Dr. Erman is clinical professor in the Department of Psychiatry at the University of California, San Diego School of Medicine, a staff scientist for the Scripps Research Institute Department of Neuropharmacology, and chief medical officer of Avastra USA.

Disclosures: Dr. Erman is a consultant to Cephalon, Mallinckrodt, Neurocrine, sanofi-aventis, and Takeda; is on the speaker’s bureaus of Forest, sanofi-aventis, and Takeda; is on the advisory boards of Cephalon, Neurocrine, sanofi-aventis, and Takeda; has received grant/research support from Arena, Cephalon, Eli Lilly, GlaxoSmithKline, Mallinckrodt, Merck, Organon, Pfizer, Pharmacia, ResMed, sanofi-aventis, Schwarz Pharma, and Takeda; and owns stock in Cephalon, Forest, Merck, Neurocrine, Pfizer, sanofi-aventis, and Sepracor.




Complaints of fatigue and sleepiness are common in psychiatric patients. Their expression may reflect core components of various psychiatric disorders, may relate to comorbid conditions which may affect their emotional state, or may occur as a side effect of medications used to treat psychiatric disorders.


Fatigue versus Sleepiness

The first challenge involved in assessment of the complaint “I am tired” is trying to make a distinction between sleepiness or drowsiness and fatigue. Fatigue is usually defined as a feeling of weariness, tiredness, or lack of energy. When such a complaint is raised by patients receiving psychiatric care, specific medical causes (eg, hypothyroidism, anemia) must be ruled out, but the symptom will typically be assessed in the context of the underlying psychiatric complaint being evaluated (eg, depression, anxiety). In such a context, the complaint may be perceived to be understandable or even expected—“fatigue or low energy,” for example, being a core diagnostic component of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,1 criteria for depression. The fatigue complaint may also be presumed to be associated with an accompanying or related condition such as chronic fatigue syndrome or fibromyalgia.

What differentiates complaints of fatigue from those of sleepiness? Patients who are actually “sleepy” (as opposed to “fatigued”) report sleeping an excessive amount, taking involuntary naps, fighting sleepiness while sedentary, or report the capacity to nap voluntarily if given the opportunity. Sleepiness and fatigue may co-exist, but when frank sleepiness is present an effort must be made to identify its cause and to determine what treatment, if any, is appropriate.

Sleepiness complaints may be assessed in various ways. Patients may be asked to rate their sleepiness on a scale of 1–10, or may mark a point on a visual analog scale. Such techniques allow a baseline to be established and provide some basis for assessing responses to interventions. The simple, validated Epworth Sleepiness Scale2 is quite helpful in quantifying the severity of sleepiness complaints. This instrument, developed at the Epworth Hospital in Australia, asks the subject to rate his or herself from 0 (not sleepy) to 3 (very sleepy) in eight situations (eg, sitting quietly in a car, sitting and talking to someone). The maximum score is 24; the minimum is 0. Based on norms established at the time of the original publication, scores of ≥10 are considered to reflect pathologic sleepiness. It may be argued that in “real world” situations scores of <10 may be of clinical concern, especially for individuals in occupations that demand sustained alertness.


Insufficient Sleep

Numerous specific medical conditions have been identified as capable of causing excessive sleepiness. Interestingly, the most common cause of this complaint in modern society is likely to be insufficient sleep, a condition that is identified as a disorder in the formal sleep nosologic schema, The International Classification of Sleep Disorders, Second Edition (ICSD).3 It is estimated by the American Academy of Sleep Medicine that approximately 20% of adult Americans attain little sleep and may suffer consequences as a result.4 This may be on a voluntary basis; the 21st century provides an unending menu of activities that may keep people from their beds and prevent them from getting adequate amounts of sleep. Insufficient sleep may also occur as a consequence of personal or family responsibilities (eg, serving as a caregiver to a sick family member, dealing with the needs of newborn infants or young children) or as a consequence of extended work hours, lengthy commutes, or other job-related issues.

Although the “treatment” for this disorder may arguably be simple—ie, the direction to “get more sleep”—the patient must be willing to give up voluntary, enjoyable activities (eg, late night television, surfing the Internet, Online gaming) or be able to make other changes in their social setting (eg, obtaining help from other family members to help with care provision) that may not be readily accomplished.


Obstructive Sleep Apnea

Another common cause of sleepiness is obstructive sleep apnea (OSA). According to Young and colleagues,5 the lifetime prevalence of OSA in adults has been estimated to be 9% in men and 4% in women. However, this is likely a low estimate since subjects needed a substantial number of apnea events (15/hour) and to complain of excessive sleepiness in order to be defined as positive for this study. The prevalence increases with age, particularly in postmenopausal women. The prevalence in the elderly has been estimated to be 28% in men and 19% in women.6

The major diagnostic criterion for sleep apnea is cessation of breathing lasting at least 10 seconds. Hypopneas (a decrease in respiratory effort of ≤50%) may also produce arousal or hypoxia even when complete apneas do not occur. Most apneic episodes end with transient arousals, leading to light and disrupted sleep. During apneas and hypopneas, the blood-oxygen level often drops precipitously, and cardiac arrhythmias and nocturnal hypertension may occur.

The most common symptoms of OSA include excessive daytime sleepiness and snoring. Daytime sleepiness probably results from sleep fragmentation caused by the frequent nocturnal arousals occurring at the end of the apneas, with possible contribution from hypoxemia. Sleepiness is associated with lethargy, poor concentration, decreased motivation and performance, and inappropriate and inadvertent attacks of sleep.

Loud snoring, another typical complaint, is sometimes noisy enough to be heard throughout or even outside the house. Bed partners describe characteristic loud snoring interrupted by periods of silence, often terminated by snorts or gasps. Snoring results from narrowing of the airway caused by any of a number of factors, including obesity, large tonsils and adenoids, an elongated soft palate, hypothyroidism, or congenital narrowing of the oral pharynx. Because the prevalence of snoring increases with age, especially in women, and because snoring can have serious medical consequences, psychiatrists must give serious attention to complaints of loud snoring.

It has long been established that depression is extremely common in patients with OSA,7 and it is now also clear that effective treatment, typically with continuous nasal positive airway pressure (CPAP), reduces depressive symptomatology.8,9 The goal of OSA treatment is to keep the airway open during sleep so the patient can breathe. Nasal CPAP accomplishes this with the use of mask or interface applied to the face and connected to a small airflow generator, providing positive pressure that functions as a pneumatic splint, preventing airway collapse. When apnea is suspected—on the basis of history of snoring, observed breathing pauses, obesity, hypertension, treatment-resistant depression, and so forth—patients should be referred for sleep studies to determine if OSA is present.


