose three types of self-harm, including direct self-harm such as self-inflicted burns; self-created disease, including symptoms produced by the application of noxious agents, such as self-inflicted hypoglycemia (Case Report 1 best fits this category); and indirect or delegated harm, which includes damage or health risks created by medical interventions provoked by the patient. In such cases, the medical staff is “delegated” to carry out a procedure due to feigned symptoms or manipulated findings as exemplified by Case Report 2.

In Case Report 1, the patient engaged in behavior that put himself at risk of serious harm (eg, jumping from a high place; inviting being hit by a car) and created his own disease. In Case Report 2, the otolaryngology team initially hesitated to operate on this patient using a procedure that by itself has potential for an adverse outcome. Controversy may exist around the question of whether patients with feigned symptoms or illness should have the same kind of treatment administered to patients with “legitimate” symptoms or diseases. However, it is the physician’s ethical duty to provide adequate care if a patient’s symptoms pose a risk of serious harm if left without intervention. The two patients received care that met community standards. In Case Report 1, an evaluation for involuntary psychiatric treatment was indicated due to self-harm behaviors, and in Case Report 2 surgery was required for foreign body removal to prevent bleeding, infection, and perforation. While hospitalization would rarely be appropriate for cases of malingering, it may be indicated for patients with factitious disorders when there is an acute medical issue or a psychiatric issue that poses imminent risk of harm to self, or the patient’s symptoms are causing grave disability. Factitious disorders are rarely associated with risk of harm to others except in cases of Munchausen’s by proxy; hence, hospitalization on this ground is not indicated.

Risk Management

Tempting as it may be to dismiss patients in the emergency department who are suspected of factitious disorder, stabilization must be provided according to the Emergency Medical Treatment and Active Labor Act (Social Security Act: Sections 1866 and 1867). An individual suspected of factitious disorder has the same rights as any patient, ie, the right to reasonable care, respect, privacy, safety, and confidentiality.26 The clinician must adequately document physical and psychological findings and include positive and negative laboratory results. If confusion is an issue, decisional capacity must be established. If the standard of care is ignored, clinicians are vulnerable for risk management review and possible litigation.

Patients with factitious disorder may refuse treatment because of anger and humiliation; they may leave against medical advice or consider themselves wronged, feelings that can motivate them to sue. While no physician is immune to a lawsuit, abiding by federally mandated regulations, adhering to the standard of care, and keeping accurate documentation are the best protective measures.


From personal experiences combined with a literature review, the authors of this article conclude the following. First, in spite of provider reaction, a thorough medical and psychiatric assessment should be performed on patients whether or not they are suspected of having a factitious disorder. Serious acute problems must not be overlooked. Second, every effort must be made to engage the patient in care in the acute setting to help with immediate assessment and to encourage appropriate follow-up. Third, although there is absence of robust support for any treatment, there is some evidence for trying either a confrontational or non-confrontational approach or Eisendrath’s “double-bind” technique.5,8,15,18 Fourth, hospitalization or consideration for involuntary detainment is strongly recommended when there is potential for the patient harming him or herself or when the patient lacks decisional capacity. Fifth, creation of a care plan, easily accessible in the medical record, gives the opportunity for consistent, informed assessment and treatment. Last, all involved with patient care must accurately and neutrally provide thorough documentation to minimize legal risk for the provider and accomplish good patient care. PP


1.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994:471-472.
2.    Asher R. Munchausen’s syndrome. Lancet. 1951;1(6650):339-341.
3.    Meadow R. Munchausen syndrome by proxy. The hinterland of child abuse. Lancet. 1977;2(8033):343-345.
4.    Fehnel CR, Brewer EJ. Munchausen’s syndrome with 20-year follow-up. Am J Psychiatry. 2006;163(3):547.
5.    Eastwood S, Bisson JI. Management of factitious disorders: a systematic review. Psychother Psychosom. 2008;77(4):209-218.
6.    Jones RM. Factitious disorders. In: Kaplan HI, Sadock BJ, eds. Comprehensive Textbook of Psychiatry. 6th ed. Baltimore, MD: Williams & Wilkins; 1995:1271-1279.
7.    Lipsitt DR. Factitious disorder and Munchausen syndrome. In: UpToDate. Schwenk TL, ed. UpToDate. Waltham, MA: 2008. Available at: Accessed December 3, 2008.
8.    Eisendrath S. Current overview of factitious physical disorders. In: Feldman MD, Eisendrath SJ, eds. The Spectrum of Factitious Disorders. Washington, DC: American Psychiatric Association Press; 1996:195-213.
9.    Reich P, Gottfried LA. Factitious disorders in a teaching hospital. Ann Intern Med. 1983;99(2):240-247.
10.    Wise MG, Ford CV. Factitious disorders. Prim Care. 1999;26(2):315-326.
11.    Yates BD, Nordquist CR, Schultz-Ross RA. Feigned psychiatric symptoms in the emergency room. Psychiatr Serv. 1996;47(9):998-1000.
12.    Groves JE. Taking care of the hateful patient. N Engl J Med. 1978;298(16):883-887.
13.    Willenberg H. Countertransference in factitious disorder. Psychother Psychosom. 1994;62(1-2):129-134.
14.    Nadelson T. Victim, victimizer: interaction in the psychotherapy of borderline patients. Int J Psychoanal Psychother. 1976;5:115-129.
15.    Hollender MH, Hersh SP. Impossible consultation made possible. Arch Gen Psychiatry. 1970;23(4):343-345.
16.    Fras I, Coughlin BE. The treatment of factitial disease. Psychosomatics. 1971;12(2):117-122.
17.    Eisendrath SJ. Factitious physical disorders: treatment without confrontation. Psychosomatics. 1989;30(4):383-387.
18.    Weiss J. The integration of defences. Int J Psychoanal. 1967;48(4):520-524.
19.    Bass C, May S. Chronic multiple functional somatic symptoms. BMJ. 2002;325(7359):323-326.
20.    Schoenfeld H, Margolin J, Baum S. Munchausen syndrome as a suicide equivalent: abolition of syndrome by psychotherapy. Am J Psychother. 1987;41(4):604-612.
21.    Tucker LE, Hayes JR, Viteri AL, Liebermann TR. Factitial bleeding: successful management with psychotherapy. Dig Dis Sci. 1979;24(7):570-572.
22.    Mayo JP Jr, Haggerty JJ Jr. Long-term psychotherapy of Munchausen syndrome. Am J Psychother. 1984;38(4):571-578.
23.    Spivak H, Rodin G, Sutherland A. The psychology of factitious disorders. A reconsideration. Psychosomatics. 1994;35(1):25-34.
24.    Willenberg H, Eckhardt A, Freyberger H, Sachsse, U, Gast U. Self-destructive behavior: classification, and basic documentation. Psychotherapeut. 1997;42:211-217.
25.    Fliege H, Scholler G, Rose M, Willenberg H, Klapp BF. Factitious disorder and pathological self-harm in a hospital population: an interdisciplinary challenge. Gen Hosp Psychiatry. 2002;24(3):164-171.
26.    Medical-Legal Survival: A Risk Management Guide for Physicians. Oak Brook, IL: University Health System Consortium; 2007.


Dr. Luo is associate clinical professor in the Department of Psychiatry and Biobehavioral Sciences at the University of California in Los Angeles; past president of the American Association for Technology in Psychiatry (AATP) in New York City; and Gores Informatics Advocacy chair at the AATP.
Disclosure: Dr. Luo is consultant to S.M.A.R.T. Link Medical, Inc., on the speaker’s bureau of Epocrates, and on the advisory board of Spyglass Consulting.


Today’s computers actually have more power and memory than most users need. Ten years ago, a high-end computer with the fastest processor, most memory, and large capacity hard drive would cost over $3,000, destined primarily for computer gamers and video editing. Today, even the most basic computers (under $1,000) have sufficient computing power for the majority of users, who typically only use office productivity software such as a word processor, spreadsheet, and database programs, as well as a Web browser to access information on the Internet. As health information and medical software increasingly become Web based, such as the National ERx initiative,1 maximizing the Web-browsing experience has become a must for medical professionals.


The medical office needs a variety of tools, which have increasingly become dependent on the Internet for delivery. Today’s practice can no longer maintain high levels of productivity with just practice management software and a word processor for documentation. Electronic communication with patients is increasingly becoming the norm, and eventually Web-based appointment scheduling will be the predominant appointment booking method. Patients will rely more upon e-mail appointment reminders with subsequent integration into their iPhone or Blackberry calendar than the traditional phone call confirmation. Just as the need for intense computing power has diminished over the years, the medical office will depend less upon medical software and information installed on office-based computers and rely heavily on subscriptions to Web-based applications such as electronic health records.

There are many reasons for this switch from office-based computing to Web-based delivery. Access is easier for multiple providers at different locations if the electronic health record system is centralized on the Internet. Timely backup and data integrity is improved since the busy practice manager or physician is no longer responsible for daily backup of records, billing, and scheduling. Communication between multiple health plans and healthcare service providers to streamline financial, clinical, and administrative transactions has now gone online. To enhance the experience with these services requires the optimization of the Web browser.


In the medical setting, the security of the browsing experience is of paramount importance beyond the Health Insurance Portability and Accountability Act. Although the Web is a portal to web-based medical software and medical information, it is also the gateway for vulnerability of computers to viruses and hackers. Phishing is the type of attack that uses both social engineering and technical subterfuge to steal personal identity data and financial account credentials.2 These social-engineering schemes use “spoofed” e-mails, which appear to be from a credible Website, to lead victims to counterfeit Websites designed to trick them into divulging financial data or providing account information. Medical offices are vulnerable because they often have demographic information such as social security number, birthday, and address that hackers may use for other purposes. Technical subterfuge schemes implore users to click on a button on a Website, which plants “crimeware” onto computers. This software, usually a Trojan keylogger, basically captures keystrokes and sends them to phishers so that they can steal information directly.

AntiPhishing.org3 provides general advice to consumers to avoid phishing tactics. These include recommendations such as not to use links embedded in e-mails if there is suspicion that the e-mail is not authentic, and checking on the URL to determine if the site is authentic. Even the yellow lock on a URL and its “https://” can be forged by phishers. It is highly recommended that instead of clicking on e-mail links, enter the web site URL directly in the browser to avoid being sent to a phishing site.

There are a variety of tools to avoid phishing sites. Earthlink4 and Netcraft5 provide free toolbars that can be embedded into Internet Explorer or Firefox browsers to alert users if they have entered a site that may be risky. GreenBorder is a Windows-based Web browser that provided secured browsing by using virtualization technology to keep the Web browser from being hijacked and taking over the operating system. Google purchased GreenBorder in 2006, and its developers helped contribute to Google’s own Web browser, Chrome.6

Chrome is an open-source browser compiled by Google from a variety of sources.7 It uses components from Apple’s WebKit, which is incorporated into Apple’s Safari browser, and elements from Mozilla’s Firefox. These components have been tweaked to run complex Web applications better and to run clean as well as fast. Elements from GreenBorder’s technology help Chrome keep each tab in a secure “sandbox” so that they do not crash the browser and improve protection from phishing sites. At present, this product is still in beta and only for the Windows operating system, but Mac OS X and Linux versions are promised.

Microsoft has not been idly watching the secure browsing phenomenon. The new version 8 of Internet Explorer (IE8), now in beta testing, also offers secure Web browsing features.8 IE8 has a SmartScreen Filter that detects phishing sites, and domain highlighting which focuses the user’s attention to the domain name in the URL to spot misleading addresses.


Even 20 seconds waiting for a Website to load can create frustration for the medical office. Google’s Chrome browser and Microsoft’s IE8 are faster than earlier versions of Internet Explorer and Mozilla’s Firefox by incorporating various technologies to enhance the speed of access to information. Chrome has a simple interface and a revamped JavaScript engine to improve speed of Web-based applications. Application shortcuts in Chrome are specialized windows in the Chrome browser just for Web applications. They can be invoked from the desktop once the shortcut is created and they also do not display tabs, menus, and the address bar to maximize the application speed and appearance. IE8 has “Web slices,” which are favorite Websites that are routinely checked by IE8 for updates and then highlighted for the user. IE8 also has Web accelerators, installed mini-applications that help users copy information on one Website to be used on another with one click.

Fans of Firefox who desire speed but do not want to give up their favorite browser still have options. For the Microsoft Windows operating system, K-Meleon9 is an extremely fast, lightweight Web browser based on the Gecko layout engine used in Firefox. For Mac OS X, Camino10 is a specifically compiled web browser based on the same Gecko engine. These browsers, in essence, are similar to Firefox but have fewer features and add-ons. Additionally, their tighter integration with the specific operating system makes a significant improvement in speed.


One of the issues with current Web browsers is many users have important bookmarks on home computers and work computers, and it is a challenge to synchronize the two. An easy solution for Firefox Web browser users is Foxmarks.11 This product is a free add-on extension to the Firefox browser that enables users to synchronize specific bookmarked sites between different computers as well as access and edit these bookmarks online from a third computer. Bookmarks can be shared between members as well as accessed on a mobile device such as an iPhone. Bookmarks are saved on the server, which functions as a backup. For Internet Explorer, there are many services that work as Foxmarks, but BookmarkSync12 is recommended because it can sync between IE and Firefox.

For the adventurous, to share bookmarks is a novel way to discover new Websites that have relevant information. Stumbleupon13 is a Website where members rate other Websites with a thumb up or down and then share this opinion with friends. Stumbleupon will then recommend Websites based on search topics chosen by users. Delicious.com14 is another popular bookmark-sharing Website. Here, users bookmark Websites and tag them on search terms of their own choosing. Users can then create their own network of colleagues with whom to share favorite Websites or they can search for Websites tagged by other members based on keywords.

Web Applications

As mentioned in a previous “Tech Advisor,”15 there are numerous Web-based office productivity software programs such as Google Docs16 and Thinkfree.17 These Web applications free users from dependence on specific productivity software on a computer as well as from carrying files on a USB flash drive. One advantage of using Google Docs is that a Microsoft PowerPoint presentation slideshow can be run directly from the Web browser. Glide OS18 takes this premise one step further toward desktop replacement. Glide OS offers Microsoft Office-compatible programs for word processing, spreadsheets, and presentations, but also offers photo and video management, e-mail, calendar, contact manager, and bookmark management. Eye OS19 is another desktop “operating system” where all software functions on a computer are delivered via the Web browser. Eye OS offers its software via the GNU Affero Public License version 3, which means that one can have one’s own private eye OS server for family, company, or network completely free. The source code is available and with eye OS development tools. The software can be customized with new applications that fit specific needs.


At first thought, the Web browser appears to be a limited tool for medical information and office management. However, with proper customization, it can be the portal to all functions of the medical office such as communication with health insurance companies using NaviNet,20 an electronic medical record system such as ValentMed,21 e-prescribing with NationalERx,1 medication information with Epocrates Online,22 and numerous medical content sites such as PsychiatryOnline.23 Once WiMax, the full wireless Internet for mobile access, arrives, basic Internet tablet devices and inexpensive ultramobile PCs may be sufficient for the daily medical practice. PP


1.    National ERx. National ePrescribing Patient Safety Initiative. Available at: Accessed October 8, 2008.
2.    APWG. What is Phishing and Pharming? Available at: Accessed October 8, 2008.
3.    APWG. Consumer Advice: How to Avoid Phishing Scams. Available at: Accessed October 8, 2008.
4.    Earthlink Toolbar. Available at: Accessed October 8, 2008.
5.    Netcraft Toolbar. Available at: Accessed October 8, 2008.
6.    Methvin D. Google chrome answers the greenborder mystery. Information Week. September 1, 2008. Available at: Accessed October 8, 2008.
7.    Google Chrome. A fresh take on the browser. Available at: Accessed October 8, 2008.
8.    Internet Explorer 8: More secure, private, and reliable. Available at: Accessed October 8, 2008.
9.    K-Meleon. Available at: Accessed October 8, 2008.
10.    Camino. Available at: Accessed October 8, 2008.
11.    Foxmarks. Available at: Accessed October 8, 2008.
12.    BookmarkSync. Available at: Accessed October 8, 2008.
13.    StumbleUpon. Available at: Accessed October 8, 2008.
14.    Delicious. Available at: Accessed October 8, 2008.
15.    Luo JS. Free Software Tools for the Medical Practice. Primary Psychiatry. 2007;14(6):23-28.
16.    Google Docs. Available at: Accessed October 8, 2008.
17.    ThinkFree. Available at: Accessed October 8, 2008.
18.    Glide OS. Available at: Accessed October 8, 2008.
19.    Eye OS. Available at: Accessed October 8, 2008.
20.    NaviNet. Available at: Accessed October 8, 2008.
21.    ValantMed. Available at: Accessed October 8, 2008.
22.    Epocrates Online. Available at: Accessed October 8, 2008.
23.    Psychiatry Online. Available at: Accessed October 8, 2008.


Dr. Peselow is research professor at New York University School of Medicine in New York City.

Disclosure: Dr. Peselow is on the speaker’s bureaus of Forest and Pfizer.

Please direct all correspondence to: Eric D. Peselow, MD, Research Professor, School of Medicine, Psychiatry, New York University School of Medicine, 550 First Ave, New York, NY 10016-8304; Tel: 917-376-6755; Fax: 718-763-1677; E-mail:


Over the past 50 years, psychotropic agents have revolutionized the field of psychiatry. With the discovery of lithium,1 typical antipsychotics,2 tricyclic antidepressants,3 and benzodiazepine anxiolytics,4 psychiatry has advanced from a psychoanalytic to a biologic field. The discovery of newer agents for mood stabilization (carbamazepine, divalproex sodium), atypical antipsychotics, selective serotonin reuptake inhibitors (SSRIs), and buspirone has led to incremental improvement in treating these disorders. However, despite these remarkable advances, a large number of patients still do not respond to treatment. This issue discusses agents currently being tested for major psychiatric syndromes.

Eric D. Peselow, MD, and colleagues evaluate historic treatments that are no longer used, holistic medical techniques involving an orthomolecular strategy, and “natural” herbal products which are used despite lack of evidence-based trials. In addition, the authors assess the current state of these agents to identify whether these agents will prove to be safe and effective in various disorders or whether they will pass into history.

Yujuan Choy, MD, and  Franklin R. Schneier, MD, present findings of recent controlled trials that examine the evidence of efficacy of various classes of drugs (SSRIs, typical and atypical antipsychotics, anticonvulsants, and novel drug treatments of anxiety disorders) which effect the gamma-aminobutyric acid-ergic, serotonergic, and glutamatergic systems.

Ira D. Glick, MD, and Eric D. Peselow, MD, describe the current antipsychotics in the pipeline that are being clinically tested. They describe preclinical and clinical studies on a variety of agents that affect multiple receptors, including serotonin (5-HT)1A, 5-HT2A, 5-HT2C, dopamine (D)1, D2, D3, D2/D4, alpha-adrenergic receptors (alpha-1 and alpha-2) muscarinic (M)1 and M2 and histamine-1 receptors that are thought to be related to etiology. The authors point out that pursuing diverse molecular targets and validating these targets as effective in the treatment of schizophrenia appears to be the future for developing antipsychotics in the treatment of schizophrenia.

Patrick Ying, MD, evaluates new medications in mood disorders. Some of these medications continue in the existing paradigm of modifying serotonin, norepinephrine, and/or dopamine. Others employ novel mechanisms of action and hold the potential to improve the treatment of patients, such as by modifying the hypothalamic-pituitary-adrenal axis, affecting the tachykinin neuropeptide transmitters, and modulating the glutamatergic system. These drugs may not only improve the efficacy of treatment, but could potentially improve the speed and tolerability of pharmacotherapy.

Laurence M. Westreich, MD, and Deborah Finklestein, MD, evaluate the pipeline of investigational medications and vaccines used in the treatment of various illicit drugs. In addition to  these vaccines and the Food and Drug Administration-approved medications, other addiction remedies need to be understood by the general physician. The authors note that clinicians can provide substantial benefit to their addicted patients by making newly developed medications part of the treatment package.

Understanding these newer agents and treatment strategies may provide enhanced efficacy for patients with various psychiatric disorders. PP


1.    Cade JF. Lithium salts in the treatment of psychotic excitement. Med J Aust. 1949;2(10):349-352.
2.    Bower WH. Chlorpromazine in psychiatric illness. N Engl J Med. 1954;251(17):689-692.
3.    Kuhn R. The treatment of depressive states with G 22355 (imipramine hydrochloride). Am J Psychiatry. 1958;115(5):459-464.
4.    Kerry RJ, Jenner FA. A double blind crossover comparison of diazepam (Valium, Ro5-2807) with chlordiazepoxide (Librium) in the treatment of neurotic anxiety. Psychopharmacologia. 1962;3:302-306.


NeuroStar TMS Therapy Approved by FDA for MDD

The NeuroStar Transcranial Magnetic Stimulation (TMS) Therapy system was approved by the United States Food and Drug Administration for the treatment of major depressive disorder (MDD). Mark George, MD, of the Medical University of South Carolina (MUSC) initiated research on the treatment.

“I began researching prefrontal TMS as a potential treatment for depression back in 1993, reasoning from the effects of electroconvulsive therapy, emerging brain imaging findings in depression and sadness, and new papers describing corticothalamic regulator loops,” Dr. George said. “The ideas were heretical at first, as most people wrongly assumed that a seizure was needed for an electrical stimulation method to work.”

NeuroStar TMS Therapy is a non-systemic, non-invasive form of neuromodulation that requires no anesthesia or sedation. The 40-minute outpatient procedure involves magnetic resonance imaging-strength magnetic pulses that stimulate nerve cells in areas of the brain associated with depression. These pulses should be administered daily for 4–6 weeks.

The randomized controlled trial conducted for the FDA showed no systemic side effects (eg, sedation, nausea, dry mouth) and no adverse effects on concentration and memory. TMS treatments were safely performed with no seizures and no device-drug interactions. Mild-to-moderate scalp pain at the treatment area was experienced during treatment but dissipated after the first week. This option is for adults with MDD who failed to receive benefit with other treatments. It is not recommended for patients with implanted metallic devices or non-removable metallic objects in or around the head.

Despite over 15 years of research, a rigorous trial sponsored by the National Institute of Mental Health is being conducted at MUSC and three other sites to test the efficacy of prefrontal TMS in depression.

“We have extensive imaging, genetic, demographic, and neuropsychological testing in these patients to help understand the mechanism of action and determine who best responds, and whether biomarkers might help monitor or predict response,” Dr. George said.

The NeuroStar TMS Therapy has not been studied in patients who have received previous antidepressant treatment. Further, efficacy has not been established in patients whose condition did not improve after ≥2 prior antidepressant treatments at minimal effective dose and duration in the current episode.

Funding for this research was provided by the National Alliance for Research on Schizophrenia and Depression. (Further information can be found at –ML

Researchers Determine Rates of Child and Adolescent Bipolar I Disorder Becoming Adult Bipolar I Disorder

Current research has found that approximately 1% of the United States population <20 years of age suffers from bipolar disorder. With the onset of bipolar I disorder generally occurring in late adolescence or young adulthood, research is needed to determine whether child bipolar I disorder would become continuous adult bipolar I disorder.

Barbara Geller, MD, and colleagues from the Washington University in St. Louis, Missouri studied 115 children whose average age was 11.1±2.6 years to determine these potential prevalence rates. All of the children met the criteria for a first episode Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition bipolar I disorder mixed or manic phase; had one or both of the cardinal symptoms of bipolar I disorder (elation or grandiosity); and scored <60 on the Children’s Global Assessment Scale (CGAS). Geller and colleagues assessed the patients using the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia, the Psychosocial Schedule for School Age Children-Revised, and the CGAS. 

Over an 8-year period there were nine follow-up visits and approximately 94% of patients completed the study. Geller and colleagues found that these patients spent approximately 60% of weeks with any mood episodes and approximately 40% of weeks with episodes of mania. Approximately 88% of patients recovered from mania; however, approximately 73% of these patients relapsed. Geller and colleagues found that approximately 44% of these children with bipolar I disorder became young adults with bipolar I disorder. These patients continued to have manic episodes while 35.2% had a substance use disorder. This rate is similar to the rate found in adults.

“As we found, these data add to the validation of child bipolar I disorder as a similar illness to the adult form,” Dr. Geller said. “These data are consistent with our earlier publication showing that both child onset and adult onset bipolar I disorder occur within the same families.”

Geller and colleagues plan on following the sample into adulthood. They believe that the rate was similar in young adults because “these prospective longitudinal data and family psychopathology data support that they are the same illness and therefore would have similar comorbidity with substance use disorders. These are the first data to prospectively demonstrate continuity between child and adult bipolar I disorder.”

Funding for this research was provided by the National Institute of Mental Health. (Arch Gen Psychiatry. 2008;65(10):1125-1133.) –CDN

Adolescent Insomnia May Indicate Depression and Substance Abuse in Young Adulthood

Brandy Roane, MS, and Daniel J. Taylor, MD, of the University of North Texas in Denton conducted a study suggesting signs of adolescent insomnia symptoms are linked to depression, suicide, and substance abuse. This study is the first to longitudinally evaluate adolescent insomnia symptoms as a risk factor for mental health problems in young adulthood.

The researchers chose 145 middle, junior, and high schools in the United States based on size, school type, census region, urbanization level, percentage of Caucasian and African-American students, grade span, and curriculum. The sample consisted of 4,494 participants 12–18 years of age at baseline and 3,582 young adults 18–25 years of age at 6- to 7-year follow up. Self-report measures were used to assess mental health conditions. A cross-sectional, prospective design was used to evaluate the association between adolescent insomnia and mental health during adolescence and young adulthood.

Results indicated that 9.4% of adolescents reported insomnia symptoms (ie, difficulty falling asleep every day or almost every day). Cross-sectional analysis showed that these symptoms were associated with use of alcohol (ie, binge drinking; drinking ≥5 alcoholic beverages consecutively), cannabis, and other drugs (eg, cocaine) as well as suicide ideation or attempts. In addition, gender differences emerged for substance abuse and depression. Males were more likely to endorse substance abuse while females were twice as likely to develop depression. Sex and baseline depression were controlled for a prospective analysis that indicated adolescent insomnia symptoms were a significant risk factor for young adult depression (odds ratio=2.3). In addition, when participants suffering from depression and suicide at baseline were excluded, the insomnia cohort showed greater risk of experiencing recurrences of depression and suicidal activities.

These findings indicate that insomnia is a prevalent problem for adolescents. Roane and colleagues argue for future treatment-outcome studies to evaluate the efficacy and effectiveness of various insomnia interventions in this age group. (Sleep. 2008;31(10):1351-1356.) –ML

Children May Present With Course of OCD Similar to Older Peers and Adolescents

Marked by recurrent, unwanted thoughts and/or repetitive behaviors often aimed at relieving these obsessions, obsessive-compulsive disorder (OCD) is not only present in adult populations, but has also been found in children <3 years of age. Prior studies have shown that OCD development in childhood and adolescence features a unique presentation and poses risks to later growth and development.

Despite the differed presentation and risk, there have been few studies into the development of OCD in children. In addition, studies of youths with OCD often do not distinguish between those who present with the disorder as children and patients who develop OCD later in life. Researchers at the Bradley Hasbro Children’s Research Center Pediatric Anxiety Research Clinic in Providence, Rhode Island, recently sought to determine differences in OCD presentation among youths with the disorder.

Abbe M. Garcia, PhD, and colleagues studied 58 children (4–8 years of age; 23 male and 35 female) for distinguishing factors of early-onset OCD presentation. Early-onset OCD was defined as the presence of OCD, according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, prior to the 8 years of age, and was determined (along with comorbid conditions) by use of a structured interview. OCD severity was evaluated using the Children’s Yale-Brown Obsessive Compulsive Scale.

Garcia and colleagues found that the mean age of OCD onset was approximately 5 years and the mean age of presentation was 6–7 years. Mean symptom severity was in the moderately severe range while, among all children studied, approximately 19% had been previously treated with medication and 24% had received previous psychotherapy for OCD. Approximately 22% of children in the study also had comorbid attention-deficit/hyperactivity disorder and approximately 20% had comorbid generalized anxiety disorder. In addition, 20% of children in the study reported a first-degree family history of the disorder.

Regarding OCD symptoms of children in the study, common obsessions included contamination and aggressive/catastrophic thoughts, such as death or harm to family members, and common compulsive behaviors included washing and checking. The authors found that children with OCD presented with similar symptoms, severity levels, and family history as adolescents with the disorder, which may indicate that children can progress to the mature OCD course typically found in adults.

Garcia and colleagues concluded that presence of various obsessions and compulsions as well as multiple comorbid conditions indicate that, for some children with OCD, the disorder is not in a beginning phase that will progress as children age. However, they found that children can be affected with similar OCD severity as older children and adolescents. They added that researchers need to have a more developed understanding of the course of OCD in children in order to reduce the severity of symptoms that can impair patients’ quality of life.

Funding for this research was provided by the National Institute of Mental Health. (J Psychopathol Behav Assess. 2008. [Epub ahead of print].) –CP

10-Year Study on Smoking and Depression in Women

A longitudinal study investigated the strength of smoking as a risk factor for major depressive disorder (MDD). One thousand forty-three Australian women, participants in the Geelong Osteoporosis Study, had been monitored for 10 years. At the 10-year mark, participants were given a psychiatric examination. Julie Pasco, BSc(Hons), at the University of Melbourne, and colleagues conducted their assessment using case-control and retrospective cohort methods. MDD was diagnosed using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria; smoking was self-reported. Pasco and colleagues found that smoking and depression had a significant association, especially for heavy smokers (>20 cigarettes/day).

There were 165 women with a diagnosis of MDD with 806 controls. Smoking was associated with a significantly higher odds ratio for MDD (1.46, 95% CI 1.03–2.07). For heavy smokers (>20 cigarettes/day), the odds ratio for MDD was more than twice that of non-smokers. Among the 671 women with no history of MDD at baseline, 13 out of 87 smokers (14.9%) and 38 out of 584 non-smokers (0.07%) developed MDD during the 10-year study period. Overall, after controlling for alcohol consumption and physical activity, smoking increased the risk of MDD by 93% (hazard ratio 1.93, 95% CI 1.02–3.69).

Funding for this research was provided by Eli Lilly. (Br J Psychiatry. 2008;193(4):322-326) –LS

US Youths More Commonly Prescribed Psychotropic Drugs Compared to Western European Counterparts

Prescriptions for psychotropic medications have been increasing throughout Western Europe and the United States for the last 10 years. In addition, previous research indicates that use of psychotropic medications is higher in the US. According to a cross-sectional study by Julie M. Zito, PhD, of the University of Maryland School of Pharmacy in Baltimore, and colleagues, youths 0–19 years of age are more likely to receive prescriptions for psychotropic drugs in the US than in Western Europe.

The researchers investigated administrative claims data from the year 2000 on insured youths from  Germany (n=356,520), the Netherlands (n=110,944), and the US (n=127,157). A population-based analysis of psychotropic medication use was performed according to children’s age group, gender, drug subclass pattern, and concomitant use. Results found that annual prevalence of any psychtropic medication in youths was 6.7% in the US, which is substantially greater than in both the Netherlands (2.9%) and Germany (2%). The US demonstrated ≥3 times greater antidepressant and stimulant prevalence than the Netherlands and Germany; antipsychotic prevalence was 1.5–2.2 times greater. While the atypical antipsychotic subclass represented 48% in the Netherlands and 5% in Germany, the US represented 66%. Though psychotropic drugs such as α-agonists, lithium agents, and antiparkinsonian agents were prescribed less in all three countries, rarely used anxiolytics were twice as prevalent in Dutch youths as in US and German youths. Prescription hypnotics were 50% as common as anxiolytics in Dutch and US youths; they were uncommon in German youths the most. Concomitant drug use was twice as prevalent in youths in the US (19.2%) as those in the Netherlands, and three times as those in Germany.

Zito and colleagues concluded that there are great differences in psychotropic medication treatment patterns between US youths and Western European youths. It is possible that such differences raise from direct-to-consumer (DTC) drug advertising, government regulation, reimbursement policies, diagnostic classification systems, and cultural beliefs concerning medication’s role in emotional and behavioral treatment. Further, a demographic explanation of this phenomenon suggests that the number of child psychiatrists per capita is higher in the US than in Western Europe.

The study was limited by the cross-sectional nature of the investigation and lack of diagnostic information of enrollees. In addition, that DTC advertising is allowed only in the US among the three countries is confounding as is the fact that US data were confined to children covered under the State Children’s Health Insurance Program. Lack of information on reimbursement patterns, differences in access to specialist care, and lack of information on over-the-counter drugs limited the study as well. (Child Adolesc Psychiatry Ment Health. 2008;2(1):26.) –ML

MDD and Anxiety May Worsen COPD Symptoms Leading to Increased Hospitalizations

Major depressive disorder (MDD) and other depressive disorders as well as generalized anxiety are frequently occurring comorbid conditions for patients with chronic obstructive pulmonary disease (COPD). Although the increased prevalence of these psychiatric conditions in patients with COPD is widely known, few studies have investigated the link between these conditions and COPD disease course, including frequency of COPD exacerbation and subsequent hospital stays. The effect of MDD and anxiety on COPD presentation is of particular importance as the mental health conditions can be treated, which may potentially alter the disease outcome for a patient with COPD.

Jean Bourbeau, MD, of the Respiratory Epidemiology and Clinical Research Unit of McGill University in Montreal, Canada, and colleagues, studied 491 patients with stable COPD for symptoms of MDD and/or anxiety. The authors hypothesized that COPD patients with comorbid MDD or anxiety would be at increased risk for a greater number of exacerbations and hospitalizations. All patients were gathered from respiratory departments of 10 hospitals in Beijing, China and were evaluated for MDD and anxiety symptoms as well as COPD progression at the study beginning. For study inclusion, patients had to be ≥30 years of age, have physician-diagnosed COPD, have no worsening of respiratory symptoms 4 weeks prior to study beginning, and have an expected survival rate of ≥6 months, among other criteria.

MDD and anxiety symptoms were assessed using the Hospital Anxiety and Depression Scale, which assesses symptom severity among hospital and primary care patients. COPD progression was measured by spirometry and bronchodilator response tests, assessment of cough production and chest wheeze, and self-report. Exercise capacity and quality of life were also evaluated. Patients were then evaluated once-a-month for 12 months to assess occurrence of exacerbations or hospitalizations.

Bourbeau and colleagues found that 112 patients had probable MDD while 47 had probable anxiety. During the study period, 876 symptom-based and 450 event-based exacerbations were recorded, and 183 of these symptom exacerbations led to hospitalization. When compared to patients without psychiatric disorders, patients with probable MDD had significantly increased rates of symptom-based and event-based exacerbations, increased mortality, and increased hospital stays that were longer than non-depressed patients. Patients with anxiety experienced more frequent symptom-based exacerbations and longer hospital stays, when compared to non-anxious patients.

They also found that depressed patients had a higher percentage of concurrent anxiety, had lower levels of education attained, were less likely to be married, and had increased rates of past exacerbations and hospitalizations. Patients with both probable MDD and anxiety had lower levels of self-efficacy and social support. These results also persisted after adjusting for confounding variables.

Bourbeau and colleagues concluded that their findings show that symptoms of depression and anxiety are causally linked to increased rates of exacerbations and hospitalizations for patients with COPD. This relationship may be due to depression effecting change in the immune system or affecting a patient’s ability to adapt to chronic symptoms as well as decreasing self-confidence, which may lead to poorer medication adherence. Thus, clinicians should note that treatment of MDD and anxiety may lead to better COPD treatment outcomes.

Funding for this research was provided by the Canadian Institute of Health Research. (Am J Respir Crit Care Med. 2008;178(9):913-920.) –CP

Psychiatric dispatches is written by Michelisa Lanche, Christopher Naccari, Carlos Perkins, Jr, and Lonnie Stoltzfoos.



Dr. Sussman is editor of Primary Psychiatry as well as professor of psychiatry and interim chairman in the Department of Psychiatry at the New York University School of Medicine in New York City.