Shift Work

Shift work may also provoke sleepiness complaints. Shift work problems occur when work demands put intrinsic circadian sleep-wake rhythms in conflict with sleep patterns determined by work schedules. Rotating schedules, particularly rapidly shifting schedules, are most problematic because endogenous circadian drives readjust slowly to the imposed sleep-wake cycle. Shift workers demonstrate impaired performance and increased risk of accidents, somatic complaints, and poor morale.10 Hypnotics, stimulants, and alcohol are often used excessively in relationship to unusual or shifting work schedules.

A specific disorder associated with shift work, shift work sleep disorder, has been defined in the ICSD.3 Based on research data showing symptomatic improvements in treated shift workers,10 the United States Food and Drug Administration has approved treatment with modafinil 200 mg 1 hour before the start of shift work for treatment of this disorder.



Narcolepsy, first described by Gelineau in France in the 1870s, is less common than the above-mentioned causes of sleepiness, but is not a rare disease. Its prevalence rate of 0.03% to 0.16% approximates that of multiple sclerosis.

Narcolepsy is associated with a pentad of symptoms. First, it is associated with excessive daytime sleepiness, characterized by irresistible “attacks” of sleep in inappropriate situations such as driving a car, talking to a supervisor, or social events. Second, narcolepsy is associated with cataplexy, a sudden bilateral loss of muscle tone, precipitated by strong emotions such as laughter, anger, or surprise. Third, it is associated with poor or disturbed nocturnal sleep. Fourth, it is associated with hypnagogic hallucinations, which are vivid dreams or dream-like experiences occurring at sleep onset. Last, narcolepsy is associated with sleep paralysis, which is brief paralysis associated with the transitions into, and out of, sleep.
Narcolepsy is associated with significant social and financial impairment for affected individuals and their families. For example, automobile accidents may result from either sleepiness or cataplexy. Most states prohibit narcoleptic patients from driving, at least as long as they are symptomatic.
The first narcolepsy symptom to present is most often excessive sleepiness, typically developing during the late teens or early twenties. The full syndrome including cataplexy and other symptoms usually presents at a later age, typically within several years, but at time presenting in the fifth or sixth decade of life. Once established, narcolepsy symptoms are usually relatively stable, without progressive increases in severity of hypersomnia complaints.

Sleep paralysis and hypnagogic imagery may be seen without cataplexy, and cataplexy may present in isolation without other rapid eye movement (REM)-associated phenomena. Rarely, narcolepsy may present with hallucinations occurring at transitions from wake to sleep that may lead to a diagnosis of psychosis.

Treatment of narcolepsy attempts to improve quality of life, reduce excessive daytime sleepiness, and prevent cataplectic attacks, if present. Wake-promoting medications approved to treat narcolepsy include modafinil, various formulations of amphetamines, and methylphenidate. Modafinil is preferred on grounds of efficacy, safety, availability, and low risk of abuse and diversion. Selective serotonin reuptake inhibitors, such as fluoxetine and citalopram, and tricyclic antidepressants, such as protriptyline and clomipramine, have been used in the past to treat cataplexy, sleep paralysis, and hypnogogic hallucinations, but sodium oxybate, is now approved by the FDA for treatment of cataplexy and symptoms of sleepiness in patients with narcolepsy.11

When narcolepsy is suspected, full sleep studies, including daytime testing of sleep and REM-propensities (multiple sleep latency testing) is typically required to establish the diagnosis. These studies are often needed for a definitive diagnosis to allow access to medications used to treat this disorder, which are expensive and may be tightly controlled due to perceived abuse potential.


Periodic Limb Movements in Sleep and Restless Legs Syndrome

Periodic limb movements in sleep (PLMS) and restless legs syndrome (RLS) are other relatively common disorders associated with complaints of excessive sleepiness. PLMS is a disorder in which repetitive, brief, and stereotyped limb movements occur during sleep, often with a periodicity of approximately 20–40 seconds. RLS is associated with disagreeable sensations in the lower legs, feet, or thighs that occur in a recumbent or resting position and cause an almost irresistible urge to move the legs.12 These disorders are usually associated with transient arousals in sleep, demonstrated by disruptions in the electroencephalograph recording in sleep studies. Both PLMS and RLS usually occur in middle-aged people, but many patients report having had the same sensations as adolescents and even as children. Although these conditions usually present initially with complaints of insomnia, when they become established they may be associated with hypersomnia.

The treatment of choice for both RLS and PLMS are dopamine agonist compounds. To date, only ropinirole and pramipexole have been approved by the FDA for the treatment of RLS. These agents often lead to dramatic relief from symptomatic complaints, including excessive sleepiness, which have plagued RLS and PLMS sufferers for years.



Other conditions may provoke sleepiness complaints but are seen much less frequently. These include idiopathic hypersomnia, also known as primary hypersomnia, and periodic hypersomnias such as Kleine-Levin syndrome, usually seen in male adolescents. The etiology of these disorders is not understood, and symptomatic treatment with alerting or stimulant medications is the usual therapeutic approach.



Psychiatric patients with sleepiness complaints deserve the same careful diagnostic and therapeutic attention as does any other patient. Patients with depression may have hypersomnia complaints distinct from the fatigue associated with their depression, and are likely to have reductions in depressive symptoms when a breathing-related sleep disorder is treated. Shift workers with daytime emotional dysfunction may benefit from treatment with modafinil, with reductions in interpersonal distress as well as improvements in alertness. Recognition of the existence of, and treatment of, long-standing disorders such as narcolepsy and RLS/PLMS may allow patients to be much more active and productive individuals, with associated benefits as well in social and emotional function. The keys to treating sleepiness are attention to the symptomatic complaint of sleepiness, use of appropriate diagnostic procedures to establish that a treatable condition may be present, and provision of appropriate therapy once a diagnosis is established. PP



1.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
2.    Johns MW. Sleepiness in different situations measured by the Epworth sleepiness scale. Sleep. 1994;17(8):703-710.
3.    The International Classification of Sleep Disorders. 2nd ed. Westchester, NY: American Academy of Sleep Medicine; 2005.
4.    Sleep Deprivation. Available at: www.aasmnet.org/Resources/FactSheets/SleepDeprivation.pdf. Accessed April 5, 2008.
5.    Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep disordered breathing among middle-aged adults. N Engl J Med. 1993;328(17):1230-1235.
6.    Ancoli-Israel S, Kripke DF, Klauber MR, Mason WJ, Fell R, Kaplan O. Sleep disordered breathing in community-dwelling elderly. Sleep. 1991;14(6):486-495.
7.    Reynolds CF, 3rd Kupfer DJ, McEachran AB, Taska LS, Sewitch DE, Coble PA. Depressive psychopathology in male sleep apneics. J Clin Psychiatry. 1984;45(7):287-290.
8.    Schwartz DJ, Karatinos G. For individuals with obstructive sleep apnea, institution of CPAP therapy is associated with an amelioration of symptoms of depression which is sustained long term. J Clin Sleep Med. 2007;3(6):631-635.
9.    Suhner AG, Darko DD, Erman MK, Riel KF, Mitler MM. Depressive symptoms in patients with OSA and the impact of nasal CPAP treatment. Sleep. 2003;25:A225.
10.    Czeisler CA, Walsh JK, Roth T, et al. Modafinil for excessive sleepiness associated with shift-work sleep disorder. N Engl J Med. 2005;353(5):476-486. Erratum in: N Engl J Med. 2005;353(10):1078.
11.    Littner M, Johnson SF, McCall WV, et al. Practice parameters for the treatment of narcolepsy: an update for 2000. Sleep. 2001;24(4):451-466.
12.    Walters AS, LeBrocq C, Dhar AK, et al. Validation of the international restless legs syndrome study group rating scale for restless legs syndrome. Sleep Med. 2003;4(2):121-132.