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


Generations of physicians have been accustomed to receiving pens, pads, mugs, and assorted models of the spine, the brain, and other organs, all courtesy of pharmaceutical and medical device manufacturers. Most, if not all, of these gifts will cease as of January 2009, when a new guideline for interactions of pharmaceutical companies with health care professionals goes into effect.1 This code is voluntary, but if brand name drug manufacturers follow this code of the Pharmaceutical Research and Manufacturers of America, freebies will be history. Tickets to shows, concerts, and sporting events are also banned. However, there will be some exceptions. For example, educational items without company logos or drug names are permissible if they are valued at <$100. Drug representatives can still provide meals for physicians, but they must be inexpensive, infrequent, and must take place in a clinical setting such as an office or hospital. When meals are provided, they must be accompanied by the presentation of information about the product belonging to the sponsor of the meal. Thus, this code is not as severe as it would seem as first, and it is not mandatory, so pharmaceutical companies can elect to participate, or not. 

The new code does not mention sampling, however, this is under assault as well. According to some observers, after January 1, 2009 free drug samples will be the last form of in-office marketing. For those of us in clinical practice, samples are helpful in getting people started on medications. Often, I have patients take the first pill in my office because I sense they might be ambivalent about taking medication or they are concerned about the side effects. The major objection to samples is that they get patients started on more expensive branded medications instead of more economical generics.  In most cases the less expensive, generic medication is as effective as the brand medication.

Apart from the ethical questions raised about the provision of samples and starter coupons, there is the fact that that many of you have already noticed that the variety of drug samples in your cabinets has decreased in the past few years. This is because many widely prescribed psychotropic medications have lost patent protection over the past two years and they have not been replaced by newer agents. The United States Food and Drug Administration has not approved any new psychotropic agents recently, and those that have been approved are not radically different from existing agents. 2008 may have been the year with the fewest introduction of new psychiatric medications in the past two decades.

Conflicts of Interest and Consulting Arrangements

The past year has also seen a number of highly publicized findings involving influential psychiatric “thought leaders.” The Senate Finance Committee found highly visible researchers had not fully disclosed the extent of financial relationships they had with industry.2-4 These reports are embarrassing to the field, however, more importantly, they disturbing because they call into question the motives and accuracy presentations and publications by these individuals. Although prominent academics have gotten the headlines, much of the abuse of this system probably involves arrangements where high-prescribing local clinicians are retained as consultants or speakers simply to win their loyalty to a product. This can also be seen as a kickback. Under the new guidelines, consultants who provide advisory services may “be offered reasonable compensation for their time, considering the value of the type of services provided, and to be offered reimbursement for reasonable travel, lodging, and meal expenses.” Also, “Any compensation or reimbursement made…in conjunction with a consulting arrangement should be reasonable and based on fair-market value.” 

On balance, I think these changes will result in less promotional/marketing driven distortion of clinical decision-making. It will also make whatever information is disseminated more credible. Greater transparency regarding conflicts of interest in publications and Continuing Medical Education programs is long overdue. PP


1.     Code on Interaction with Healthcare Professionals. Accessed November 25, 2008. 
2.    Psychiatric Group Faces Scrutiny Over Drug Industry Ties. Accessed November 25, 2008.
3.     Researchers Fail to Reveal Full Drug Pay. Accessed November 25, 2008.
4.     Top Psychiatrists Didn’t Report Drug Makers’ Pay. Accessed November 25, 2008.



Needs Assessment: Many clinicians have little information about the newer medications used to treat addiction, and often hold biases against using medications in the treatment of addiction. This paper places medications within the full context of addiction treatment and provides guidance on how to select and use the anti-addiction medications.

Learning Objectives:
• Place medications within the context of full treatment for addiction
• List the Food and Drug Administration-approved medications for alcohol dependence
• Give an example of common side effects for varenicline
• Know the usual effective dose for buprenorphine

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 James C.-Y. Chou, MD, associate 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: November 20, 2008.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Chou receives honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, and Pfizer.

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 December 1, 2010 to be eligible for credit. Release date: December 1, 2008. Termination date: December 31, 2010. The estimated time to complete all three articles and the posttest is 3 hours. 

Primary Psychiatry. 2008;15(12):73-80


Dr. Westreich is an associate professor of clinical psychiatry and Dr. Finklestein is an instructor in clinical psychiatry in the Department of Psychiatry’s Division on Alcoholism and Drug Abuse at New York University School of Medicine in New York City.

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

Off-label disclosure: This article contains discussion of the following unapproved medications for the treatment of addiction: baclofen, citalopram, flumazanil, fluoxetine, gabapentin, gamma-vinyl GABA, hydralazine, modafinil, propranolol, tiagabine, and topiramate.

Please direct all correspondence to: Deborah Finklestein, MD, Instructor in Clinical Psychiatry, Division on Alcoholism and Substance Abuse, Department of Psychiatry, New York University School of Medicine, 550 First Ave, New York, NY 10016; Tel: 212-579-4142; Fax: 212-579-7849; E-mail:


Can new medications help in the treatment of substance use disorders? The short answer to that question is yes. Despite the historical resistance of addiction treaters to using medications in their treatment of addicted people, recent advances and more sophisticated methods for integrating medications into standard addiction treatment have led to a surge in new anti-addiction medications available to the addicted person. Medications like depot naltrexone and acamprosate have shown substantial effects in decreasing alcohol craving, while suboxone has provided relief to opiate addicts who simply would not have come to treatment in the past. Despite the apparent post-marketing emergence of side effects like agitation and nightmares, varenicline is a step in the right direction for those looking for help with their nicotine addiction. Although not yet available to the public, the pipeline of investigational medications includes several cocaine vaccines. In addition to these vaccines and the Food and Drug Administration-approved medications, other addiction remedies have been touted in the press and should be understood by the general physician; in this widely publicized but unproven category is the proprietary medication “cocktail” offered by Prometa. Clinicians can provide substantial benefit to their addicted patients by making newly developed medications part of the treatment package. This article reviews the clinical use of these new medications.


The Epidemiologic Catchment Area study1 noted that 7.9% of the general population suffered from alcohol dependence over their lifetime, while 4.4% suffered from drug dependence. Despite some leveling off of teenager’s use of addictive substances over the past decade, 9.2% of all high school seniors acknowledged illicit use of non-heroin narcotics such as acetaminophen plus hydrocodone.2 However, these numbers do not reflect the desperation that addicted people, their loved ones, and their clinicians feel when confronted with a life-threatening addiction. Their anguish often engenders hope for a “magic pill” which will cure the addiction and return the sufferer to his or her previous state of health.

Despite the promise of some older medications as well as the medications reviewed below, no such panacea exists. The absence of such a curative biologic remedy arises in part from the remedial nature of understanding of addiction’s biology, and in part from the inherent impossibility of the task. No biologic substance will cure addiction since addiction is not (purely) a biologic condition. The successes of relapse prevention psychotherapy,3 network therapy,4 and other biopsychosocial treatments as well as peer-led support groups like Alcoholics Anonymous5 attest to the potential for effective non-biologic treatment of addiction.

However, biologic treatments like the medications in this article can substantially benefit the addicted person. Despite some resistance in the field of addiction psychiatry, most clinicians now see medications as a useful adjunct, if not the mainstay of treatment. Considerable controversy remains about the use of maintenance prescription of opiates, as with buprenorphine. But there is little disagreement about the need for more and better biologic approaches to the treatment of addiction. The medications below represent the newest and best of those approaches.


Since the 1970s, behavioral treatments6-8 have proven the most prevalent form of treatment in the United States. However, in the last several years, pharmacologic research has introduced some new medications as another means to enhance abstinence and prevent relapse.

The US Food and Drug Administration has approved disulfiram, acamprosate, and naltrexone (the latter in both daily oral and monthly injectable formulations) for the treatment of alcohol dependence. Previous articles1,2 have outlined the clinical uses of disulfiram and oral naltrexone. This article provides an update on the above medications as well as describes the applications of depot naltrexone and acamprosate, medications that are currently being used in the treatment of alcohol dependence.


Since the 1970s, disulfiram has been widely used as a deterrent to alcohol use secondary to its unpleasant side effects when alcohol is consumed. As a result, disulfiram primarily benefits patients who are adherent or receive medication under supervision. Controlled studies9-11 of disulfiram have revealed mixed results. Some provide evidence that drinking frequency is reduced, but the data show no convincing and sustained improvement in continuous abstinence rates. However, it still appears to be one of the most used pharmacotherapies available in the market and is dosed daily at 500 mg/day.

Naltrexone Oral Formulation

In 1994, naltrexone was approved by the FDA to treat alcohol dependence. An opioid antagonist, naltrexone is thought to dampen the pleasurable effects of alcohol-induced endogenous upload activity in the brain, thus reducing drinking frequency and the likelihood of relapse to heavy drinking.12,13 The standard regimen is one 50-mg tablet per day; duration of treatment can vary depending on the patient’s needs, but usually does not exceed 12 months. Initial nausea usually subsides after a few days, and other side effects (eg, heightened liver enzymes) are rare but necessitate monitoring of liver function tests.

Multiple controlled studies12,14-16 have shown naltrexone’s superiority over placebo, as patients receiving naltrexone were shown to be less likely to relapse to heavy drinking and more likely to drink on fewer days. Additionally, several meta-analyses17,18 have added support for the efficacy of naltrexone for improved abstinence. Other studies, however, have reported no or minimal effectiveness, attributing the outcome to poor medication adherence and adverse effects, especially nausea.19,20

Despite these findings, some patients find naltrexone helpful in itself or as an adjunct to other psychopharmacologic or psychosocial treatments. Clinicians should consider it as possiblity in treating their alcohol-dependent patients.

Naltrexone Depot Formulation

In an attempt to improve patient adherence and avoid some of the adverse effects associated with oral naltrexone, a monthly injectable formulation was approved by the FDA in April 2006. This formulation is administered by intramuscular (IM) injection of 380 mg and lasts for up to 30 days. Patients are advised to abstain from alcohol 3–7 days prior to first dose, but one study18 reported positive results in actively drinking patients with little to no abstinence period. Although FDA guidelines indicate that naltrexone should be used for up to 3 months to treat alcoholism, the Substance Abuse and Mental Health Administration (SAMHSA) recommends that treatment providers individualize the length of naltrexone treatment according to each patient’s needs. Certain patients may be appropriate candidates for long-term (eg, up to 1 year) naltrexone treatment if they demonstrate evidence of compliance with medication and psychosocial treatment regimens.

To date, the most reported adverse event has been injection site reactions. The FDA has received 196 reports of injection site reactions including cellulitis, induration, hematoma, abscess, sterile abscess, and necrosis, 16 of which required surgical intervention. In response to this, the FDA has recently issued an alert to healthcare professionals who are administering naltrexone to their patients. The recommendations are as follows:

Physicians who administer naltrexone should refer a patient who develops pain, swelling, bruising, pruritus, and redness at the injection site that does not improve within 2 weeks of naltrexone administration to a surgeon. Naltrexone should be administered as directed as an intramuscular (IM) gluteal injection. Naltrexone should not be administered intravenously, subcutaneously, or inadvertently into fatty tissue. Healthcare providers should ensure that the naltrexone injection is given correctly with the pre-packaged 1.5-inch needle that is specifically designed for this drug. In addition, the FDA reports data that shows women may be physiologically at higher risk for injection site reactions due to typically higher gluteal fat thickness.3

Several studies4,5 demonstrate that long-acting naltrexone is well tolerated and associated with a significant reduction in heavy drinking in a population of actively drinking patients. In one recent study,21 the abstinence rate was significantly higher for IM naltrexone compared with placebo: median time to first drink was 41 days versus 12 days, respectively, and rate of continuous abstinence at end of the study was 32% versus 11% (P=.02). In addition, the patients who received naltrexone extended release (ER) showed substantially increased time to first heavy drinking event (>180 days vs. 20 days; P=.04) and decreased the median number of any drinking days per month by 90% (0.7 days vs. 7.2 days; P=.005) and heavy drinking days per month by 93% (0.2 days vs. 2.9 days; P=.007).

However, more data are needed to determine whether this treatment would similarly benefit alcohol-dependent women. Adverse events associated with the depot formulation appear to be milder than those associated with the use of oral naltrexone, but a direct comparison between the oral and depot formulations within the same clinical trial has yet to be studied.


In 2004, following use of acamprosate in Europe for more than a decade, the FDA approved this drug for treatment of alcohol dependence. Acamprosate targets the brain’s glutamate system and has been shown in European metanalyses to reduce the motivation to drink.22 However, several US studies23,24 have found it to have little efficacy, especially in non-motivated and non-abstinent populations. The reason for these contradictory results is unclear, but researchers speculate that they may reflect differences in patient characteristics included in the European and US studies as well as study designs. One early observational study25 suggested that acamprosate is useful in heavy drinking populations and is safe for use even early in the alcohol detoxification process. Trials continue and many researchers in the US and abroad continue to support the efficacy of acamprosate in maintaining abstinence and reducing alcohol consumption.26,27

Acamprosate is dosed as a 333-mg tablet TID and treatment duration can vary from 3–12 months. It is generally well tolerated and adverse events tend to be mild and transient, primarily involving the gastrointestinal tract with diarrhea and abdominal discomfort in approximately 10% of patients. Acamprosate should not be taken by those with kidney problems or allergies to the drug.28


Despite the overall plateau in illicit drug use in the US, opioid dependence remains a growing and deadly affliction. The number of current US heroin users rose from 136,000 in 2005 to 338,000 in 2006,29 while admissions for heroin dependence treatment actually decreased over the same 2 years.30 One out of every 20 high school seniors reported having tried oxycodone over the previous year31 and many, if not most, opioid-related deaths were due to misuse and abuse of prescription opioids.32   

In the 50 years since the introduction of methadone, clinicians have had few other effective medications for opioid addiction until the FDA’s approval of suboxone in October 2002. Previous articles have outlined the clinical applications of methadone for detoxification and opioid maintenance,33 naltrexone for opioid blockade,34 and clonidine for opioid detoxification.35 Levo-a-acetyl-methadol, a previously available opioid agonist, was taken off the market in early 2004 because of cardiac side effects.36 This article reviews the clinical usage of the newer medications buprenorphine and injectable depot naltrexone and outlines the case against Prometa in the treatment of opioid addiction.


Buprenorphine, a partial opioid agonist, was approved by the FDA and became commercially available in January 2003 with a sublingual tablet as a sole agent as well as in a preparation mixed with naloxone, designed to prevent illicit intravenous use.

Under the auspices of the Drug Addiction Treatment Act of 2000,37 office-based physicians with special licenses were permitted to prescribe buprenorphine and other opioid medications for the treatment of addiction for the first time. The required training for these special licenses, in the form of an 8-hour course, is available from professional organizations like the American Academy of Addiction Psychiatry.38

Like methadone, buprenorphine can be used in a tapering protocol for detoxification or at stable dose for opioid maintenance. The differences between buprenorphine and methadone are substantial; buprenorphine can be prescribed in a private physician’s office, it has a “ceiling effect” which makes overdose unlikely, and its partial opioid agonism makes addictive use less likely, though far from impossible. Buprenorphine does not, as yet, engender the same sort of societal stigma as methadone, so the medication is acceptable to a cohort of opioid-dependent individuals who would avoid methadone clinics.

After determining that the patient is appropriate for either buprenorphine detoxification or maintenance, the treating clinician arranges a medication induction. One good source for treatment planning, SAMHSA’s Clinical Guide for the Use of Buprenorphine in the Treatment of Opioid Addiction,39 recommends (amongst other things) that the prospective patient choose buprenorphine after reviewing all the treatment options, be reasonably complaint, understand the risk and benefits of treatment, and not be dependent on other central nervous system (CNS) depressants like benzodiazepines and alcohol.

Induction onto buprenorphine can be complicated, especially with a patient who is less than fully compliant. Standard recommendations for induction40 suggest that the patient show actual withdrawal symptoms before a test dosage of buprenorphine 2–4 mg is administered, followed by close observation of withdrawal symptoms, with a first-day total maximum dosage of 8 mg and a second-day maximum dosage of 16 mg.

Once stabilized on buprenorphine, patients clearly benefit in terms of opioid avoidance. One outpatient study41 compared buprenorphine, buprenorphine/naloxone, and placebo in the treatment of 326 opiate-addicted people. The high efficacy of both buprenorphine preparations necessitated in preventing illicit opioid use necessitated an early end to the study; the subjects’ urine toxicologies at 4 weeks and self-reported opioid craving were both so low that the study was stopped and the placebo group was offered active medication.

In comparison to methadone, buprenorphine is similarly effective at the higher dosage range. One study42 of 116 opioid-dependent subjects compared high and low doses of both buprenorphine and methadone and found (predictably) that at 24 weeks, opioid positive urine toxicologies were highest (77% and 72%) in those randomly assigned to take the low doses of methadone 20 mg/day and buprenorphine 4 mg/day. Conversely, opioid-positive urine toxicology rates were lowest for those assigned to high doses of methadone 65 mg/day and buprenorphine 12 mg/day, at 45% and 58%, respectively.

One exciting possibility for buprenorphine is a depot preparation which can last 6 months. In Phase III FDA clinical trials,43 the 6-month depot form of buprenorphine was found to be better than placebo in preventing opioid use and very unlikely to be used illicitly, both to a very high degree of statistical significance (P=.0117 and P=.0004, respectively).

Depot Naltrexone

Naltrexone, a highly effective and long-lasting opioid receptor antagonist, is approved by the FDA, as noted above, as an anti-craving agent for alcohol. The 2008 Physician’s Desk Reference notes that naltrexone “…is not indicated for the purpose of opioid blockade or the treatment of opiate dependence…”44 because of the possibility that patients will attempt to overwhelm the opiate blockade and suffer respiratory collapse. Despite this rather overstated warning, (those taking oral naltrexone could try to overwhelm the blockade also,) clinicians have made the obvious maneuver of using naltrexone in their opioid-addicted patients. One preliminary study45 of IM naltrexone ER in 27 opioid-using adults found that blockade of hydromorphone as measured by pupil size and a visual analog scale of reported drug effect was complete for 28 days, based on dosages of IM naltrexone ER 150 mg and 300 mg. (Naltrexone is sold in 380 mg vials.)

Another randomized, double-blind, placebo-controlled study46 noted oral naltrexone’s “high dropout rates during treatment and poor compliance with medication ingestion.” At 8 weeks, the investigators found a 39% retention in treatment for those receiving placebo, while those receiving IM naltrexone 192 mg had a 60% retention rate and those receiving IM naltrexone 384 mg were retained in treatment at the rate of 68%. The article concludes that there is “…new evidence of the feasibility, efficacy, and tolerability of long acting antagonist treatments for opioid dependence.”46


While smoking rates have leveled off or declined in developed nations, tobacco use in the developing world continues to rise at a rate of approximately 3.4% per year.47 The US Centers for Disease Control and Prevention6 describes tobacco use as “the single most important preventable risk to human health in developed countries and an important cause of premature death worldwide.”

Since the early 1990s, clinicians have been able to help their patients quit or to temporarily abstain from smoking by using a variety of nicotine-containing tobacco substitutes, or nicotine-replacement therapy (NRT). Most nicotine-replacement products are available over the counter and are fundamental tools for physicians helping patients taper themselves off of nicotine. The most popular are options such as the nicotine patch, nicotine gum, and nicotine inhaler. The patch which is placed on the upper body (usually the upper arm/deltoid) delivers nicotine through the skin to the bloodstream for approximately 24 hours. The treatment period may last for ≥8 weeks. The nicotine gum is a gum-like resin that delivers nicotine to the bloodstream, available in a 2-mg dose for regular smokers and a 4-mg dose for heavy smokers. The maximum number of pieces per day is 20 and treatment is recommended for 1–3 months, with a maximum of 6 months. The nicotine lozenge is a tablet that dissolves in the mouth and is available in 2-mg and 4-mg doses. The recommended dose is one lozenge every 2–3 hours for 6 weeks, with a gradual increase in intervals between lozenges over the next 6 weeks. Some prefer a nicotine inhaler that is shaped somewhat like a cigarette holder; when inhaled, it gives off nicotine vapors which help to relieve withdrawal symptoms. A nicotine nasal spray available with prescription has a quicker delivery system than most of the other NRTs. It is usually prescribed for 3-month periods, for a maximum of 6 months.

For many, these substitutes temporarily lessen the physical withdrawal symptoms of smoking cessation, along with peer support often in the form of groups and telephone helplines. However, for many, these treatments have fallen short of relieving symptoms and helping them to attain or maintain abstinence. This article reviews the clinical uses of two new medications that are currently being used for the treatment of nicotine addiction, bupropion and varenicline.


Bupropion is an atypical antidepressant that acts as a norepinephrine and dopamine reuptake inhibitor and nicotinic antagonist. Initially researched and marketed as an antidepressant, bupropion was subsequently found to be effective for smoking cessation and in 1997 was approved by the FDA for use as a smoking cessation aid.48

Bupropion is widely reported to reduce the severity of nicotine cravings and withdrawal symptoms that accompany smoking cessation. After a seven-week treatment,49 27% of subjects who received bupropion reported that an urge to smoke was a problem, versus 56% of those who received placebo. In the same study,49 the patients taking bupropion reported fewer mood swings than the placebo group (21% vs. 32%, respectively).

Bupropion for smoking cessation treatment was originally recommended as a 7–12-week course, with the patient stopping the use of tobacco approximately 10 days into the course. However, many patients find that a longer course (possibly several months) has proven beneficial so clinicians can tailor treatment to patients’ needs as long as they continue to monitor for adverse effects. Dosing should begin at 150 mg/day given every day for the first 3 days, followed by a dose increase for most patients to the recommended usual dose of 300 mg/day. In comparison to nicotine replacement therapy, bupropion is similarly efficacious. Bupropion approximately doubles the chance of quitting smoking successfully after 3 months. One study50 demonstrated that 1 year after the treatment, the odds of sustaining smoking cessation were 1.5 times higher in the bupropion group than in the placebo group.


Varenicline is a more recently introduced medication indicated for smoking cessation. It is a partial agonist of the α4β2 subtype of the nicotinic acetylcholine receptor that was approved for the treatment of smoking cessation in May 2006 after demonstrating superior efficacy over NRT and bupropion with a minimal side-effect profile.

The FDA approved its use as a 12-week trial51 that, if proven successful, can be continued for another 12 weeks. However, if the patient is not successful at completely stopping smoking within the first 12-week period, continued use is not recommended.

In early comparison studies,50,52 varenicline was more effective than other strategies in helping to reduce nicotine craving and maintain abstinence. One metanalysis study50 identified varenicline to be more effective in reducing craving to both placebo and bupropion and in indirect comparisons with NRT. Another study52 demonstrated that after 1 year, the rate of continuous abstinence was 10% for placebo, 15% for bupropion, and 23% for varenicline. Varenicline has not been tested in children, those <18 years of age, or pregnant or breastfeeding women, and, therefore, is not recommended for use by these populations.

The side effects that are most commonly reported are nausea, headache, insomnia, and abnormal dreams. However, in late 2007 the FDA reported receiving several post-marketing reports of patients experiencing more serious symptoms such as suicidal ideation, erratic and suicidal behavior, and extreme drowsiness.

In early 2008 the FDA issued an alert7 to further clarify its findings, noting that “it appears increasingly likely that there is an association between varenicline and serious neuropsychiatric symptoms.” In spite of this, many patients have reported success with the medication and may decide with their physician that the short- and long-term health risks of smoking outweigh the possible dangers of a trial of this smoking cessation therapy.53 As with all new medications, clinicians are recommended to exercise caution in the use of varenicline and consider the use of alternative approaches to smoking cessation while more research is being conducted to further understand the short- and long-term risks associated with the medication.


Stimulant and cocaine dependence continue to present a major health and societal concern despite increasing public awareness of the dangers that accompany illicit drug use. According to a SAMHSA report54 in 2006, “the demand for treatment for cocaine dependence remained roughly level from 1992–2005, while the demand for treatment for amphetamine dependence increased about eight-fold.” As a result, the National Institute on Drug Abuse has pushed the scientific research community to develop treatments aimed at combating the craving, addiction, and overdose of the drug. To date, however, no treatment has been approved by the FDA.

Cognitive-behavioral therapy, motivational therapy, contingency management, and group therapy (such as 12-step programs) are behavioral therapies empirically proven to be effective in treating cocaine addiction.55-57 However, these treatments could be significantly augmented by pharmacotherapeutic agents to help patients attain initial abstinence or prevent relapse. Medications that ease the symptomatology of cocaine withdrawal (often characterized by anxiety, depression, and fatigue) are options currently available to clinicians, but they still fall far short of treating the greater problem.

Previous articles58,59 have outlined the clinical applications of the antidepressant desipramine and the anti-epileptic carbamazepine for minimizing craving for cocaine. These, however, along with several other antidepressants such as citalopram,60 bupropion,61,62 and fluoxetine,63 have shown insufficient results in treating those with cocaine dependence.

Recently, numerous medications have been shown in placebo-controlled, double-blind, randomized-controlled trials to significantly decrease cocaine dependence (BH Herman, PhD, A Elkashef, MD, and F Vocci PhD, personal communication, July 29, 2008). The focus has mostly been on substitution with stimulant medications to decrease cocaine use by inhibiting craving, reducing withdrawal, and producing tolerance to the acute reinforcing effects of cocaine.

Modafinil and propanolol have demonstrated their potential to attain abstinence by minimizing withdrawal symptoms and reducing cocaine reinforcement.64-67 Other prospective agents minimize relapse by reducing cocaine-induced euphoria and cue-induced craving. These include disulfiram68 and several gamma-aminobutyric acid (GABA)-ergic agents like baclofen,69 tiagabine,70 gamma-vinyl GABA,71 and topiramate.72

A novel approach being studied for relapse prevention is the development of a cocaine vaccine that has been shown to produce cocaine-specific antibodies that bind the drug and prevent it from crossing the blood-brain barrier.73 Similarly, another alternative method being studied is a CNS immunopharmacotherapy for the treatment of cocaine addiction. Intranasal administration of an engineered bacteriophage with cocaine sequestering antibodies on its surface is proposed to bind cocaine in the CNS and block its behavioral effects.74

The pursuit for medications to treat amphetamine and methamphetamine dependence has only recently begun. Thus, fewer medications have been tested and none approved. However, the similarities between the actions of amphetamines and those of cocaine in the brain suggest that the same medications may help with both addictions.75 As a result, studies are underway to examine many of the above proposed treatments for amphetamine and methamphetamine dependence.


The Prometa program is a heavily advertised75,76 proprietary program for the treatment of alcohol and stimulant dependence, which, according to promotional materials “…integrates physiological, nutritional, and psychosocial therapies, designed to help patients meet their individual recovery goals….”77 Although the actual medications used in the treatment are not mentioned in the promotional materials, one article78 describes the off-label use of flumazenil, hydralazine, and gabapentin in an open-label study of 50 methamphetamine addicts. During the 12-week, open-label, single-group study, the subjects received, for 3 consecutive days, hydoxyzine 50 mg, followed by flumazenil .1–.3 mg, followed by gabapentin 300 mg/day up to 1,500 mg/day, as tolerated. On days 21 and 22 of the study, the subjects were given “booster” injections of flumazenil. Among the patients treated in this study, there was a 47% reduction in self-reported use over 84 days of treatment as well as significant reductions in urine toxicology results and self-reported craving. However, since no randomized, placebo-controlled studies have been published in the peer-reviewed literature, there is no acceptable evidence that the Prometa program’s risk and expense are justified by its benefits.


Many new medications offer efficacious and effective clinical options to the general physician. The next generation of treatments (including vaccines and “cocktails”) in the pipeline also show exciting potential for further relieving these complex conditions. However, medication management alone remains limited. Comprehensive treatment of substance use disorders can only be maximized by a full biopsychosocial plan which mutually reinforces medication compliance, more traditional psychotherapy, and peer-led help groups. PP


1.    Helzer JE, Burnam A, McEvoy T. Alcohol abuse and dependence. In: Robin LN, Regier A, eds. Psychiatric Disorders in America: The Epidemiologic Catchment Area Study. New York, NY: Free Press; 1991:81-115.
2.    Monitoring the Future Study. Available at:, Accessed November 4, 2008.
3.    Marlatt GA, Gordon JR. Relape Prevention: Maintenance Strategies in the Treatment of Addictive Behavior. New York, NY: Guilford Press; 1985.
4.    Galanter M. Network Therapy for Alcohol and Drug Abuse: A New Approach in Practice. New York, NY: Basic Books; 1993.
5.    Nace EP. Alcoholics Anonymous. In: Lowinson JH, Ruiz, P, Millman RB, Langrod JC. Substance Abuse: A Comprehensive Textbook. 3rd ed. Baltimore, MD: Lippincott Williams & Wilkins; 1997.
6.    Carroll KM, Schottenfeld R. Nonpharmacologic approaches to substance abuse treatment. Med Clin North Am. 1997;81(4):927-944.
7.    Miller WR, Wilbourne PL. Mesa grande: a methodological analysis of clinical trials of treatments for alcohol use disorders. Addiction. 2002;97:265-277.
8.    Finney JW, Monahan SC. The cost-effectiveness of treatment for alcoholism. J Stud Alcohol. 1996;57(3):229-243.
9.    Fuller RK, Roth HP. Disulfiram for the treatment of alcoholism. Ann Intern Med. 1979;90(6):901-904.
10.    Fuller R, Roth H, Long S. Compliance with disulfiram treatment of alcoholism. J Chronic Dis. 1983;36(2):161-170.
11.    Schuckit MA. A one-year follow-up of men alcoholics given disulfiram. J Stud Alcohol. 1985;46(3):191-195.
12.    O’Malley SS, Jaffe AJ, Chang G, Schottenfeld RS, Meyer RE, Rounsaville B. Naltrexone and coping skills therapy for alcohol dependence: a controlled study. Arch Gen Psychiatry. 1992;49(11):881-887.
13.    Volpicelli JR, Alterman AI, Hayashida M, O’Brien CP. Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry. 1992;49(11):876-880.
14.    Anton RF, Moak DH, Waid LR, Latham P, Malcolm R, Dias JK. Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: results of a placebo-controlled trial. Am J Psychiatry. 1999;156(11):1758-1764.
15.    Chick J, Anton R, Checinski K, et al, A multicentre, randomized, double-blind, placebo-controlled trial of naltrexone in the treatment of alcohol dependence or abuse. Alcohol Alcohol. 2000;35(6):587-593.
16.    Morris PL, Hopwood M, Whelan G, Gardiner J, Drummond E. Naltrexone for alcohol dependence: a randomized controlled trial. Addiction. 2001;96(11):1565-1573.
17.    Krystal JH, Cramer JA, Krol WF, Kirk GF, Rosenheck RA. Naltrexone in the treatment of alcohol dependence. N Engl J Med. 2001;345(24):1734-1739.
18.    Kranzler HR, Van Kirk J. Efficacy of naltrexone and acamprosate for alcoholism treatment: a meta-analysis. Alcohol Clin Exp Res. 2001;25(9):1335-1341.
19.    Streeton C, Whelan G. Naltrexone, a relapse prevention maintenance treatment of alcohol dependence: a meta-analysis of randomized controlled trials. Alcohol. 2001;36(6):544-552.
20.    Kuehn BM. New therapies for alcohol dependence open options for office-based treatment. JAMA. 2007;298(21):2467-2468.
21.    O’Malley SS, Garbutt JC, Gastfriend DR, Dong Q, Kranzler HR. Efficacy of extended-release naltrexone in alcohol-dependent patients who are abstinent before treatment. J Clin Psychopharmacol. 2007;27(5):507-512.
22.    Wilde MI, Wagstaff AJ. Acamprosate: a review of its pharmacology and clinical potential in the management of alcohol dependence after detoxification. Drugs. 1997;53(6):1038-1053.
23.    Anton RF. O’Malley SS. Ciraulo DA. et al. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006;295(17):2003-2017,
24.    Mason BJ. Acamprosate. Recent Dev Alcohol. 2003;16:203-215.
25.    Brasser SM, McCaul, ME, Houtsmiller EJ. Alcohol effects during acamprosate treatment: A dose-response study in humans. Alcohol Clin Exp Res. 2004;28(7):1074-1083.
26.    Chick J, Lehert P, Landron F.; Plinius Maior Society. Does acamprosate improve reduction of drinking as well as aiding abstinence? J Psychopharmacol. 2003;17(4):397-402.
27.    Mason BJ. Acamprosate for alcohol dependence: an update for the clinician. Focus. 2006;4:505-511.
28.    Acamprosate Oral. Available at: Accessed November 11, 2008.
29.    Results from the 2006 National Survey on Drug Use and Health: National Trends. SAMHSA. Available at: Accessed November 4, 2008.
30.    NIDA InfoFacts: Heroin. Available at: Accessed November 11, 2008.
31.    Johnston L. Monitoring the Future. Ann Arbor, MI: University of Michigan. December 11, 2007. Press Release.
32.    Paulozzi LJ. Testimony to U.S. House of Representatives by Leonard J. Paulozzi, MD. Atlanta, GA: Centers for Disease Control and Prevention; 2007.
33.    Margolin A, Kosten TR. Opioid detoxification and maintenance with blocking agents. In: Miller NS, ed. Comprehensive Handbook of Drug and Alcohol Addiction. New York, NY: Marcel Dekker; 1991:1127-1141.
34.    Institute of Medicine (IOM). Development of Medications for the Treatment of Opiate and Cocaine Addictions: Issues for the Government and Private Sector. Washington, DC: National Academy of Sciences; 1995.
35.    Kleber HD, Riordan CE, Rounsaville B, et al. Clonidine in outpatient detoxification from methadone maintenance. Arch Gen Psychiatry. 1985;42(4):391-394.
36.    Food and Drug Administration. FDA Announces Labeling Changes Following Cardiac Adverse Events With Addiction Drug. Rockville, Md: National Press Office. April 20, 2001. Talk Paper T01-15.
37.    Buprenorphine. Available at: Accessed November 4, 2008.
38.    American Academy of Addiction Psychiatry. Available at: Accessed November 4, 2008.
39.    U.S. Department of Health and Human Services. Clinical Guidelines for the Use of Burprenorphine in the Treatment of Opioid Addiction, A Treatment Improvement Protocol, TIP 40. Rockville, MD: U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Substance Abuse Treatment; 2004.
40.    Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction, A treatment Improvement Protocol, TIP 40. Laura McNicholas, Chair. DHHS Publication No. (SMA) 04-3939; 2004.
41.    Fudala PJ, Bridge TP, Herbert S, et al. Office-based treatment of opiate addiction with a sublingual-table formulation of buprenorphine and naloxone. N Engl J Med. 2003;349(10);949-958.
42.    Schottenfeld RS, Pakes JR, Oliveto A, Ziedonis D, Kosten TR. Buprenorphine vs. methadone maintenance treatment for concurrent opioid dependence and cocaine abuse. Arch Gen Psych. 1997;54(8):713-720.
43.    Titan Pharmaceuticals Announces Positive Results From Phase III Clinical Trial Of Probuphine For The Treatment Of Opioid Addiction. Available at: Accessed November 4, 2008.
44.    Physician’s Desk Reference. 62nd ed. Montvale, NJ: Thomson Healthcare Inc; 2008:972.
45.    Preston GE, Kenzie L, Schmittner J, et al. A randomized, single dose, opioid challenge study of extended release naltrexone in opioid-using adults. Poster presented at: the 45th Annual Meeting of the American College of Neuropsychopharmacology; December 3-7, 2006; Hollywood, FL.
46.    Comer SD, Sullivan MA, Yu E, et al. Injectable, sustained-release naltrexone for the treatment of opioid dependence: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2006;63(2):210-218.
47.    World Health Organization. Regional Office for the Western Pacific. Smoking Statistics. Available at: Accessed November 4, 2008.
48.    Whiten L. Bupropion Helps People With Schizophrenia Quit Smoking. National Institute on Drug Abuse. Research Findings. 2006;20(5):1.
49.    Tonnesen P, Tonstad S, Hjalmarson A, et al. A multicentre, randomized, double-blind, placebo-controlled, 1-year study of bupropion SR for smoking cessation. J Intern Med. 2003;254(2):184-192.
50.    Wu P, Wilson K, Dimoulas P, Mills EJ. Effectiveness of smoking cessation therapies: a systematic review and meta-analysis. BMC Public Health. 2006;6:300.
51.    Food and Drug Administration. FDA Approves Novel Medication for Smoking Cessation. Rockville, Md: National Press Office. May 11, 2006. Press Release P06-67.
52.    Jorenby DE, Hays JT, Rigotti NA, et al. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA. 2006;296(1):56-63. Erratum in: JAMA. 2006;296(11):1355.
53.    Centers for Disease Control and Prevention. Annual smoking-attributable mortality, years of potential life lost, and productivity losses—United States, 1997-2001. MMWR Morb Mortal Wkly Rep. 2005;54(25):625-628.
54.    Substance Abuse and Mental Health Services Administration. Office of Applied Studies. Treatment Episode Data Set (TEDS): 1994-2004. National Admissions to Substance Abuse Treatment Services, DASIS Series: S-33, DHHS Publication No. (SMA) 06-4180. Rockville, Md: Substance Abuse and Mental Health Services Administration; 2006.
55.    Hoffman JA, Caudill BD, Koman JJ 3rd, Luckey JW, Flynn PM, Hubbard RL. Comparative cocaine abuse treatment strategies: enhancing client retention and treatment exposure. J Addict Dis. 1994;13(4):115-128.
56.    Higgins ST, Budney AJ, Bickel WK, Foerg FE, Donham R, Badger GJ. Incentives improve outcome in outpatient behavioral treatment of cocaine dependence. Arch Gen Psychiatry. 1994;51(7):568-576.
57.    Kosten T, Poling J, Oliveto A. Effects of reducing contingency management values on heroin and cocaine use for buprenorphine- and desipramine treated patients. Addiction. 2003;98(5):665-671.
58.    Campbell J, Nickel EJ, Penick EC, et al. Comparison of desipramine or carbamazepine to placebo for crack cocaine-dependent patients. Am J Addict. 2003;12(2):122-136.
59.    McDowell D, Nunes EV, Seracini AM, et al. Desipramine treatment of cocaine-dependent patients with depression: a placebo-controlled trial. Drug Alcohol Depend. 2005;80(2):209-221.
60.    Moeller FG, Schmitz JM, Steinberg JL, et al. Citalopram combined with behavioral treatment reduces cocaine use: A double-blind, placebo-controlled trial. Am J Drug Alcohol Abuse. 2007;33(3):367-378.
61.    Poling J, Oliveto A, Petry N, et al. Six-month trial of bupropion with contingency management for cocaine dependence in a methadone-maintained population. Arch Gen Psychiatry. 2006;63(2):219-228.
62.    Shoptaw S, Heinzerling KG, Rotheram-Fuller E, et al. Bupropion hydrochloride versus placebo, in combination with cognitive behavioral therapy, for the treatment of cocaine abuse/dependence. J Addict Dis. 2008;27(1):13-23.
63.    Grabowski J, Rhoades H, Elk R, et al. Fluoxetine is ineffective for treatment of cocaine dependence or concurrent opiate and cocaine dependence: two placebo-controlled, double blind trials. J Clin Psychopharmacol. 1995;15:163-174.
64.    Dackis CA, Lynch KG, Yu E, et al. Modafinil and cocaine: A double-blind, placebo-controlled drug interaction study. Drug Alcohol Depend. 2003;70(1):29-37.
65.    Dackis CA, Kampman KM, Lynch KG, Pettinati HM, O’Brien CP. A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Neuropsychopharmacology. 2005;30(1):205-211.
66.    Kampman KM, Dackis C, Lynch KG, et al. A double-blind, placebo-controlled trial of amantadine, propranolol, and their combination for the treatment of cocaine dependence in patients with severe cocaine withdrawal symptoms. Drug Alcohol Depend. 2006;85(2):129-137.
67.    Kampman KM, Volpicelli JR, Mulvaney F, et al. Effectiveness of propranolol for cocaine dependence treatment may depend on cocaine withdrawal symptom severity. Drug Alcohol Depend. 2001;63(1):69-78.
68.    Carroll KM, Fenton LR, Ball SA, et al. Efficacy of disulfiram and cognitive behavior therapy in cocaine-dependent outpatients: a randomized placebo-controlled trial. Arch Gen Psychiatry. 2004;61(3):264-272.
69.    Shoptaw S, Yang X, Rotheram-Fuller EJ, et al. Randomized placebo-controlled trial of baclofen for cocaine dependence: preliminary effects for individuals with chronic patterns of cocaine use. J Clin Psychiatry. 2003;64(12):1440-1448.
70.    Gonzalez G, Sevarino K, Sofuoglu M, et al. Tiagabine increases cocaine-free urines in cocaine-dependent methadone-treated patients: results of a randomized pilot study. Addiction. 2003;98(11):1625-1632.
71.    Brodie JD, Figueroa E, Laska EM, Dewey SL. Safety and efficacy of gamma-vinyl GABA (GVG) for the treatment of methamphetamine and/or cocaine addiction. Synapse. 2005;55(2):122-125.
72.    Kampman KM, Pettinati H, Lynch KG, et al. A pilot trial of topiramate for the treatment of cocaine dependence. Drug Alcohol Depend. 2004;75(3):233-240.
73.    Kosten TR, Rosen M, Bond J, Settles M, Roberts JS, Shields J, Jack L, Fox B. Human therapeutic cocaine vaccine: safety and immunogenicity. Vaccine. 2002;20(7-8):1196-204.
74.    Martell BA, Mitchell E, Poling J, Gonsai K, Kosten TR. Vaccine pharmacotherapy for the treatment of cocaine dependence. Biol Psychiatry. 2005;58(2):158-164.
75.    Dickerson TJ, Janda KD. Recent advances for the treatment of cocaine abuse: central nervous system immunopharmacotherapy, AAPS J. 2005;7(3):E579-E586.
76. Thursday, March 30, 2006. Chris Farley drug ads. Available at: Accessed November 4, 2008.
77.    Weinstein LM, Jack T, Wesson DR, Sabnani S. Scientic Basis of the Prometa© Program. Los Angeles, CA: Mythiam Medical Affairs; 2007.
78.    Urschel HC, Hanselka LL, Gromov I, et al. Open-Label study of a propietrary treatment program targeting type A γ-aminobutyric acid receptor dysregulation in methamphetamine dependence. Mayo Clin Proc. 2007;82(10):1170-1178.