e-mail: ns@mblcommunications.com


In this issue of Primary Psychiatry, an article by Surilla Randall, PhD, and colleagues, provides an overview of what is known regarding the efficacy and safety of popular nonprescription products used for insomnia. Both the prevalence of chronic (estimates can range from approximately 10% to 50%) and self-treatment with over-the-counter (OTC) sleep aids, herbal and dietary supplements, and/or alcohol are very common. The authors report the findings of a survey that showed that 25.9% of respondents reported using some substance to aid their sleep. Of those who used medications (either prescription, OTC drugs, or both) to improve sleep, 57% reported using OTC sleep aids. The authors note that most of the evidence about the efficacy and safety of OTC sleep aids is inconclusive, mainly due to problems with research design and lack of placebo-controlled groups. There is also little data to support long-term usage. As with other sedating agents, prolonged use of antihistaminic drugs may result in tolerance and/or dependence and produce daytime sleepiness. The authors concede that treatment of insomnia with antihistamine-containing OTC sleep aids may help occasional mild insomnia. The data on other non-prescription sleep aids is too limited or inconsistent in results to consider their use. While alcohol may have initial sedative effects, it is associated with rapid tolerance development and dose escalation.

Gary K. Zammit, PhD, focuses on treating sleep disorders in patients with psychiatric disorders. In his article, Dr. Zammit comments about mood disorders and insomnia often being comorbid conditions, and about medications potentially disrupting or enhancing sleep in a variety of different ways. His article examines the evidence supporting the efficacy and safety of mood stabilizers in the treatment of comorbid and primary insomnia. He also points out that insomnia may be a precursor to depression. He notes that in every study completed to date, insomnia was found to be a significant risk factor for the subsequent onset of depression. A greater incidence of affective disorder has been found in people with insomnia. Treatment options to address both depression and insomnia are reviewed.

An article by Adriana J. Pavletic, MD, MS, and colleagues, focuses on the importance of medical screening of volunteers participating in research on mental illness. The authors describe a study of how medical screening identified a relatively high rate of conditions in both healthy controls and patients. This study potentially impacts on mental health research. The authors emphasize the need to develop standards in medical screening procedures for volunteers in psychiatric research.

Circadian disruption is invariably a part of a depressive episode. Numerous studies have shown changes in sleep patterns, daytime alertness, and sleep tendencies in people with depression. Seithikurippu R. Pandi-Perumal, MSc, and colleagues, note that the frequency of circadian dysfunction in affective states supports a major role of the circadian system in the etiology and the treatment of affective disorders. Ironically, many commonly used antidepressants can worsen sleep by producing insomnia, vivid dreams, bruxism, night sweats, and myoclonus. This article discusses melatonin and drugs that act on melatonon receptors. Melatonin influences sleep-promoting and sleep/wake rhythm-regulating actions through the specific activation of receptors, highly concentrated in the suprachiasmatic nuclei of the anterior hypothalamus. Melatonin agonists, such as ramelteon (which is marketed in the United States) and agomelatine (which the European Medicines Agency declined to approve in 2006 because efficacy had not been sufficiently shown) represent possible alternatives for treating sleep disturbances and circadian rhythm sleep disorders associated with mental illness. Agomelatine has shown some anti-anxiety and antidepressant effects in clinical trials. In this article, the authors suggest that combination therapy using an antidepressant plus a melatonergic agent may be an effective strategy for treating sleep disorders in the context of depression. The action of agomelatine is due to its agonist activity on melatonin (MT)1 and MT2 receptors in the suprachiasmatic nucleus. In addition to describing key aspects of brain chemistry involved in insomnia, the authors speculate that disruptions in circadian rhythms are linked to depressive states and that agomelatine’s effectiveness in treating these symptoms may be broader than other antidepressants and, thus, may more effectively address the complexities of depressive illness.

In a response to “Clinical Updates in Sleep Medicine,”1 a critique of trazodone and other non-benzodiazepines analogs for off-label use as soporifics, Michael S. Hanau, MD, FAPA, argues, among other matters, that despite the absence of well-controlled trials, these agents have an extensive history of safe and effective use in clinical practice. He adds that some of the newer agents produce parasomnias, visual hallucinations, and abuse. Milton K. Erman, MD, provides a detailed response to Dr. Hanau’s letter and concludes that, in any event, clinicians should certainly consider issues of risk and benefit before prescribing any medication. PP


1. Erman MK. Is it a sleeping pill? Primary Psychiatry. 2008;15(1)34-36.


This interview took place on February 28, 2008, and was conducted by Norman Sussman, MD.


This interview is also available as an audio PsychCastTM at http://psychcast.mblcommunications.com.

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


Dr. King is president of the American Academy of Family Physicians (AAFP), which respresents 94,000 physicians and medical students nationwide. He is volunteer faculty at the University of Tennessee Center for Health Sciences, Memphis, and medical director of Chester County Healthcare Services in Selmer. In 1997, Dr. King received the Family Physician of the Year Award from the Tennessee Academy of Family Physicians. As member of the board of directors of FamMedPAC, the AAFP’s political action committee, Dr. King advocates the legislative goals of family medicine to members of Congress.


Are there data that show the percentage of patients seen in the primary care setting who have a psychiatric disorder?

Yes. In 2003, reports from the Institute of Medicine showed that approximately 65% to 80% of people with mental illness presented to a primary care physician (PCP) for their first clinical visit.1  Most studies show that approximately 39% to 40% of those patients will continue to be cared for by the family physicians or general internists to whom they intially presented. The physicians may refer as many as 60% of the patients to psychiatrists.1


What is the most common psychiatric disorder seen in primary care?

The most common psychiatric disorder observed is major depressive disorder (MDD). Bipolar and other generalized anxiety disorders are noted, and substance abuse, if it is looked for on a regular basis, can also be seen. Children with attention-deficit/hyperactivity disorder are often cared for as well.


What kind of clinical presentations trigger a referral to a psychiatrist or other mental health clinicians?