Dr. Levenson is professor in the Departments of Psychiatry, Medicine, and Surgery, chair of the Division of Consultation-Liaison Psychiatry, and vice chair for clinical affairs in the Department of Psychiatry at Virginia Commonwealth University School of Medicine in Richmond.
Disclosure: Dr. Levenson reports no affiliation with or financial interest in any organization that may pose a conflict of interest.


This column continues a series reviewing the interface between dermatology and psychiatry. Dermatologists and primary care physicians frequently encounter important psychiatric issues affecting diagnosis and management of patients with dermatologic complaints. Psychological factors affect many dermatologic conditions, including atopic dermatitis, psoriasis, alopecia areata, urticaria and angioedema, and acne vulgaris. Some dermatologic conditions are best considered as idiopathic functional disorders, such as idiopathic pruritus, which can be generalized or focal (eg, pruritus ani, vulvae, and scroti). Some primary psychiatric disorders present with primarily physical symptoms to dermatologists, including body dysmorphic disorder (BDD) and delusional disorder, somatic type (eg, delusions of parasitosis, delusions of a foul body odor). Indeed, most patients with delusions of parasitosis or BDD avoid seeing psychiatrists or other mental health professionals, and resist referral. Dermatologists also see patients with compulsive behaviors that may be part of obsessive-compulsive disorder, or that stand alone, eg, trichotillomania, psychogenic excoriation, and onychophagia. Factitious skin disorders include factitious dermatitis (also called dermatitis artefacta) and psychogenic purpura. Another important aspect of the interface between psychiatry and dermatology is the range of dermatologic adverse reactions to psychotropic drugs. More detailed coverage of these topics can be found elsewhere.1,2 The first part of the series focused on atopic dermatitis and psoriasis,3 and the second reviewed alopecia areata, urticaria, and angioedema.4 This third installment reviews acne vulgaris and chronic idiopathic pruritus.

Acne Vulgaris

Acne vulgaris, a common skin disease affecting sebaceous glands with sebum blocking hair follicles, is characterized by a variety of lesions, including comedones, inflammatory papules, pustules, and nodules. The face and upper neck are the most common sites, but the chest, back, and shoulders may also be involved. Most cases of acne vulgaris develop in early adolescence, affecting 85% of teenagers, and it frequently continues into adulthood. During adolescence, the frequency of acne increases with age and pubertal development. In girls, the commencement of menstruation is associated with increased frequency of acne. Perhaps this explains why adolescent girls may be more vulnerable than boys to the negative psychological effects of acne.5 The course of acne vulgaris is usually self-limited, with gradual improvement and spontaneous disappearance after several years, but it may persist into the thirties and forties. Possible complications include development of pitted or hypertrophic scars as well as psychological adverse effects, discussed below. Although women are more likely than men to have persistent acne, it tends to be more severe in men.1,2

Although the cause of acne vulgaris is unknown, many factors are probably involved in its pathogenesis, including genetics, inflammation, skin flora, hormonal activity, and stress. The relationship with stress has long been observed, but there are few prospective studies. One study6 reported that patients with acne may experience worsening of the disease during academic examinations. While there is a significant association between psychological stress and severity of acne, it does not appear to be mediated by increased sebum production.7 A variety of neuroendocrine mediators may be involved in the precipitation or aggravation of acne by stress, including adrenal steroids, corticotropin-releasing hormone, melanocortins, beta-endorphin, vasoactive intestinal polypeptide, neuropeptide Y, insulin-like growth factor, and calcitonin gene-related peptide.1,2,8 It has also been long recognized that lithium can cause or aggravate acne,9 and there have been case reports of acne resulting from aripiprazole,10 lamotrogine,11 valproate,12 and other anticonvulsants, as well as the atypical tricyclic antidepressant amineptine13 (not available in the United States).

Severe acne is associated with increased depression, anxiety, poor self-image, and poor self-esteem.1,2 Not surprisingly, psychiatric symptoms are more common in more severe acne and in the later stages of puberty.14 A cross-sectional study15 of approximately 10,000 teenagers in New Zealand found that “problem acne” was associated with an increased risk of depressive symptoms (odds ratio 2.04), anxiety (odds ratio 2.3), and suicide attempts (odds ratio 1.83). The association of acne with suicide attempts remained after controlling for depressive symptoms and anxiety (odds ratio 1.5). One study16 has estimated the incidence of suicidal ideation in patients with acne as 7.1%. However, psychiatric comorbidity may even occur with milder acne. A Turkish study17 found that patients with acne were at increased risk for anxiety and depression compared to the normal population, irrespective of the degree of severity.

Acne can substantially interfere with social and occupational functioning and result in impairment in quality of life (QOL). There are numerous available rating scales for quantifying QOL in patients with acne.18 Acne negatively affects quality of life, and there is not always a correlation between the severity of acne and its impact on QOL. The magnitude of anxiety and depression is proportional to degree of impairment of QOL due to acne.17 Acne patients with greater social sensitivity experience poorer QOL compared to other patients with the same severity of acne.19 Anger, similarly, is associated with poorer QOL and less satisfaction with treatment, independent of other variables.20

Successful treatment of acne with isotretinoin leads to reduction in anxiety and depression and significant improvement in self-image.1,2 However, patients’ perceptions of the results of treatment for acne can differ from their physician’s judgment, with more pessimistic self-assessment in those with emotional distress.21

Anecdotal reports of depression, suicidal ideation, suicide attempts, and suicide with the use of isotretinoin for treatment of acne vulgaris were widely reported in the media and led the US Food and Drug Administration to expand the label warning to include that “accutane may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors.”22 However, a recent systematic review23 of nine controlled trials found that rates of depression among isotretinoin users were similar to the rates in oral antibiotic control groups, ranging from 1% to 11%. Trials that compared depression before and after isotretinoin treatment did not show a statistically significant increase in depression symptoms or diagnoses. Some even found a trend toward reduction in depressive symptoms after isotretinoin therapy, particularly in patients with higher pretreatment depression scores. Similar reductions have been reported in uncontrolled trials.24 Another recent study25 in Canada using a retrospective case-crossover design found that, the relative risk for those exposed to isotretinoin of developing a depression diagnosis was 2.68 (95% CI=1.10–6.48), after adjusting for confounders. In contrast, another Canadian group26 recently reported a prospective controlled cohort study that concluded that isotretinoin does not appear to be associated with the development of depression. The literature to date has not proven a causative association between isotretinoin use and depression or suicidal behavior. Interpretation of the literature is complicated both by important methodologic limitations in many of the studies and by the association of acne itself with depression, anxiety, and possibly suicidal behavior.

The FDA and isotretinoin’s manufacturer subsequently added a warning regarding the possible development of aggressive and/or violent behavior to the psychiatric disorder warning section of the package insert previously focused on depression and suicidality. While there have been reports of several cases of manic psychosis in association with isotretinoin treatment,27 large population-based cohort studies have found no evidence that use of isotretinoin is associated with an increased risk for psychosis.28

One may ask how clinicians should proceed, given the FDA’s black box warning and the case reports suggesting an association between isotretinoin and depression and suicide, yet an overall lack of support for these associations in the more rigorous observational and epidemiologic studies. It is prudent to continue to prescribe isotretinoin to treat severe acne, while at the same time educating patients (and the parents of minor patients) of the importance of actively monitoring for depressive symptoms; if symptoms appear, referral to a psychiatrist and discontinuation of isotretinoin should be considered. In addition, patients should be cautioned not to self-medicate for depression with St. John’s Wort both because it is ineffective and because its metabolic interaction with hormonal contraceptives may reduce their effectiveness.

Numerous reports attest to the benefits of a wide variety of psychiatric and psychological treatments for acne, including paroxetine,29 olanzapine,30 relaxation techniques, hypnosis, cognitive-behavioral therapy, and biofeedback,31,32 but no controlled clinical trials except for one.33

Chronic Idiopathic Pruritus

Pruritus, or itchiness, is a common symptom of dermatologic diseases, several systemic diseases (eg, hepatic or renal failure, HIV), and advanced age,1,2 but the cause in chronic pruritus is often not identifiable. Such idiopathic pruritus is typically experienced on a daily basis, especially at night and in the evening, resulting in mostly having difficulty falling asleep. Generalized idiopathic pruritus mainly involves the legs, arms, and back. The most common focal presentations of idiopathic pruritus are pruritus ani, vulvae, and scroti. Idiopathic pruritus may be described as crawling, tickling, stinging, or burning.34,35 In one study,34 idiopathic pruritus patients described the itching as unbearable (73%), bothersome (72%), annoying (67%) and/or worrisome (45%). The pathophysiology of pruritus is not well understood, and it is unclear why it is worse at night.36 While psychiatric symptoms are common in idiopathic pruritus, and idiopathic pruritus is common in psychiatric patients, idiopathic pruritus should be considered as a functional disorder rather than a psychogenic one. New onset of unexplained pruritus should lead to evaluation for occult medical disease before considering it to be idiopathic pruritus.

Recent stressful life events, and degree of anxiety and/or depressive symptoms have been correlated with an increased ability to experience itching.1,2 In a study37 of 100 psychiatric inpatients, idiopathic pruritus was reported by 42% of the subjects, 34% of the men, and 58% of the women, with increased prevalence in those without adequate social support and in those without regular employment. It is not surprising that depression is common in patients with idiopathic pruritus, especially given the chronicity and sleep disturbance.38

For focal idiopathic pruritus (eg, pruritus ani, vulvae, and scroti), topical treatments are used. For both generalized and focal idiopathic pruritus, the most commonly prescribed oral medications are antihistamines, which usually provide some short-term relief. Tricyclic antidepressants, especially doxepin, can relieve chronic idiopathic pruritus. Paroxetine has also been reported to be helpful.39 Opiate receptor antagonists and anticonvulsants (gabapentin, pregabalin, carbamazepine) have also been suggested as possible remedies.40 Behavioral treatment, such as habit-reversal training and cognitive-behavioral therapy, may also be helpful in interrupting the itch-scratch cycle,1,2 and there is one case report of the benefits of hypnosis.41 PP