A major trigger is when patients do not respond to a medication the way the clinician thinks they should be responding since the start of treatment, particularly in suicidal or homicidal patients. In such cases, the clinician would recommend them for inpatient care under the supervision of a psychiatrist as well. If psychotic symptoms are observed, the patient will be quickly referred to a psychiatrist for help. For example, a patient with bipolar disorder who is manic will be sent to the psychiatrist for a follow-up evaluation.


What kind of barriers do PCPs face when referring patients to psychiatrists?

It is not so much the insurance company barriers, but the main barrier is geographical incovenience and impracticality. For example, I am in Summerton, Tennessee, and the closest psychiatrist is 50 miles away. Having patients be able to visit a psychiatrist and getting them in to see one on a timely basis is difficult. Appointments for some patients run weeks behind. When I try to refer a patient to a psychiatrist at the local mental health center, that psychiatrist comes to Summerton only once a month or once every 2 weeks. Sometimes, it may be 3 months before a patient can see a psychiatrist. As a result, the patient and I have to work with each other for the next 2–3 months until he or she can see the psychiatrist.


What kind of communication between a PCP and psychiatrist would you like to see when they share a patient’s care?

I would like to see a kind of communication very similar to that which physicians have with other subspecialists. Physicians should have a report from the psychiatrist returned to them as quickly as possible that discusses the patient’s condition, treatment plan, and newly administered medications. Because other comorbid problems are possibly being taken care of (eg, diabetes, hypertension, asthma, or arthritis), physicians need that information to make sure the medications do not clash and that everyone is trying to accomplish the same goal. Physicians also need to relay that type of information to the  psychiatrist as soon as possible. Quick, frequent communications between the PCP and the psychiatrist is crucial to ensure that psychiatrists always know that this patient has a family physician and a medical “home.”


Based on your experience, what could psychiatrists do differently or better to improve physicians’ overall treatment of patients?

Psychiatrists and physicians seem to be more concerned with Health Insurance Portability and Accountability Act violations and issues with security and privacy to the point where they have to jump through several hoops to get that information, even though they are both healthcare providers who need to communicate with each other about the patient.

Every person should have a medical home with a PCP. Patients with mental disorders may often need a psychiatrist as part of the team caring for the patient. We need to make sure that we have a two-way communication between healthcare providers so that the many barriers under the name of privacy are removed to provide the best care for the patient. Psychiatrists should make an effort to find out if a patient has a PCP and make sure that physician has needed medical information, such as medicines, diagnosis, and treatment plans as soon as possible.


Where do family doctors get their information about diagnosis and treatment of psychiatric disorders?

There are a few sources from which family doctors get their information, including journals. For example, The American Family Physician, which is the official clinical journal of the American Academy of Family Physicians, usually discusses a psychiatric or mental health condition in each month’s issue. It is one of the favorites of medical students because it gets to the point and helps the physician take care of his or her patient. Family doctors seek other journals as well particularly because there are so many sent to their offices. In addition, physicians are beginning to use electronic health records for information. For example, I have electronic health records in my practice, and the system is frequently updated. If a patient comes in with a particular concern, I can immediately educate myself on that specific problem even while the patient is in the room. Browsing the Internet, attending standard medical meetings, and listening to lectures on a regular basis are other ways through which family doctors get their information.


Do you have a particular area of interest in terms of diagnosing and treating psychiatric disorders?

I usually focus on the patients who have chronic medical conditions such as diabetes, hypertension, heart disease, or cancer complemented by a mental illness. These patients with multiple chronic diseases also very often have mental disorders such as depression and anxiety disorders. It is important to treat the entire patient.


Of the patients who initially present to PCPs with psychiatric symptoms, what percentage are ultimately experiencing the result of a physical disorder or treatment side effect?

I do not have literature that could provide a specific figure, but as an estimate from my practice, approximately 10% to 15%. The most common situation I have encountered is drug treatment side effects. For example, a person could be taking propanolol for his or her blood pressure or another beta blocker, and this medication can lead to depressive symptoms. Even the daily ingestion of chronic pain medications could cause a patient to come across as depressed. In addition, elderly patients who are on medications that lead to mental confusion can cause physicians to question whether the patient has Alzheimer’s disease, depression, or other problems.

When a patient’s lab results do not match his or her symptoms, I usually consider that the patient’s condition could be an impairment based on his or her dependency on a drug or alcohol. I look for those types of things to see which possible condition is coming across.


Are PCPs comfortable with using atypical neuroleptics?

Atypical neuroleptics are very expensive drugs; however, they are fairly safe. They are mostly used by patients with bipolar disorder who are dealing with a manic phase or mood disorder. Atypical neuroleptics may be prescribed to patients who have an extremely agitated type of depression.

As PCPs, we have to make a decision over two issues. We first need to determine whether the patient should be referred to a psychiatrist. Another issue concerns the addition of an atypical neuroleptic to a patient’s treatment. If the patient’s condition is severe, I would refer him or her to a psychiatrist. However, since contacting and meeting with a psychiatrist is difficult to do, I may try the medication and evaluate how it affects the patient.


Has there been a decreased use of antidepressants as a result of all the publicity and the label changes surrounding suicidality?

I have not seen a decrease in the use of  antidepressants. Most family physicians spend more time talking to patients about the suicidal side effects. With my patients, I always inform them of a slight increased risk of suicidal tendencies and let them know that they can contact me if they feel that way. As with any other drugs, PCPs need to make sure that the patient understands and looks for appropriate side effects.


Is there anything else you would like to stress?

It is difficult to tease out the psychiatric perspective from the physical perspective. PCPs do a great job of taking care of mental health issues. However, they need help from psychiatrists regularly as well.

From a personal standpoint, I think that once the insurance industry and patrons of health care realize that mental health is the same thing as diabetes, they will start paying PCPs and psychiatrists equally, regardless of which condition each takes care of. In Tennessee, if a physician gives the insurance company a patient’s mental health diagnosis, the psychiatrist would be paid half of what he or she would have received if a diabetes diagnosis had been turned in. That naturally leads to creative coding. For example, what would be considered a mental health diagnosis might be referred to as a physical diagnosis such as fatigue, tiredess, or insomnia. In order for the data to be accurate, this reality needs to change. PP



1.    American Family Physician. Graham Center One-Pager. Family Physicians Are an Important Source of Mental Health Care. Available at: www.aafp.org/afp/20030401/graham.html. Accessed March 27, 2008.


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 is on the depression advisory board for Eli Lilly.




Psychiatric issues are common in sickle cell disease (SCD)1 but have not received sufficient attention in the clinical or research literature. These issues are further complicated by the social, economic, and healthcare disparities experienced by many African Americans. This column reviews the following psychiatric issues in SCD, with particular focus on recent research: first, depression and anxiety resulting from living with a chronic stigmatizing disease associated with chronic pain, unpredictable painful crises, multiple serious complications, poor health-related quality of life (HRQOL), and high mortality; second, problems of pain management, frequent undertreatment, and potential for substance abuse and addiction; third, coping styles; fourth, alcohol abuse; and last, central nervous system (CNS) injury and resulting cognitive dysfunction from strokes, primarily during childhood.


Overview of Sickle Cell Disease

SCD is an autosomal recessive genetic disorder of hemoglobin (Hb) structure and the most common of the hemoglobinopathies. While it usually results in anemia, the primary symptomatic manifestation of SCD is pain. The most severe form of SCD, homozygous sickle cell anemia (Hb SS), occurs when Hb S is inherited from both parents. In the United States, this happens in approximately one in 375 African-American births. Other genetic variants producing SCD include two forms of sickle cell-beta thalassemia (Sβ° and Sβ+ ) and sickle cell-hemoglobin C (SC). Individuals with sickle cell trait, ie, heterozygotes for Hb S, do not experience any adverse clinical consequences (except under acute hypoxic conditions, eg, exposure to high altitude without time to accommodate) and have had a selective advantage against malaria. Those with the homozygous disease face a chronic disease, with onset in childhood leading to devastating consequences.

SCD occurs primarily in those of African descent, but it also afflicts people of Mediterranean, Middle Eastern, and Asian origins. Approximately one in 300 African-Americans have SCD (>70,000 people) and 8% have sickle cell trait. The consequences of SCD are aggravated by social, economic, and healthcare disparities. African Americans are on average poorer, have more limited access to healthcare services, and die sooner than Caucasians.2 Medical advances, such as prophylactic penicillin for children, have transformed the disease from a pediatric illness with few surviving beyond adolescence into one chronically extending into adulthood. Life expectancy has increased from a mean of 14 years of age in the 1970s to close to 50 years of age at present.3 By the 1980s, the federally funded Cooperative Study of Sickle Cell Disease (CSSCD)4 found median survival was into the fourth decade for homozygous patients. Patients with doubly heterozygous forms of SCD, such as Hb SC, fared even better, and the presence of a higher percentage of persistent fetal hemoglobin (Hb F) was associated with less severe disease and greater longevity.

This improved survival has created the relatively new phenomenon of adults with chronic SCD. Consequently, much less is known about psychosocial factors in adults with SCD than in many other chronic medical disorders, with most studies to date addressing prevalence of depression (see below). The increase in longevity has also resulted in physicians for adults treating pain resulting from a disease for which they have limited training and experience. In one inpatient study, one-third of patients reported inadequate pain relief and nearly 50% reported long delays in being treated for pain.5 The evidence base used to guide treatment for the growing population of adults with SCD has been very limited, with even less data regarding psychosomatic interactions, though both are now an active focus of investigators.

Most familiar to clinicians are the acute painful episodes known as “sickle cell crises,” thought to be due to acute vaso-occlusion by sickled red blood cells. Recurrent crises represent the most common reason patients seek acute medical care. Dehydration, temperature extremes, infection, changes in altitude, stress, and physical exertion may precipitate crises, but most crises occur without an identifiable cause. Vaso-occlusion causes acute pain in the short run and chronic pain and end-organ damage in the long run, potentially affecting all organ systems with particular harm to bones, kidneys, lungs, eyes, and brain. Complications include acute chest syndrome, avascular necrosis, priapism, ischemic leg ulcers, transient ischemic attacks and stroke, osteomyelitis, gallstones and cholecystitis, and renal insufficiency.

Clinicians and investigators have tended to focus on acute crisis pain and to equate crisis with acute healthcare utilization, ie, emergency room visits or hospitalization. However, the recent Pain in Sickle Cell Epidemiology Study (PiSCES)6-13 has demonstrated that pain in adults with SCD is far more prevalent and severe than previous studies have portrayed, and it is mostly managed at home.6 Therefore, it has been vastly underestimated when measured by using only healthcare utilization. In this prospective study, >50% of adults with SCD experienced pain, crises, or healthcare utilization on >50% of the days. Almost 33% experienced pain nearly every day, with the mean intensity in the middle range. In contrast, only approximately 15% rarely experienced pain. Crises and healthcare utilization were far less common than reported pain days; pain days that were not associated with a crisis occurred 10 times more often as pain days associated with healthcare utilization. Thus, contrary to commonly held belief, pain in adults with SCD is the rule rather than the exception. Since SCD adults infrequently utilize health care even in response to severe pain, there is a vast, mostly submerged iceberg of sickle cell pain that is managed outside of medical facilities and not seen by most professionals.

Smaller longitudinal studies measuring daily pain in children have also found that pain was most often managed at home rather than within healthcare facilities.7 How might this be explained? Behavioral theories suggest that many factors, besides pain itself, influence the response to pain.7 Adults with SCD carefully weigh the decision to come to a busy emergency department for treatment of even severe pain, where they may face long waits, stigmatization, and labeling as “drug-seeking.” Some manage their pain at home because of barriers in accessing health care, especially finding clinicians with SCD expertise, competing life priorities (eg, no child care), and lack of transportation. Evidence of each of these may be found in behavioral studies of SCD.7

HRQOL in adults with SCD is significantly worse than national norms.8 Adults with SCD have quality of life (QOL) that is similar to dialysis patients and poorer than adults with cystic fibrosis (except for mental health). Not surpisingly, QOL in adults with SCD significantly decreases as pain levels increase.


Depression and Anxiety

As with most chronic diseases, depression and other psychiatric disorders are common in SCD.13-15 Rates of depression are similar to those found in other serious chronic medical disorders, ranging from 18% to 44%,16-18 and are increased over rates in the general population even when one controls for illness-related physical symptoms.19 In a Nigerian study, subjects with SCD had a prevalence rate of depression greater than those with cancer or malaria (but less than those with HIV/AIDS).20 While studies of depression in children with SCD have shown mixed results, children experience high rates of fatigue and other somatic complaints, impaired self-esteem, feelings of hopelessness in the context of frequent hospitalizations, absences from school, and the inability to experience a normal childhood.1

There are many potential contributing causes to symptoms of depression and anxiety in SCD. These include the chronicity of the illness; unpredictability of crises; chronic pain; overwhelming nature of medical complications, including anemia, fatigue, growth retardation, physical deformities, leg ulcers, renal failure, strokes, and substantially reduced life expectancy; and racial prejudice and stereotyping. SCD may result in social derision, disability, and financial stress21 as well as stigmatization for pseudoaddiction to opioid analgesics.22 One study found that adults with SCD had lower self-esteem than those with HIV/AIDS or cancer.20 Chronically prescribed opioids may contribute a component of substance-induced mood disorder.15

Children with SCD are often underweight, shorter than normal children, and have delayed puberty. With their small stature, adolescents with SCD encounter problems with self esteem, dissatisfaction with body image, and social isolation, with participation in athletics also limited due to fear of initiating a vaso-occlusive crisis.1 School performance suffers when hospitalizations lead to missing multiple school days. Accordingly, adolescents often experience hopelessness and social withdrawal.23

PiSCES found that 27.6% of adults with SCD were depressed and 6.5% had ananxiety disorder.13 Depressed subjects had pain on significantly more days than nondepressed subjects (mean pain days=71.1% versus 49.6%, P<.001). On non-crisis days, depressed subjects had higher mean pain, distress from pain, and interference from pain than those without depression. Both depressed and anxious subjects had poorer functioning on all dimensions of HRQOL, even after controlling for demographics, hemoglobin type, and pain. The anxious subjects had more pain, distress from pain, and interference from pain, both on non-crisis days and on crisis days, and used opioids more often. Anxious patients were also more likely to be emergency room “frequent flyers.”