1. Arnold L. Dermatology. In: Levenson JL, ed. American Psychiatric Publishing Textbook of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2005:629-646.
2. Arnold L. Dermatology. In: Levenson JL, ed. Essentials of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2007:629-646.
3. Levenson JL. Psychiatric issues in dermatology, part 1: atopic dermatitis and psoriasis. Primary Psychiatry. 2008;15(7):35-38.
4. Levenson JL. Psychiatric issues in dermatology, part 2: alopecia areata, urticaria and angioedema. Primary Psychiatry. 2008;15(9):31-34.
5. Aktan S, Ozmen E, Sanli B. Anxiety, depression, and nature of acne vulgaris in adolescents. Int J Dermatol. 2000;39(5):354-357.
6. Chiu A, Chon SY, Kimball AB. The response of skin disease to stress: changes in the severity of acne vulgaris as affected by examination stress. Arch Dermatol. 2003;139(7):897-900.
7. Yosipovitch G, Tang M, Dawn AG, et al. Study of psychological stress, sebum production and acne vulgaris in adolescents. Acta Derm Venereol. 2007;87(2):135-139.
8. Zouboulis CC, Böhm M. Neuroendocrine regulation of sebocytes—a pathogenetic link between stress and acne. Exp Dermatol. 2004;13(suppl 4):31-35.
9. Yeung CK, Chan HH. Cutaneous adverse effects of lithium: epidemiology and management. Am J Clin Dermatol. 2004;5(1):3-8.
10. Mishra B, Praharaj SK, Prakash R, Sinha VK. Aripiprazole-induced acneiform eruption. Gen Hosp Psychiatry. 2008;30(5):479-481
11. Nielsen JN, Licht RW, Fogh K. Two cases of acneiform eruption associated with lamotrigine. J Clin Psychiatry. 2004;65(12):1720-1722.
12. de Vries L, Karasik A, Landau Z, Phillip M, Kiviti S, Goldberg-Stern H. Endocrine effects of valproate in adolescent girls with epilepsy. Epilepsia. 2007;48(3):470-477.
13. De Gálvez Aranda MV, Sánchez PS, Alonso Corral MJ, Bosch García RJ, Gallardo MA, Herrera Ceballos E. Acneiform eruption caused by amineptine. A case report and review of the literature. J Eur Acad Dermatol Venereol. 2001;15(4):337-339.
14. Kilkenny M, Stathakis V, Hibbert ME, Patton G, Caust J, Bowes G. Acne in Victorian adolescents: associations with age, gender, puberty and psychiatric symptoms. J Paediatr Child Health. 1997;33(5):430-433.
15. Purvis D, Robinson E, Merry S, Watson P. Acne, anxiety, depression and suicide in teenagers: a cross-sectional survey of New Zealand secondary school students. J Paediatr Child Health. 2006;42(12):793-796.
16. Picardi A, Mazzotti E, Pasquini P. Prevalence and correlates of suicidal ideation among patients with skin disease. J Am Acad Dermatol. 2006;54(3):420-426.
17. Yazici K, Baz K, Yazici AE, et al. Disease-specific quality of life is associated with anxiety and depression in patients with acne. J Eur Acad Dermatol Venereol. 2004;18(4):435-439.
18. Dréno B. Assessing quality of life in patients with acne vulgaris: implications for treatment. Am J Clin Dermatol. 2006;7(2):99-106.
19. Krejci-Manwaring J, Kerchner K, Feldman SR, Rapp DA, Rapp SR. Social sensitivity and acne: the role of personality in negative social consequences and quality of life. Int J Psychiatry Med. 2006;36(1):121-130.
20. Rapp DA, Brenes GA, Feldman SR, et al. Anger and acne: implications for quality of life, patient satisfaction and clinical care. Br J Dermatol. 2004;151(1):183-189.
21. Jones-Caballero M, Pedrosa E, Peñas PF. Self-reported adherence to treatment and quality of life in mild to moderate acne. Dermatology. 2008;217(4):309-314.
22. FDA Approved Drug Products. Available at: Accessed September 24, 2008.
23. Marqueling AL, Zane LT. Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic review. Semin Cutan Med Surg. 2007;26(4):210-220.
24. Kaymak Y, Kalay M, Ilter N, Taner E. Incidence of depression related to isotretinoin treatment in 100 acne vulgaris patients. Psychol Rep. 2006;99(3):897-906.
25. Azoulay L, Blais L, Koren G, LeLorier J, Bérard A. Isotretinoin and the risk of depression in patients with acne vulgaris: a case-crossover study. J Clin Psychiatry. 2008;69(4):526-532.
26. Cohen J, Adams S, Patten S. No association found between patients receiving isotretinoin for acne and the development of depression in a Canadian prospective cohort. Can J Clin Pharmacol. 2007;14(2):e227-e233.
27. Barak Y, Wohl Y, Greenberg Y, et al. Affective psychosis following Accutane (isotretinoin) treatment. Int Clin Psychopharmacol. 2005;20(1):39-41. Erratum in: Int Clin Psychopharmacol. 2005;20(3):182.
28. Jick SS, Kremers HM, Vasilakis-Scaramozza C. Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide. Arch Dermatol. 2000;136(10):1231-1236.
29. Moussavian H. Improvement of acne in depressed patients treated with paroxetine. J Am Acad Child Adolesc Psychiatry. 2001;40(5):505-506.
30. Gupta MA, Gupta AK. Olanzapine may be an effective adjunctive therapy in the management of acne excoriée: a case report. J Cutan Med Surg. 2001;5(1):25-27.
31. Shenefelt PD. Using hypnosis to facilitate resolution of psychogenic excoriations in acne excoriée. Am J Clin Hypn. 2004;46(3):239-245.
32. Shenefelt PD. Biofeedback, cognitive-behavioral methods, and hypnosis in dermatology: is it all in your mind? Dermatol Ther. 2003;16(2):114-122.
33. Hughes H, Brown BW, Lawlis GF, Fulton JE Jr. Treatment of acne vulgaris by biofeedback relaxation and cognitive imagery. J Psychosom Res. 1983;27(3):185-191.
34. T-J Goon A, Yosipovitch G, Chan YH, Goh CL. Clinical characteristics of generalized idiopathic pruritus in patients from a tertiary referral center in Singapore. Int J Dermatol. 2007;46(10):1023-1026.
35. Yosipovitch G, Ansari N, Goon A, Chan YH, Goh CL. Clinical characteristics of pruritus in chronic idiopathic urticaria. Br J Dermatol. 2002;147(1):32-36.
36. Patel T, Ishiuji Y, Yosipovitch G. Nocturnal itch: why do we itch at night? Acta Derm Venereol. 2007;87(4):295-298.
37. Kretzmer GE, Gelkopf M, Kretzmer G, Melamed Y. Idiopathic pruritus in psychiatric inpatients: an explorative study. Gen Hosp Psychiatry. 2008;30(4):344-348.
38. Sheehan-Dare RA, Henderson MJ, Cotterill JA. Anxiety and depression in patients with chronic urticaria and generalized pruritus. Br J Dermatol. 1990;123(6):769-774.
39. Zylicz Z, Krajnik M, Sorge AA, Costantini M. Paroxetine in the treatment of severe non-dermatological pruritus: a randomized, controlled trial. J Pain Symptom Manage. 2003;26(6):1105-1112.
40. Lynde CB, Kraft JN, Lynde CW. Novel agents for intractable itch. Skin Therapy Lett. 2008;13(1):6-9.
41. Rucklidge JJ, Saunders D. Hypnosis in a case of long-standing idiopathic itch. Psychosom Med. 1999;61(3):355-358.


This interview took place on September 24, 2008, and was conducted by Norman Sussman, MD.


This interview is also available as an audio PsychCastTM at

Disclosure: Dr. Perkins is a consultant to Dainippon Sumitomo Pharma Co., Ltd; is on the speaker’s bureaus of AstraZeneca and Eli Lilly; and receives grant support from Janssen.


Dr. Perkins is professor of psychiatry in the Department of Psychiatry at the University of North Carolina (UNC) School of Medicine in Chapel Hill. She is medical director of Outreach and Support Intervention Services at UNC Hospitals and the UNC-Chapel Hill School of Medicine. Dr. Perkins’ research emphasizes treatment of the prodromal period and early intervention of the first episode of schizophrenia. Currently investigating pharmacologic and psychotherapeutic treatments for psychosis, she focuses on managing side effects of atypical antipsychotics and the weight gain mechanism in patients taking psychotropic medications. In addition, Dr. Perkins is investigating the genetic basis of schizophrenia.


How has the pathogenesis of schizophrenia evolved in the last century?

It is known that both gene and environment contribute to schizophrenia risk. For example. when an identical twin has schizophrenia, his or her counterpart has a 50% chance of having schizophrenia as well.1 This compares to the population risk of .01%. It is also likely that genetic or environmental risk factors act by changing when and how much protein is made.2

In addition, some forms of schizophrenia are likely neurodevelopmental disorders, meaning that the brains of some people who developed schizophrenia may have developed differently from those unaffected with schizophrenia. It may also be that an environmental event is needed to trigger the disorder in an at-risk person.3 There is also strong evidence that neurocircuits involving the front of the brain, especially the prefrontal cortex, are involved in schizophrenia. Much work needs to be conducted, however, to determine the underlying causes of schizophrenia.

It has been found that schizophrenia is a heterogeneous disorder similar to pneumonia; it is likely that there are hundreds of independent causes to schizophrenia. Such heterogeneity makes it challenging to further decipher the pathogenesis of schizophrenia.

How do parents influence their children having schizophrenia?

One epidemiologic finding is that schizophrenia risk is associated with higher paternal age at the time of conception.  We do not know the reason for this association, but I could speculate that perhaps it is because men make sperm throughout their life, and as they age genetic mistakes may accumulate in the germ line, including variations in the number of copies of genomic regions as well as point mutations. New evidence suggests that the genetic risk of schizophrenia may be due to de novo mutations in the patient.4,5 This may explain why approximately 70% of people who develop schizophrenia do not have a relative with the disorder.6

Is there anything specific about viruses implicated in early development that might be associated with schizophrenia?

There is a wealth of epidemiologic research showing increased risk in individuals who had certain prenatal environmental exposures. An example is maternal starvation where the risk of schizophrenia in offspring doubles.7 While data show most people whose mothers starved did not develop schizophrenia, there is still a small group that may have a biologic vulnerability. Some leading hypotheses suggest it is micro nutrium, meaning some critical nutrients (eg, vitamins D or B) were not received in utero. The second epidemiologic observation involves the fetus’ exposure to an infectious disease process in utero. As a result of this exposure, risk of schizophrenia in adulthood increases by 2–3 fold. Research on that relationship has tried to determine whether it is brain infection with the virus or the maternal immune response that affects brain development, increasing later risk of schizophrenia. Numerous animal models point to the immune maternal response. For example, if there is an infection or something provoking the maternal immune response, then antibodies, cytokines, or other aspects of the immune system response cross the placenta, enter the fetus, and affect brain development. Epidemiologic studies also find that maternal exposure to a traumatic event during pregnancy is associated with an increased risk of schizophrenia. One mechanistic theory involves stress hormones affecting brain development in utero, making a person vulnerable to schizophrenia in adulthood.

There have been studies investigating viral exposures in childhood  and later risk of schizophrenia. For example,  one recent population-based epidemiologic study8 found that childhood cytomegalovirus in the central nervous system was associated with a 16-fold increase in schizophrenia risk.

Is there a connection with gene expression?

One percent of a genome codes for a protein. Until recently, the remaining 99% was considered “junk deoxyribonucleic acid (DNA).” There was no explanation for its function; junk DNA was considered an evolutionary relic. However, in the past 5 years, it has been found that ≥50% of DNA is transcribed into ribonucleic acid (RNA), but this RNA is not translated into protein. Instead, this RNA regulates when and how much of the protein-coding genes are expressed. Numerous post-mortem studies of schizophrenia find altered levels of specific RNAs or proteins, suggesting that some process regulating the expression of a protein is impaired. There is no firm evidence of what regulatory processes might be altered, but research is now focusing on the variety of factors that impact protein expression.

Is there evidence that antipsychotics used earlier are neuroprotective?

Eighty-five percent of patients with schizophrenia will report prodromal symptoms; for example, they may report having weird ideas, illusions, or transient hallucinations (eg, hearing clicking noises, someone calling their name when no one was around). In the prodromal stage of psychosis, people may also complain of increased distractability, problems in school, and social problems. Researchers have been looking at the kinds of symptoms that can help distinguish people at highest increased vulnerability to schizophrenia. The best predictors of psychosis risk appear to be altered thought process (eg, ideas of reference) and abnormal perceptions (eg, illusions or brief hallucinations) that also interfere with social or vocational function.

Current estimates are that approximately 35% to 40% of people experiencing these “clinical high-risk” symptoms will develop a psychotic disorder within 2 years.9 Note that most people who are experiencing these “psychosis-like” symptoms do not go on to develop a psychotic disorder. Some (approximately 20%) will remit; here the symptoms may have been the result of a rough time or a glitch in adolescent brain development that self-corrected. Other times the person was experiencing early symptoms of anxiety disorders, depression, or a personality disorder, but not schizophrenia.

There is great interest in improving the ability to predict risk. One factor that has emerged is functional impairment. The more severe the symptoms, the more they significantly interfere with function. Environmental factors, such as marijuana use or severe stress may further increase psychosis vulnerability. However, more research is required to appropriately identify symptoms before prevention is possible. Studies10-12 examined people experiencing prodromal symptoms who have investigated an antipsychotic, an antipsychotic plus psychotherapy, or psychotherapy alone. In these studies, all interventions were equally successful in preventing psychosis, meaning both pharmacologic and psychotherapeutic interventions could benefit patients.

When the clinician is faced with an adolescent or young adult having clinical high risk symptoms and also struggling in school, treatment decisions are complicated by the fact that most (>50%) will not develop a psychotic illness. While preventative antipsychotic treatment may benefit the approximately 40% who are truly in the earliest stages of illness, antipsychotics are not appropriate for the other 60% of patients. These patients would be unnecessarily exposed to the risks of antipsychotics, such as metabolic or neurologic side effects. In addition, the clinical trials find that patients who are clinically at risk for psychosis are only protected from psychosis while they are taking the antipsychotic. When the antipsychotic is discontinued, the patients continue to be at high risk, and eventually 35% to 40% will develop a psychotic disorder. I think treating clinical high-risk symptoms with an antipsychotic is premature and should only be used when a patient is suffering severe functional impairment. Psychotherapy, however, is a relatively benign and effective treatment. Clinicians should consider some form of psychotherapy, especially a cognitive-behavioral type to help people cope with symptoms, manage stress, and deal with life issues conducive to stress.

Do atypical antipsychotics cause less risk of tardive dyskinesia than the older treatments?

Despite the ongoing debate on this issue, I think they do. In the early part of my career, only typical antipsychotics were available. Tardive dyskinesia was not at all unusual. In my clinical practice tardive dyskinesia is unusual.  Many medical or nursing students rotating through inpatient and outpatient settings will not see a single case of tardive dyskinesia.

Studies on tardive dyskinesia risk are difficult to conduct. Unmedicated people with schizophrenia will develop dyskinetic movements that are indistinguishable from tardive dyskinesia. While dyskinetic movements are not necessarily caused by antipsychotics, there is clear evidence showing antipsychotics increase the risk of developing those movements. In order to understand the difference between the two treatments, patients may have to be followed for several years. Unfortunately, studies of that length are almost impossible to conduct. The reinterpretation of short-term clinical studies suggest that tardive dyskinesia happens less often  with patients treated with atypical antipsychotics. Tardive dyskinesia can certainly emerge in people treated with atypical antipsychotics, but it appears less likely than in patients treated with typical antipsychotics.

Why do antipsychotics tend to cause weight gain and metabolic syndrome?

These adverse effects are seen mostly with newer antipsychotics. For example, patients taking quetiapine, olanzapine, or risperidone have increased risk of weight gain while aripiprazole or ziprasidone might not cause weight gain (at least in adults). In children, there is some increased risk of weight gain and metabolic syndrome with ziprasidone.

There are three possible mechanisms that could explain weight gain and metabolic syndrome in antipsychotic treatment patients. First, the patient’s appetite might increase once starting the antipsychotic. Second, patients using sedative drugs experience increased sleep time, resulting in a decrease in the amount of calories spent in a 24-hour period. Decreased activity is conducive to weight gain. Third, there may be changes in metabolism—for example, how readily a person may tap into fat stores.

I advise patients to exercise regularly and go on a low carbohydrate diet such as the American Diabetic Association diet or the Atkins diet. I have had patients who were able to follow that kind of diet and lose weight associated with antipsychotics. However, weight loss and behavioral change is a difficult task to accomplish, even for people who have schizophrenia. In addition to lifestyle changes, there is emerging evidence from clinical trials13 that metformin may attenuate or even reverse antipsychotic-related weight gain. In addition, there are clinical trials13 suggesting similar benefits from topirimate and amantadine.

Are there developing treatments that may benefit people who are not being treated effectively?

We are learning more about how to best use available treatments. Most clinical trials with antipsychotics were conducted by pharmaceutical industries. As the studies are highly regulated, the data are valid. However, the problem with industry-sponsored studies is that they are initially designed in favor of the company’s drugs. For example, if there is a drug that could cause weight gain, the researchers might not weigh people in the study. There is a fundamental problem with depending on the people who may profit from the drug conducting all of the studies with that drug.

The Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study14 involved the atypical antipsychotics that were FDA approved at the time, namely risperidone, quetiapine, and olanzapine. Ziprasidone was added once it was approved by the Food and Drug Administration. Perphenazine was chosen as a typical antipsychotic comparator because the researchers wanted a drug that was unfamiliar and not used. The outcome measure in the CATIE study was all-cause treatment discontinuation. This was picked because it was thought to reflect both clinicians’ and patients’ judgment on how well a medication was working. If a patient experiences enough benefit from a medication and the side effects are not too troublesome, he or she is willing to continue using it. However, if the benefits seem negligible or the side effects are too much relative to the benefit, the patient will stop taking that medication. This was a novel outcome measure that is still somewhat controversial, but it was chosen as a measure of overall effectiveness. The study was large; it randomized 1,400 patients from the United States. Unlike most pharmaceutical industry studies, the CATIE study did not restrict inclusion to those patients who are very healthy, who do not use street drugs, and/or who do not require treatment with other medications, making the findings generalizable to routine clinical practice.

Overall, the study found that 74% of patients discontinued treatment prior to the end of the 18-month study. The time to discontinuation was significantly longer for olanzapine compared to risperidone and quetiapine, and was longer at a trend level compared to perphenazine- and ziprasidone-treated patients. However, olanzapine-treated patients were more likely to gain weight and have lipid abnormalities, so that the improved effectiveness came at the price of more severe side effects. One of the surprising findings of the CATIE study was how well the typical antipsychotic perphenzine peformed compared to the other antipsychotics, especially since other studies had shown that other typical antipsychotics, like haloperidol and chlorpromazine, were not as efficacious as the atypical antipsychotics. Perphenazine prescribing has increased since the publication of the CATIE study.

 What can also be concluded from the CATIE study is that none of the study drugs are optimal, and that treatment discontinuation rates overall are very high. There are now efforts to develop better strategies to improve medication treatment adherence, both with schizophrenia as well as other chronic diseases. Only approximately 50% of patients being treated for chronic illness are compliant with that treatment by 1 year,15 and the reasons for poor adherence are similar in schizophrenia and other chronic disease. We know that there will be a low rate of treatment adherence if a clinician simply writes a prescription and hands that prescription to the patient. A different kind of therapeutic model is needed.

There is growing evidence of a “concordance” model of care, where the patient’s experience of the illness and how treatment affects his or her life is taken into consideration. The clinician may engage in a negotiation with the patient until both agree with the treatment plan. However, it is important to note that even the best-intended patient will likely have difficulties in complying long term. It is difficult to remember to take a medication every day. To be successful, patients usually need to actively work on medication adherence, and the clinician can help. For example, the clinician can keep the medication regimin as simple as possible and also encourage the use of “cognitive adaptive strategies,” where patients develop environmental cues, like pill boxes or alarms to help with adherence.16 The lessons from the CATIE study reveal more than just the need for a new drug. Better ways to use available medication and optimize treatment are needed as well.

There may be breakthrough drugs on the horizon, however. There is a recent clinical trial of a drug that is a selective agonist at certain glutamate receptors (mGluR2 and mGluR3), but that does not affect dopamine receptors. The first published clinical trial17 is promising, and this new drug, at this point called “LY2140023,” may open up a new strategy for treating schizophrenia. Other promising areas include drugs targeting nicotinic receptors. PP


1.    Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait—evidence from a meta-analysis of twin studies. Arch Gen Psych. 2003;60(12):1187-1192.
2.    Perkins et al. microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol. 2007;8(2):R27.
3.    Lewis DA, González-Burgos G. Neuroplasticity of neocortical circuits in schizophrenia. Neuropsychopharmacology. 2008;33(1):141-165.
4.    Stefansson H, Rujescu D, Cichon S, et al. Large recurrent microdeletions associated with schizophrenia. Nature. 2008;455(7210):232-236.
5.    International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008;455(7210):237-241.
6.    Mortensen PB, Pedersen CB, Westergaard T, et al. Effects of family history and place and season of birth on the risk of schizophrenia. N Engl J Med. 1999;340(8):603-608.
7.    Penner JD, Brown AS. Prenatal infectious and nutritional factors and risk of adult schizophrenia. Expert Rev Neurother. 2007;7(7):797-805.
8.    Dalman C, Allebeck P, Gunnell D, et al. Infections in the CNS during childhood and the risk of subsequent psychotic illness: a cohort study of more than one million Swedish subjects. Am J Psychiatry. 2008;165(1):59-65.
9.    Cannon TD, Cadenhead K, Cornblatt B, et al. Prediction of psychosis in youth at high clinical risk: a multisite longitudinal study in North America. Arch Gen Psychiatry. 2008;65(1):28-37.
10.    Morrison AP, French P, Parker S, et al. Three-year follow-up of a randomized controlled trial of cognitive therapy for the prevention of psychosis in people at ultrahigh risk. Schizophr Bull. 2007;33(3):682-687.
11.    Phillips LJ, McGorry PD, Yuen HP, et al. Medium term follow-up of a randomized controlled trial of interventions for young people at ultra high risk of psychosis. Schizophr Res. 2007;96(1-3):25-33.
12.    McGlashan TH, Zipursky RB, Perkins D, et al. Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis. Am J Psychiatry. 2006;163(5):790-799.
13.    Baptista T, ElFakih Y, Uzcátegui E, et al. Pharmacological management of atypical antipsychotic-induced weight gain. CNS Drugs. 2008;22(6):477-495.
14.    Lieberman JA, Stroup TS, McEvoy JP, al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223.
15.    Adherence to Long Term Therapies: Evidence for Action. Geneva, Switzerland: World Health Organization; 2003.
16.    Velligan DI, Diamond PM, Mintz J, et al. The use of individually tailored environmental supports to improve medication adherence and outcomes in schizophrenia. Schizophr Bull. 2008;34(3):483-493.
17. Patil ST, Zhang L, Martenyi F, et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med. 2007;13(9):1102-1107.


Dr. Ying is director of New York University (NYU) Behavioral Health Programs and clinical assistant professor at NYU School of Medicine in New York City.

Disclosure: Dr. Ying reports no affiliation with or financial interest in any organization that may pose a conflict of interest.
Off-label disclosure: This article includes discussion of the following unapproved medications for depression or bipolar disorder: aprepitant, ketamine, memantine, mifepristone, paliperidone, and riluzole.

Please direct all correspondence to: Patrick Ying, MD, Director, NYU Behavioral Health Programs, Clinical Assistant Professor, NYU School of Medicine, Faculty Practice Tower, 530 First Ave, #7D, New York, NY 10016; Tel: 212-774-1459; Fax: 212-263-7460; E-mail:


Focus Points

• In the last few years, the only medications approved for mood disorders are existing medications or derivatives of them.
• New medications for mood disorders rely on both the existing monoaminergic and novel mechanisms of action.
• Medications that work on tachykinins, glutamate, and the hypothalamic-pituitary-adrenal axis are being investigated.
• Newer mechanisms of action may allow for improved efficacy, tolerability, and speed of response.



There remains a significant need for new treatments for mood disorders. In the last 2 years, only one new drug has been approved for the treatment of major depressive disorder, desvenlafaxine; during this time, the other medications approved for the treatment of depression or bipolar disorder have been atypical antipsychotics that have already been approved for the treatment of schizophrenia. There are, however, numerous medications in development for the treatment of mood disorders. Agomelatine is an agonist at melatonin (MT)1 and MT2 receptors and a serotonin (5-HT)2C antagonist in Phase III trials. Vilazodone, which is undergoing a Phase III clinical trial, is a selective serotonin reuptake inhibitor which also has 5-HT1A agonist properties. Triple reuptake inhibitors which selectively inhibit reuptake of serotonin, norepinephrine, and dopamine are also being developed. There are also medications in development whose mechanism of action does not depend on directly affecting monoaminergic function. Glucocorticoid receptor antagonists and corticotropin releasing factor-1 antagonists, which seek to modulate the hypothalamic-pituitary-adrenal axis, are being explored for efficacy in the treatment of unipolar depression. Agents that modify the glutamatergic system, such as riluzole and ketamine, are being explored for treatment of bipolar and unipolar depression. This article reviews the rationale and evidence for these proposed agents in the treatment of mood disorders.


There remains an acute need for new, effective treatments for mood disorders. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study1 reported a cumulative 67% remission rate after four treatment steps. However, not only did approximately 33% of patients not achieve remission, but patients who went into remission during the third or fourth treatment step had relapse rates of 41% to 50%.1 Likewise, the Systematic Treatment Enhancement Program for Bipolar Disorder2 indicated that only 58.5% of patients experiencing a manic, mixed, or depressive episode achieved symptom-free recovery in up to 2 years of follow up, and of those who did, 48.5% of these individuals experienced recurrences.2 These two National Institute of Mental Health (NIMH)-funded studies, which sought to deliver “best practice” care to “real world” patients, provide an effective snapshot of effectiveness of current medications for mood disorders.

Some authors suggest that there has been no truly revolutionary drug for the treatment of mood disorders for numerous decades. Recent Food and Drug Administration approvals for bipolar disorder and unipolar depression have been for compounds that have already been approved for other disorders or reformulations or metabolites of already available medications. However, the pharmacologic treatment of mood disorders remains an area of intense and exciting research. Multiple approaches that appear promising are being investigated, some of which hold the promise of extending existing paradigms of mood disorder psychopharmacology.3-5

Atypical Antipsychotics

Atypical antipsychotics continue to expand their indications for bipolar disorder. Quetiapine has received approval for maintenance treatment of bipolar disorder as an adjunct to lithium or divalproex. Applications have been made to the FDA for the extended-release version quetiapine for treatment indications for manic and depressed episodes of bipolar disorder, and for unipolar depression. (The steps for FDA approval are defined in the Table.6) Aripiprazole has received expanded indications for the acute treatment of manic or mixed episodes in pediatric patients. Perhaps the most notable FDA indication is the approval of aripiprazole as an augmentation agent for the treatment of unipolar depression. This represents the first indication of an atypical antipsychotic for unipolar depression. Curiously, two large studies7 were unable to demonstrate aripiprazole’s effectiveness as monotherapy for bipolar depression.


Two large randomized placebo-controlled trials8,9 demonstrated aripiprazole’s efficacy as augmentation treatment in unipolar depression. Both studies started with a screening phase, where patients were determined to be in a major depressive episode for at least 8 weeks, had between 1–3 adequate antidepressant trials for which they had a <50% response, and had a Hamilton Rating Scale for Depression (HAM-D)17 score of >18. If patients met these criteria, they entered an 8-week prospective treatment phase. Patients received single-blind treatment; escitalopram, paroxetine, sertraline, fluoxetine, or venlafaxine; and an adjunctive placebo. Antidepressant choice was based on the investigator’s clinical assessement. After 8 weeks, if patients did not respond, they entered a randomized double-blind study phase where they received aripiprazole or a placebo in addition to the antidepressant selected by the investigator. Doses started at 5 mg, were increased to 10 mg if tolerated, and could be lowered to 2 mg if not tolerated. Investigators could also increase the dose by 5 mg/week to 20 mg/week if there was no response. Patients in both studies had significant drops in the Montgomery Åsberg Depression Rating Scale (MADRS) total score, the primary outcome measure. Separation from placebo began at week 2 in both studies. Remission rate at 6 weeks was statistically significant for both studies at 25.4% to 26.0% versus 15.2% to 15.7% for placebo. The average dose of aripiprazole was 11.1–11.8 mg, somewhat below the dose for bipolar disorder and schizophrenia.8,9


Desvenlafaxine was approved in 2008 for treatment of major depressive disorder (MDD). It is the major active metabolite of venlafaxine, and like venlafaxine is a serotonin norepinephrine reuptake inhibitor. Desvenlafaxine has a greater effect on norepinephrine reuptake relative to its effect on serotonin reuptake compared to venlafaxine, although it is similar to venlafaxine in that it continues to have a greater effect on serotonin reuptake than norepinephrine reuptake overall. Desvenlafaxine is not predominately metabolized by the cytochrome P450 (CYP) system and is eliminated primarily by phase II metabolism; as a result, it has lower potential for drug interactions, especially with the CYP 2D6 pathway. It is suggested that a potential advantage of desvenlafaxine over venlafaxine is greater predictability with regard to the ratio of inhibition of norepinephrine reuptake to serotonin reuptake. Since venlafaxine is converted to desvenlafaxine by CYP 2D6, patients who are taking 2D6 inhibitors or who are genetically poor metabolizers will have a greater ratio of venlafaxine to desvenlafaxine and, therefore, comparatively less norepinephrine reuptake compared to serotonin reuptake.10

Efficacy has been demonstrated by four fixed-dose double-blind placebo controlled studies.11-14 Two studies11,12 examined 50 mg and 100 mg doses, while one study13 examined 100 mg, 200 mg, and 400 mg doses. The last study14 examined 200 mg and 400 mg doses. Desvenlafaxine demonstrated superiority over placebo in all four studies in terms of decrease in HAM-D17 scores, although in one study did not separate from placebo at the 100 mg dose. Overall, there was no statistically significant  improvement in efficacy at doses >50 mg and these higher doses were associated with higher dropout rates and more adverse events; as a result, the recommended dose is 50 mg.15 In one published study11 with the recommended 50-mg dose, the remission rate was 34%, significantly greater than for placebo group, 24%; in the other study,12 while the response rate at 50 mg dose was significantly greater than placebo, 65% to 50%, the remission rate did not significantly separate from placebo, 37% to 29%.

Desvenlafaxine appears to be well tolerated. The most common adverse events leading to discontinuation are nausea (4%), dizziness (2%), headache (2%), and vomiting (2%). Nausea was reported by 22% of patients taking 50 mg, and this increases in dose dependent fashion to where 41% of patients taking 400 mg report nausea.15 As with the other serotonergic antidepressants, the caveats regarding the risk of combination with monoamine oxidase inhibitors (MAOIs) apply. Serotonergic antidepressants are frequently associated with weight gain and sexual dysfunction. In premarketing studies,15 decreased libido, delayed ejaculation, and erectile dysfunction were noted in men, especially at higher doses, whereas in women only anorgasmia was notable at the 400 mg dose. However, with regard to weight gain, patients lost an average 0.4–1.1 kg in short-term studies,15 In one long-term study,15 there was no difference in mean weight change between patients who were on desvenlafaxine or placebo for 6 months. Like venlafaxine, desvenlafaxine is associated with sustained elevations in blood pressure. Venlafaxine is associated with elevations at higher doses; however, desvenlafaxine is associated with sustained diastolic hypertension at all doses. Curiously, there is no clear dose response relationship. The incidence of sustained hypertension is 1.3% at a dose of 50 mg of desvenlafaxine, 0.7% at 100 mg, 1.1% at 200 mg, 2.3% at 400 mg, and 0.5% for placebo. Venlafaxine is known to have significant discontinuation syndrome related to its short half-life and serotonergic action. Desvenlafaxine’s half-life is approximately 11 hours, and it is also associated with a discontinuation syndrome. Since desvenlafaxine comes in an extended-release tablet that is not recommended to be cut or split, the recommendation is to taper the medication by increasing the interval between doses.15

The clinical utility of desvenlafaxine over its parent compound remains an open question. The decrease in potential drug-drug interaction is an incremental benefit. However, it is not clear that desvenlafaxine’s greater ratio of norepinephrine to serotonin reuptake inhibition compared to venlafaxine is clinically meaningful with regards to efficacy or tolerability.

With the relative dearth of novel agents for mood disorders, it is worth surveying drugs that are in development. There are >50 drugs in phases I, II, or III clinical trials for depression and bipolar disorder.16 What follows is not a comprehensive survey, but rather an overview of compounds that may be close to an approval decision or have a novel mechanism of action.

New Atypical Antipsychotics

The success of atypical antipsychotics in mood disorders will lead to newer atypical antipsychotics to be tried in mood disorders as well. Paliperidone, the active metabolite of risperidone and recently approved for schizophrenia, is in phase III trials for the treatment of manic and mixed episodes. Asenapine, a serotonin (5-HT2)/dopamine-2 antagonist, has been submitted to the FDA for approval for both mania and schizophrenia. Bifreprunox, a dopamine partial agonist, which received a non-approvable letter for a schizophrenia indication, is in phase III trials for bipolar depression.16


Agomelatine, a melatonergic agonist at melatonin (MT)1 and MT2 receptors and a 5-HT2C antagonist, is in phase III clinical trials in the United States for the treatment of MDD. Blockade of 5-HT2C receptors on gamma-aminobutyric acid interneurons is thought to result in the increase of norepinephrine and dopamine in the prefrontal cortex. In addition, its activity at the MT1 and MT2 receptors is thought to have positive effects on sleep promotion and the regulation of circadian rhythms.17 Efficacy of agomelatine in MDD was demonstrated in three published double-blind, placebo controlled trials.18-20 The first trial18 involved 711 depressed patients with either MDD or bipolar type II, comparing 1 mg, 5 mg, and 25 mg of agomelatine to 20 mg of paroxetine and placebo. Both the 25 mg agomelatine group and the paroxetine group showed statistically significant decreases in HAM-D scores. Both groups had significantly more remitters than the placebo group—30.5% for 25 mg agomelatine and 25.7% for the paroxetine group—compared to 15.7% for placebo.18 Two additional trials,19,20 which featured flexible dosing starting at 25 mg and going to 50 mg after 2 weeks of nonresponse, also showed significant improvement in HAM-D scores and response rates after 6 weeks. All three trials performed subanalyses that showed significant improvement in severely depressed patients with HAM-D scores >25.21

Agomelatine appears to be well tolerated. In all three studies18-20 mentioned above, agomelatine did not have significantly more adverse events than placebo. Separate studies found that agomelatine compares favorably to venlafaxine with regards to sexual dysfunction22 and was also not associated with discontinuation symptoms.23 Notably, in a 24-week relapse prevention study,6 patients on agomelatine did not have significant changes in sexual functioning, weight, cardiovascular effects, or laboratory studies.

Agomelatine has initially been rejected by regulatory agencies in the European Union on efficacy grounds, particularly in long-term studies, although efforts to gain approval continue in Europe and the US. Although not appearing to have significant efficacy advantages, agomelatine would appear to have significant advantages in tolerability, especially with regards to weight gain and sexual dysfunction.


Vilazodone, a selective serotonin reuptake inhibitor (SSRI), also has partial agonist properties at the 5-HT1 receptor. It is undergoing a Phase III clinical trial for the treatment of depression. Partial agonism at 5-HT1 is thought to enhance the action of SSRIs, perhaps by accelerating the desensitization of somatodendritic autoreceptors. This has been borne out clinically by studies indicating the effectiveness of buspirone, a 5-HT1 partial agonist, in the augmentation of SSRI treatment, most notably in the STAR*D trial. In addition, there is thought that activity at the 5-HT1 receptor can mitigate sexual side effects of SSRIs. There is also some evidence that buspirone is effective in treating sexual dysfunction brought on by SSRIs, although it is somewhat equivocal. In one 8-week, double-blind, placebo-controlled study24 of 410 patients, vilazodone had significant decreases in HAM-D and MADRS scores beginning at week 1. Vilazodone also had a significantly higher percentage of responders and remitters. Principal adverse events include diarrhea, nausea, and somnolence. Sexual dysfunction was examined using the Arizona Sexual Experiences Scale, and no significant differences were noted between treatment and placebo group. Furthermore, the investigators identified a genetic biomarker which identifies patients that had significantly more improvement after 8 weeks of vilazodone treatment. Patients with the biomarker and treated with vilazodone had significantly more improvement compared to patients without the biomarker and treated with vilazodone as well as patients treated with placebo regardless if they had the biomarker.24

Triple Reuptake Inhibitors

The monoaminergic hypothesis of depression underlies existing antidepressants and the preceding compounds. All existing antidepressants are thought to modify mood based on effects on serotonin, norepinephrine, or dopamine. However, the majority of antidepressants only have significant effects on serotonin and norepinephrine. Substantial evidence exists linking the importance of dopaminergic pathways to depression. In particular, anhedonia and lack of motivation are thought to be connected to dopaminergic deficits. Of existing antidepressants, bupropion is thought to work by increasing levels of dopamine and norepinephrine; only the MAOIs, which carry significant drug interactions and have tolerability issues, are thought to increase all three neurotransmitters. Triple reuptake inhibitors, compounds that add blockade of the dopamine transporter to actions blocking serotonin and norepinephrine, seek to increase level of all three neurotransmitters while maintaining the tolerability found in SSRIs or serotonin norepinephrine reuptake inhibitors.25

Triple reuptake inhibitors have been referred to as “broad spectrum,” being able to target a wide range of symptoms that have been associated with either serotonergic, noradrenergic, or dopaminergic deficits. Theoretically, such an agent might have a more rapid onset of action and higher remission rates. There are proposed tolerability advantages as well. Dopaminergic activity might serve to attenuate serotonergic-mediated sexual dysfunction and weight gain.26 However, dopaminergic agents, with their effects on reward pathways, may have abuse liability. Dopamine transporter drugs that produced >50% dopamine transporter blockade within 15 minutes were reinforcing.27

Numerous triple reuptake inhibitors have shown promise in animal models of depression and have progressed to clinical trials. DOV 21,947 has completed eight Phase I trials and is now recruiting for Phase II clinical trials for the treatment of MDD. DOV 21,947 is an enantiomer of DOV 216,303 which has also been developed as a triple reuptake inhibitor, although patent life concerns have halted development. Results of a double-blind Phase I study with DOV 216,303 showed significant decreases in HAM-D scores after 2 weeks of treatment. The study was limited by the lack of a placebo arm and the short time frame. The length of the study was limited by the amount of safety data at the time. Instead of a placebo arm, there was an active comparator arm using citalopram 20 mg BID, which also showed significant decrease in HAM-D scores in the same time period.28 Another triple reuptake inhibitor, GSK 372475, is also in phase II trials for depression. A third, SEP 225289, has started phase I clinical trials.15 Conceptually, triple reuptake inhibitors are quite appealing and are the natural extension of the monoaminergic hypothesis of depression, although questions remain about what the most effective balance of neurotransmitter action would be.