Chronic and Acute Pain and Opioid Use

As noted above, recurrent painful crises represent the most common reason patients with SCD seek acute medical care. Painful crises most frequently involve the abdomen, chest, back, and extremities. The average adult patient experiences <1 vaso-occlusive crisis per year for which he or she seeks medical care, but a very small fraction (approximately 1%) do so several times per year.24 However, the PiSCES found that most self-defined painful crises do not result in acute healthcare visits.6 Both the unpredictability and the severity of crisis pain contribute to its psychological morbidity and debilitation. It is interesting that higher hematocrit is associated with more pain. Contrary to many studies of acute and chronic pain of other causes, men and women with SCD report generally similar pain experiences, both in terms of acute crisis pain and chronic pain, as well as HRQOL.8,9

Opioid analgesics are the mainstay of therapy for acute pain crises in SCD. Therefore, by adulthood, most patients have had many years of intermittent exposure to opioids. Opioids help control pain, improve functional capacity, and decrease hospitalizations in patients with SCD.25 Chronic opioid use often results in tolerance and physiologic dependence, but much less often abuse and addiction. Opioid abuse and addiction behaviors can be difficult to define when prescribed for chronic pain. While there is little evidence in the medical literature that suggests addiction is frequent in SCD, physicians and other healthcare providers routinely overestimate its risk and prevalence.26 Over 60% of nurses believe addiction is prevalent in SCD,27 and >50% of emergency department physicians and 25% of hematologists thought that >20% of SCD patients are addicted.28 Some of this distorted perception results from failure to distinguish between physiologic tolerance and dependence versus addictive behaviors.22

Because of their fear of causing or exacerbating addiction, physicians may under-treat pain in patients with SCD.29 This may result in pseudoaddiction, where addiction-like behaviors occur as a result of inadequate pain management.30 An example mislabeled as “drug-seeking behavior” occurs when a patient with acute crisis pain asks for a higher dose of opioid than he has been given because the physician has failed to increase normal dosage in recognition of tolerance developed through chronic opioid therapy.22 Opioid abuse and addiction can occur in adults with SCD; some patients may inappropriately use opioids for non-pain symptoms such as insomnia, depression, and anxiety. It should be noted, however, that opioids do not have any specific adverse effects on SCD. In contrast, cocaine is very harmful since in causing small vessel spasm it may precipitate or escalate sickling, and it increases the already elevated risk of stroke and other ischemic events.31 One form of opioid misuse in SCD to be aware of is the barter exchange of prescribed opioids for cocaine. This possibility should always be considered whenever a urine toxicology screen is negative for opioids in a SCD patient who says he has been taking his analgesic as prescribed.


Coping Style

Numerous studies have examined the influence of coping style in SCD, specifically how negative thinking and passive adherence contribute to increases in pain perception, opioid use, and healthcare utilization.11 “Negative thinking” is a cognitive set composed of catastrophizing and self-statements of fear and anger, in which catastrophizing has seemed the most important component in pain research. “Catastrophizing” refers to an exaggerated negative orientation or “mental set” toward pain stimuli and pain experience. Individuals who catastrophize may develop beliefs with a high degree of aversion to pain-eliciting situations, pay more attention to their pain sensations, and consume more opioids.32 Catastrophizing can be understood as a set that includes rumination, magnification, and helplessness to deal with pain. Although it has been identified as an important factor affecting outcomes in several painful conditions, it appears that the role of catastrophizing in other conditions cannot be generalized to SCD. While adults with SCD have higher mean catastrophizing scores than found in studies of other chronic pain conditions that are not lifelong and life-threatening, no differences were found between higher and lower catastrophizers in intensity of pain, distress, interference, opioid use, or healthcare utilization.11


Alcohol Abuse

Alcohol abuse is common in patients with chronic pain and painful medical disorders, but until recently it had not been studied in SCD. In the prospective PiSCES cohort, almost one-third of SCD adults were abusing alcohol.10 There were no significant differences between alcohol abusers and nonabusers on demographics, biologic variables, depression, anxiety, or measures of pain and crisis. Alcohol abusers did not use opioids any more often, but they reported more pain relief from opioids than did nonabusers. Alcohol abusers had fewer unscheduled clinic visits, emergency room visits, hospital days, and any healthcare utilization for SCD; however, this was only statistically significant for emergency room visits. Surprisingly, QOL was similar between both groups, except that alcohol abusers unexpectedly had better overall physical QOL. Alcohol abusers were more likely to report coping by ignoring pain, diverting attention, and using particular self statements.


Psychosocial Interventions

There have only been a few small short-term biobehavioral intervention trials that have attempted to alter pain and healthcare utilization in SCD. A multidimensional, intense intervention to improve pain management of SCD patients through counseling and carefully monitored opioid prescribing reduced emergency department visits and hospital admissions.33

In another trial,34 a pain-coping skills intervention in adults with SCD lowered pain perceptions from a laboratory-induced pain stimulus and significantly increased coping attempts. On pain days when subjects used coping strategies, they had fewer healthcare contacts than on pain days when they did not use coping strategies. Other interventions have met with limited success. A brief training in cognitive coping skills resulted in increased coping attempts, decreased negative thinking, and lower tendency to report pain during laboratory-induced noxious stimulation.35 A family intervention in children met with some success.36 Self hypnosis as an adjunct to traditional treatment improved sleep, reduced pain days, and reduced. the use of pain medications.37 There are no published randomized controlled trials of antidepressants in patients with SCD.