Novel Mechanisms of Action: Beyond Monoamines

Abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis in patients with mood disorders have been explored since the 1950s. Under normal circumstances, in response to stress, the hypothalamus releases corticotrophin releasing factor which stimulates the pituitary gland to secrete adrenocorticotropic hormone (ACTH) which, in turn, stimulates the adrenal glands to produce cortisol. High levels of cortisol produce negative feedback on corticotropin releasing factor (CRF) which ultimately leads to cortisol levels returning to normal. However, in depressed patients, this regulatory mechanism does not function properly. Depressed patients are found to have elevated cortisol levels, exaggerated adrenal responses to ACTH, and fail to suppress cortisol secretion when given the synthetic glucocorticoid dexamethasone. Chronic high levels of cortisol are thought to contribute to hippocampal volume loss and possibly neurocognitive symptoms of depression. Furthermore, successful treatment of depression leads to normalization of cortisol levels and regulation of the HPA axis. It is hypothesized that modulating the HPA axis and correcting cortisol levels will result in improvement of depressive symptoms and improved neurocognitive function.29

Numerous strategies have been employed to regulate the HPA axis in the treatment of depression. Steroid synthesis inhibitors such as ketoconazole, metyrapone, or aminogluthemide have been studied with mixed results.30 In particular, two approaches are being actively pursued as treatments for mood disorders, namely, glucocorticoid receptor antagonists and CRF-1 receptor antagonists.

Mifepristone is a glucocorticoid receptor-2 antagonist and progesterone receptor, which is approved by the FDA for termination of early pregnancy. There have been multiple published studies examining it’s efficacy in depression with psychosis. Early open-label studies demonstrated rapid and durable responses in patients after only 4–6 days of treatment with mifepristone 600 mg.31 In a large double-blind, placebo-controlled study32 of >200 patients, 58.1% of patients receiving mifepristone 600 mg achieved at 50% reduction in the Brief Psychiatric Rating Scale-Positive Symptoms Subscale in 1 week and maintained it until the fourth week compared to 38.1% in the placebo arm. However, there were no significant differences in HAM-D scores between the mifepristone and placebo group. Although three Phase III clinical trials for mifepristone have failed to demonstrate efficacy versus placebo for depression with psychosis, trials continue to examine higher doses of 1,200 mg. Two other glucocorticoid receptor-2 antagonists are in phase II trials, ORG 34517 and ORG 34850.15

Numerous CRF-1 receptor antagonists have been developed for depression and anxiety disorders. In an open-label study of 20 patients, patients who received R121919 40–80 mg had significant decreases in HAM-D and Beck Depression inventory scores over 30 days. Sleep electroencephalogram studies indicated reversal of sleep architecture changes associated with depression. However, development was halted when drug-induced reversible increases in liver enzymes were detected in a safety study, although this was thought to be unrelated to its principal method of action.33 Despite this setback, the exploration of CRF-1 receptor antagonists for the treatment of depression and anxiety disorders remains extremely active. Pexacerfont is currently in Phase III clinical trials and three other compounds are in phase I or phase II clinical trials.15,16


Substance P, neurokinin A, and neurokinin B are the three most common tachykinins. Tachykinins are short 11–13 amino acid-long peptide neurotransmitters sharing a common C-terminal sequence. Tachykinins exert their effect through G-protein-mediated receptors called neurokinin (NK)1, NK2, and NK3.34 Substance P preferentially binds NK1, neurokinin A preferentially binds NK2, and neurokinin B prefererentially binds NK3, although all three have agonist effects at all three receptors. Tachykinins—especially substance P—became of interest as targets for potential psychiatric medications, as these neuropeptides and their receptors are found in areas of the brain involved in stress, fear, and emotional response (amygdala, hippocampus, hypothalamus and frontal cortex) and closely overlap serotonergic and noradrenergic neurons.35

Antagonists to NK1 and NK2 receptors have been found to have antidepressant effects in animal models and have progressed to clinical trials. In particular, NK1 antagonists have been explored as potential treatments for depression for a number of years.  However, results with numerous compounds have been disappointing.35

Aprepitant (MK-836) had shown promise in two early studies.36,37 In the first,37 MK-836 showed superior efficacy to placebo and equal efficacy to paroxetine with improved tolerability, and had been hailed as a potential breakthrough drug. Only somnolence was found to be a more common adverse event than placebo; weight gain, sexual dysfunction, nausea or vomiting were not significant problems.37  In an another study36 in which both aprepitant and fluoxetine failed to separate from placebo, a post hoc analysis indicated the antidepressant efficacy of aprepitant in a subgroup of severely depressed patients. However, an analysis38 of five clinical trials representing over 750 patients failed to show efficacy versus placebo. Furthermore, using paroxetine 20 mg as an active comparator, investigators were able to replicate paroxetine’s efficacy versus placebo in the same studies.38  Finally, positron emission tomography studies indicate that the doses used in these clinical studies would result in 95% occupancy of NK1 receptors.38

A similar compound, with higher brain penetration and oral bioavailability, L-759274 was also studied. A double-blind placebo-controlled study39 of >162 patients demonstrated superiority to placebo in patients with depression with melancholic features, although a dose-finding trial40 has failed to show separation from placebo. Development on these two compounds for mood disorders has been halted, although aprepitant has been approved for the adjunctive treatment of chemotherapy-induced emesis. Nevertheless, many NK-1 antagonists are still being developed for depression and anxiety.16

Saredutant is a NK-2 receptor antagonist that had progressed to the point that an application for approval for depression seemed to be forthcoming. However, efficacy results were also somewhat equivocal. Of four unpublished phase III studies only two demonstrated statistically significant results compared to placebo.3 Subsequently, a long-term study.41 which compared the ability of saredutant to prevent relapse in patients who had already responded to saredutant for 3 months failed to show superiority to placebo. As a result, approval application will rest on the results of studies currently running on saredutant in combination with  citalopram and paroxetine.

Glutamate and Mood Disorders

Glutamate is the principal excitatory neurotransmitter in the brain. A growing body of research implicates abnormal glutamatergic function with an important role in the pathophysiology of mood disorders. A proposed mechanism for the mood stabilizing and antidepressant effects of lamotrigine is the inhibition of glutamate release through its effect on sodium channels. A number of compounds that modulate the glutamatergic system have been examined for the treatment of mood disorders.42

Riluzole is the only FDA-approved medication for amyotropic lateral sclerosis. It has multiple mechanisms of action which include inhibition of glutamate release through sodium channels, similar to that of lamotrigine, and the enhancement of glutamate reuptake.43 Two open-label studies44,45 have been performed in unipolar depression, and one open-label study46 in bipolar depression. The first study44 used riluzole 100–200 mg as monotherapy for unipolar depression for 19 patients. All patients had to be unresponsive to one medication trial and 53% were unresponsive to at least two trials from two different classes; 68% of the patients completed the 6-week trial. Response rates on the MADRS were 32% for all patients and 46% for completers. Remission rates were 21% for all patients and 31% for completers. In another study,45 riluzole 100 mg was used as an augmentation strategy in unipolar depression for patients who had a HAM-D24 score >21 despite being on a stable dose of medication for at least 6 weeks. After 6 weeks, the average HAM-D score was reduced 36%; significant decreases were noted in week 1. Forty percent of the 10 patients who completed the 6 weeks had responded and 30% were in remission. Patients who responded seemed to respond rapidly in the first week and held durable responses for months. Another open-label study46 looked at riluzole in addition to lithium for bipolar depression. The response and remission rate at week 8 was 50%. Notably, four patients who had remitted had failed to respond to lamotrigine in the past. Two of these patients remitted, while one had a partial response and one had no response. The NIMH is sponsoring a Phase II trial in unipolar and bipolar depression. Riluzole, while available, can cost upwards of $1,000/month. It has an extended patent due to orphan drug status, which expires in 2013.

The N-methyl-D-aspartate excitotoxic amino acid (NMDA) receptor is a subtype of glutamate receptor and has been the subject of investigation regarding depression. Ketamine, a general anesthetic which is also known as a “club drug,” is an NMDA receptor antagonist. Two randomized, double-blind, crossover studies47,48 have been published. In both studies, patients were randomized to receive either a single subanesthetic (0.5 mg/kg) infusion of ketamine over 40 minutes or a saline solution. At least 1 week later, the patient would receive the infusion that they did not receive the first time. Significant decreases in depression occurred within 110 minutes after infusion, which persisted for 1 week. In one study,48 71% of patients receiving ketamine were responders after 1 day and 35% were responders after 1 week. No patients in the placebo group showed a response at any time.47,48

The ketamine studies are notable if only for the speed of response and proof of concept. However, the need for intravenous infusion and ketamine’s notoriety as a potential drug of abuse may limit its ultimate utility as an antidepressant. Memantine is a low-affinty NMDA antagonist used for the treatment of Alzheimer’s disease. Compared to ketamine, it does not have psychotomimetic properties, is well tolerated, and is orally bioavailable. However, double-blind placebo-controlled study49 of 32 subjects with bipolar depression showed no treatment effect at doses of memantine 20 mg/day.


The need for new treatments in the pharmacotherapy of mood disorders remains. New medications, some of which continue in the existing paradigm of modifying serotonin, norepinephrine, and/or dopamine and some of which employ novel mechanisms of action hold the potential to improve the treatment of patients. Novel mechanisms of action include modifying the HPA axis, affecting the tachykinin neuropeptide transmitters, and modulating the glutamatergic system. These drugs may not only improve the efficacy of treatment, but could potentially improve the speed and tolerability of pharmacotherapy. PP


1.    Nelson JC. The STAR*D study: a four-course meal that leaves us wanting more. Am J Psychiatry. 2006;163(11):1864-1866.
2.    Perlis RH, Ostacher MJ, Patel JK, et al. Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2006;163(2):217-224.
3.    Mathew SJ, Manji HK, Charney DS. Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology. 2008;33(9):2300.
4.    Norman TR, Burrows GD. Emerging treatments for major depression. Expert Rev Neurother. 2007;7(2):203-213.
5.    Holtzheimer PE 3rd, Nemeroff CB. Advances in the treatment of depression. NeuroRx. 2006;3(1):42-56.
6.    The New Drug Approval Process. Available at: Accessed November 6, 2008.
7.    Thase ME, Jonas A, Khan A, et al. Aripiprazole monotherapy in nonpsychotic bipolar I depression: results of 2 randomized, placebo-controlled studies. J Clin Psychopharmacol. 2008;28(1):13-20.
8.    Berman RM, Marcus RN, Swanink R, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2007;68(6):843-853.
9.    Marcus RN, McQuade RD, Carson WH, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a second multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol. 2008;28(2):156-165.
10.    Stahl S. Antidepressants. In: Stahl S. Stahl’s Essential Psychopharmacology, Neuroscientific Basis and Practical Applications. 3rd ed. New York, NY: Cambridge University Press; 2008:549-550.
11.    Boyer P, Montgomery S, Lepola U, et al. Efficacy, safety, and tolerability of fixed-dose desvenlafaxine 50 and 100 mg/day for major depressive disorder in a placebo-controlled trial. Int Clin Psychopharmacol. 2008;23(5):243-253.
12.    Liebowitz MR, Manley AL, Padmanabhan SK, Ganguly R, Tummala R, Tourian KA. Efficacy, safety, and tolerability of desvenlafaxine 50 mg/day and 100 mg/day in outpatients with major depressive disorder. Curr Med Res Opin. 2008;24(7):1877-1890.
13.    DeMartinis NA, Yeung PP, Entsuah R, Manley AL. A double-blind, placebo-controlled study of the efficacy and safety of desvenlafaxine succinate in the treatment of major depressive disorder J Clin Psychiatry. 2007;68(5):677-688.
14.    Septien-Velez L, Pitrosky B, Padmanabhan SK, Germain JM, Tourian KA. A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in the treatment of major depressive disorder. Int Clin Psychopharmacol. 2007;22(6):338-347.
15.    Pristiq [package insert]. Madison, NJ: Wyeth-Ayerst. September 2008.
16.    Future treatments for depression, anxiety, sleep disorders, psychosis, and ADHD. Available at: Accessed October 24, 2008.
17.    San L, Arranz B. Agomelatine: a novel mechanism of antidepressant action involving the melatonergic and the serotonergic system. Eur Psychiatry. 2008;23(6):396-402.
18.    Lôo H, Hale A, D’haenen H. Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT(2C) antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study. Int Clin Psychopharmacol. 2002;17(5):239-247.
19.    Kennedy SH, Emsley R. Placebo-controlled trial of agomelatine in the treatment of major depressive disorder. Eur Neuropsychopharmacol. 2006;16(2):93-100.
20.    Olié JP, Kasper S. Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2C antagonistic properties, in major depressive disorder. Int J Neuropsychopharmacol. 2007;10(5):661-673.
21.    Montgomery SA, Kasper S. Severe depression and antidepressants: focus on a pooled analysis of placebo-controlled studies on agomelatine. Int Clin Psychopharmacol. 2007;22(5):283-291.
22.    Kennedy SH, Rizvi S, Fulton K, Rasmussen J. A double-blind comparison of sexual functioning, antidepressant efficacy, and tolerability between agomelatine and venlafaxine XR. J Clin Psychopharmacol. 2008;28(3):329-333.
23. Montgomery SA, Kennedy SH, Burrows GD, Lejoyeux M, Hindmarch I. Absence of discontinuation symptoms with agomelatine and occurrence of discontinuation symptoms with paroxetine: a randomized, double-blind, placebo-controlled discontinuation study. Int Clin Psychopharmacol. 2004;19(5):271-280.
24.    Rickels K, Athanasiou M, Robinson, D, Gibertini, M, Whalen H, Reed CR. Vilazodone: evidence for efficacy and tolerability in the treatment of major depressive disorder. Poster presented at: the Annual Meeting of the American Psychiatric Association; May 3-8, 2008; Washington, DC.
25.    Liang Y, Richelson E. Triple reuptake inhibitors: next-generation antidepressants. Primary Psychiatry. 2008;15(4):50-56.
26.    Skolnick P, Basile AS. Triple reuptake inhibitors (“broad spectrum” antidepressants). CNS Neurol Disord Drug Targets. 2007;6(2):141-149.
27.    Volkow ND, Wang GJ, Fowler JS, et al. The slow and long-lasting blockade of dopamine transporters in human brain induced by the new antidepressant drug radafaxine predict poor reinforcing effects. Biol Psychiatry. 2005;57(6):640-646.
28.    Skolnick P, Krieter P, Tizzano J, et al. Preclinical and clinical pharmacology of DOV 216,303, a “triple” reuptake inhibitor. CNS Drug Rev. 2006;12(2):123-134.
29.    Gallagher P, Malik N, Newham J, Young AH, Ferrier IN, Mackin P. Antiglucocorticoid treatments for mood disorders. Cochrane Database Syst Rev. 2008;(1):CD005168.
30.    Thomson F, Craighead M. Innovative approaches for the treatment of depression: targeting the HPA axis. Neurochem Res. 2008;33(4):691-707.
31.    Schatzberg AF, Lindley S. Glucocorticoid antagonists in neuropsychotic [corrected] disorders. Eur J Pharmacol. 2008;583(2-3):358-364.
32.    DeBattista C, Belanoff J, Glass S, et al. Mifepristone versus placebo in the treatment of psychosis in patients with psychotic major depression. Biol Psychiatry. 2006;60(12):1343-1349.
33.    Ising M, Holsboer F. CRH-sub-1 receptor antagonists for the treatment of depression and anxiety. Exp Clin Psychopharmacol. 2007;15(6):519-528.
34.    Rupniak NM, Kramer MS. Substance P and related tachykinins. In: Davis K, Charney D, Coyle J, Nemeroff C, Neuropsychopharmacology, the 5th Generation of Progress. New York, NY: Lippincott, Williams and Wilkins; 2002:169-176.
35.    Hafizi S, Chandra P, Cowen J. Neurokinin-1 receptor antagonists as novel antidepressants: trials and tribulations. Br J Psychiatry. 2007;191:282-284.
36.    Herpfer I, Lieb K. Substance P receptor antagonists in psychiatry: rationale for development and therapeutic potential. CNS Drugs. 2005;19(4):275-293.
37.    Kramer MS, Cutler N, Feighner J, et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science. 1998;281(5383):1640-1645.
38.    Keller M, Montgomery S, Ball W, et al. Lack of efficacy of the substance p (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder. Biol Psychiatry. 2006;59(3):216-223.
39.    Kramer MS, Winokur A, Kelsey J, et al. Demonstration of the efficacy and safety of a novel substance P (NK1) receptor antagonist in major depression. Neuropsychopharmacology. 2004;29(2):385-392.
40.    Krishnan KR. Clinical experience with substance P receptor (NK1) antagonists in depression. J Clin Psychiatry. 2002;63(suppl 11):25-29.
41.    sanofi-aventis press release, July 31, 2008. Available at:  Accessed November 6, 2008.
42.    Kugaya A, Sanacora G. Beyond monoamines: glutamatergic function in mood disorders. CNS Spectr. 2005;10(10):808-819.
43.    Pittenger C, Coric V, Banasr M, Bloch M, Krystal JH, Sanacora G. Riluzole in the treatment of mood and anxiety disorders. CNS Drugs. 2008;22(9):761-786.
44.    Zarate CA Jr, Payne JL, Quiroz J, Sporn J, Denicoff KK, Luckenbaugh D, Charney DS, Manji HK. An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry. 2004;161(1):171-174.
45.    Sanacora G, Kendell SF, Levin Y, et al. Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry. 2007;61(6):822-825.
46.    Zarate CA Jr, Quiroz JA, Singh JB, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry. 2005;57(4):430-432.
47.    Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-354.
48.    Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864.
49.    Zarate CA Jr, Singh JB, Quiroz JA, et al. A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry. 2006;163(1):153-155.