Central Nervous System Injury

Brain disease from SCD complications may begin early in life. Children with SCD may experience a wide variety of neurologic syndromes, including ischemic and hemorrhagic stroke, transient ischemic attacks, “soft neurologic signs,” seizures, headache, coma, visual loss, altered mental status, cognitive difficulties, and covert or “silent” infarction. Approximately 25% to 33% of affected children have CNS consequences of SCD.38 Seizures occur in 12% to 14%.39,40  Once very common in children with SCD, the incidence of stroke has been reduced through chronic transfusion and other interventions.41 Intellectual deficits, including borderline-to-moderate mental retardation and reduced language function, have been reported.42 Not surprisingly, cognitive deficits in children with SCD lead to educational and social problems, and even dementia later in life.43 Acquired neurologic impairments in children with SCD are associated with difficulties in the decoding of emotions of other children and adults.44 A small, nonrandomized study45 suggests that hydroxyurea therapy may improve cognitive functioning in SCD. PP



1. Becker M, Axelrod DJ, Oyesanmi O, Markov DD, Kunkel EJ. Hematologic problems in psychosomatic medicine.Psychiatr Clin North Am. 2007;30(4):739-759.
2. Committee on Understanding and Eliminating Racial and Ethnic Disparities in Health Care. Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care. 1st ed. Washington, DC: National Academies Press; 2002.
3. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994;330(23):1639-1644.
4. Lee A, Thomas P, Cupidore L, Serjeant B, Serjeant G. Improved survival in homozygous sickle cell disease: lessons from a cohort study. BMJ. 1995;311(7020):1600-1602.
5. Gaston MH, Rosse W. The cooperative study of sickle cell disease: review of study design and objectives. Am J Pediatr Hematol Oncol. 1982;4(2):197-200.
6. Smith WR, Penberthy LT, Bovbjerg VE, et al. Daily pain in sickle cell disease. Ann Intern Med. 2008;148(2):94-101.
7. Smith WR, Bovbjerg VE, Penberthy LT, et al. Understanding pain and improving management of sickle cell disease: the PiSCES study. J Natl Med Assoc. 2005;97(2):183-193.
8. McClish DK, Penberthy LT, Bovbjerg VE, et al. Health related quality of life in sickle cell patients: the PiSCES project. Health Qual Life Outcomes. 2005;3:50.
9. McClish DK, Levenson JL, Penberthy LT, et al. Gender differences in pain and health care utilization for adult sickle cell patients: the PiSCES Project. J Womens Health (Larchmt). 2006;15(2):146-154.
10. Levenson JL, McClish DK, Dahman BA, et al. Alcohol abuse in sickle cell disease: the PiSCES project. Am J Addict. 2007;16(5):383-388.
11. Citero VA, Levenson JL, McClish DK, et al. The role of catastrophizing in sickle cell disease–the PiSCES project. Pain. 2007;133(1-3):39-46.
12. Aisiku IP, Penberthy LT, Smith WR, et al. Patient satisfaction in specialized versus nonspecialized adult sickle cell care centers: the PiSCES study. J Natl Med Assoc. 2007;99(8):886-890.
13. Levenson JL, McClish DK, Dahman BA, et al. Depression and anxiety in adults with sickle cell disease: the PiSCES project. Psychosom Med. 2008;70(2):192-196.
14. Alao AO, Cooley E. Depression and sickle cell disease. Harv Rev Psychiatry. 2001;9(4):169-177.
15. Alao AO, Dewan MJ, Jindal S, Effron M. Psychopathology in sickle cell disease. West Afr J Med. 2003;22(4):334-337.
16. Wison Schaeffer JJ, Gil KM, Burchinal M, et al. Depression, disease severity, and sickle cell disease. J Behav Med. 1999;22(2):115-126.
17. Hasan SP, Hashmi S, Alhassen M, Lawson W, Castro O. Depression in sickle cell disease. J Natl Med Assoc. 2003;95(7):533-537.
18. Laurence B, George D, Woods D. Association between elevated depressive symptoms and clinical disease severity in African-American adults with sickle cell disease. J Natl Med Assoc. 2006;98(3):365-369.
19. Molock SD, Belgrave FZ. Depression and anxiety in patients with sickle cell disease: conceptual and methodological considerations. J Health Soc Policy. 1994;5(3-4):39-53.
20. Ehigie BO. Comparative analysis of the psychological consequences of the traumatic experiences of cancer, HIV/AIDS, and sickle cell anemia patients. IFE Psychologia. 2003;11(3):34-54.
21. Scott KD, Scott AA. Cultural therapeutic awareness of sickle cell anemia. J Black Psychol. 1999;25(3):316-335.
22. Elander J, Lusher J, Bevan D, Telfer P, Burton B. Understanding the causes of problematic pain management in sickle cell disease: evidence that pseudoaddiction plays a more important role than genuine analgesic dependence. J Pain Symptom Manage. 2004;27(2):156-169.
23. Hurtig AL, Park KB. Adjustment and coping in adolescents with sickle cell disease. Ann N Y Acad Sci. 1989;565:172-182.
24. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease. Rates and risk factors. N Engl J Med. 1991;325(1):11-16.
25. Brookoff D, Polomano R. Treating sickle cell pain like cancer pain. Ann Intern Med. 1992;116(5):364-368.
26. Labbe E, Herbert D, Haynes J. Physicians’ attitude and practices in sickle cell disease pain management. J Palliat Care. 2005;21(4):246-251.
27. Pack-Mabien A, Labbe E, Herbert D, Haynes J Jr. Nurses’ attitudes and practices in sickle cell pain management. Appl Nurs Res. 2001;14(4):187-192.
28. Shapiro BS, Benjamin LJ, Payne R, Heidrich G. Sickle cell-related pain: perceptions of medical practitioners. J Pain Symptom Manage. 1997;14(3):168-174.
29. Labbe E, Herbert D, Haynes J. Physicians’ attitude and practices in sickle cell disease pain management. J Palliat Care. 2005;21(4):246-251.
30. Weissman DE, Haddox JD. Opioid pseudoaddiction–an iatrogenic syndrome. Pain. 1989;36(3):363-366.
31. Strauss A, LaCandia S. Sickle cell disease and cocaine abuse–a deadly mixture? South Med J. 1989;82(11):1455-1456.
32. Elander J, Lusher J, Bevan D, Telfer P. Pain management and symptoms of substance dependence among patients with sickle cell disease. Soc Sci Med. 2003;57(9):1683-1696.
33. Grant MM, Gil KM, Floyd MY, Abrams M. Depression and functioning in relation to health care use in sickle cell disease. Ann Behav Med. 2000;22(2):149-157.
34. Gil KM, Carson JW, Porter LS, et al. Daily stress and mood and their association with pain, healthcare use, and school activity in adolescents with sickle cell disease. J Pediatr Psychol. 2003;28(5):363-373.
35. Gil KM, Carson JW, Porter LS, Scipio C, Bediako SM, Orringer E. Daily mood and stress predict pain, health care use and work activity in African-American adults with sickle cell disease. Health Psychol. 2004;23(3):267-274.
36. Vichinsky EP, Johnson R, Lubin BH. Multidisciplinary approach to pain management in sickle cell disease. Am J Pediatr Hematol Oncol. 1982;4(3):328-333.
37. Gil KM, Carson JW, Sedway JA, Porter LS, Schaeffer JJ, Orringer E. Follow-up of coping skills training in adults with sickle cell disease: analysis of daily pain and coping practice diaries. Health Psychol. 2000;19(1):85-90.
38. Schatz J, McClellan CB. Sickle cell disease as a neurodevelopmental disorder. Ment Retard Dev Disabil Res Rev. 2006;12(3):200-207.
39.Prengler M, Pavlakis SG, Boyd S, Connelly A, Calamante F, Chong WK, Saunders D, Cox T, Bynevelt M, Lane R, Laverty A, Kirkham FJ. Sickle cell disease: ischemia and seizures. Ann Neurol. 2005;58(2):290-302.
40. Liu JE, Gzesh DJ, Ballas SK. The spectrum of epilepsy in sickle cell anemia. J Neurol Sci. 1994;123(1-2):6-10.
41. Wang WC. The pathophysiology, prevention, and treatment of stroke in sickle cell disease. Curr Opin Hematol. 2007;14(3):191-197.
42. Hariman LM, Griffith ER, Hurtig AL, Keehn MT. Functional outcomes of children with sickle-cell disease affected by stroke. Arch Phys Med Rehabil. 1991;72(7):498-502.
43. Anie KA. Psychological complications in sickle cell disease. Br J Haematol. 2005;129(6):723-729.
44. Boni LC, Brown RT, Davis PC, Hsu L, Hopkins K. Social information processing and magnetic resonance imaging in children with sickle cell disease. J Pediatr Psychol. 2001;26(5):309-319.
45. Puffer E, Schatz J, Roberts CW. The association of oral hydroxyurea therapy with improved cognitive functioning in sickle cell disease. Child Neuropsychol. 2007;13(2):142-154.




Dr. Kennedy is professor in the Department of Psychiatry and Behavioral Sciences at Albert Einstein College of Medicine, and director of the Division of Geriatric Psychiatry at Montefiore Medical Center in the Bronx, New York.

Disclosure: Dr. Kennedy has received research support or honoraria from AstraZeneca, Eli Lilly, Forest, Janssen, Myriad, and Pfizer.

Please direct all correspondence to: Gary J. Kennedy, MD, Director, Department of Geriatric Psychiatry, MMC, 111 East 210th St, Klau One, Bronx, NY 10467; Tel: 718-920-4236; Fax: 718-920-6538; E-mail: gjkennedy@msn.com.



A growing body of evidence supports the efficacy and cost effectiveness of psychotherapy and disease management for mental illness provided over the telephone. However, telephone behavioral health care is not reimbursable under present Center for Medicare and Medicaid Services standards. Nonetheless, elements of telephone-based behavioral health care are being incorporated into Veterans Administration health programs and by a limited number of major insurers. A review of the evidence suggests this trend will continue.


Are Telephone-based Interventions Needed?

Cohen and colleagues1 recently wrote:

In the face of increasingly constrained resources, there is a realistic way of achieving better health results: conduct careful analysis to identify evidence-based opportunities for more efficient delivery of health care—whether prevention or treatment—and then restructure the system to create incentives that encourage the appropriate delivery of efficient interventions.1

What follows argues that telephone screening and interventions for common behavioral health problems may be both effective and efficient.

There is considerable evidence indicating that screening and interventions for both depression and at-risk or unhealthy drinking are effective by telephone. In addition, a variety of interventions for dementia caregivers conducted by “dementia managers” via telephone lead to better outcomes for both dementia patients and caregivers.2-6 Nonetheless, telephone screening and interventions for behavioral health are best characterized as emerging, rather than established, evidenced-based practices.7



In studies of depression care,8 uniformly superior outcomes result from the integration of mental health specialists into primary care sites. Nonetheless, the integration of mental health specialists is not considered economically viable, leaving the primary care practices ill-prepared to reduce the disability of depression.9 In contrast to an “integrated model” where mental health specialists are co-located with primary care physicians (PCPs), a collaborative disease management model utilizing behavioral health managers supervised by psychiatrists has demonstrated benefits. Large-scale, multisite studies10-12 have shown greater rates of response and remission as well as reduced levels of suicidality and costs associated with the disease management for depression. Even when routine care is enhanced by improved access to specialist consultation, the collaborative disease management model proves superior. The critical element that distinguishes disease management from routine care is a third party (eg, a master’s level social worker, psychologist, or nurse) who collaborates with the primary care provider, patient, and family to achieve superior outcomes. Telephone management of depression by behavioral health managers not located in the primary care sites also appears to be an effective alternative to integrated care.13,14 Studies of depression care15-17 incorporating telephone psychotherapy as part of the disease management package show benefits as well. However, the economic benefits of behavioral health management are uncertain. In contrast, disease management in managed care practices controls costs by reducing hospital admissions related to diabetes and congestive heart failure without shifting the expense from the hospital to the primary care provider or sacrificing patient satisfaction.18,19

Perhaps the most fully developed telephone disease management (TDM) is described by Oslin and colleagues14 and Zanjani and colleagues.20 TDM was originally developed for Veterans Administration outpatient programs to reduce depression and at-risk drinking as a Behavioral Health Laboratory (BHL). TDM has been adopted by AETNA and Blue Cross/Blue Shield of South Carolina to reduce costs among primary care populations by offering a more aggressive care plan to patients prescribed to antidepressants. Although cost offset data have not been made available, the explicit expectation is that the carriers’ investment in depression care will reduce the volume of claims for primary care and hospital services (DW Oslin, MD, personal communication, March 2008).

The BHL is a screening and assessment service designed to help manage the behavioral health needs of patients seen in primary care. The Core Assessment of the BHL is a briefly scripted interview that provides PCPs with an assessment of patients’ substance abuse and behavioral health symptoms. In addition, the BHL both offers structured treatment response and outcomes assessments and serves as a base for the disease management approach to specific mental illnesses. The BHL is capable of focused decision support, including triage to specialty behavioral health or substance abuse care. For older adults, the BHL quantifies the level of impairment and comorbid psychiatric disorders such as depression, at-risk drinking, and anxiety. The University of Pennsylvania and Philadelphia Veterans Affairs Medical Center are the development and founding sites of the BHL. The BHL has been recognized as a “Best Practice” for identification and early intervention in behavioral health problems of primary care patients within the Department of Veterans Affairs.

In the BHL, the telephone interaction is “facilitation” rather than psychotherapy. Facilitated care by telephone limits scope, but it does not necessarily limit the number of interactions with the patient.21 These interactions between patient and the behavioral health manager include solving problems with barriers such as reluctance to either initiate prescribed antidepressant therapy or communicate difficulties with side effects to the PCP; providing positive reinforcement and praise once barriers are overcome; monitoring progress, assessing response to treatment, and countering premature discontinuation of medication; purposefully scheduling physical activity and pleasant events for behavioral activation; and teaching self-management techniques. Periodic case reviews with a supervising psychiatrist and reports to the PCP are used to both coordinate care and facilitate referrals when psychotherapy or direct psychiatric consultations are indicated.

The BHL uses the Patient Health Questionnaire9 (PHQ) for screening (2 items), initiating treatment (9 items), and assessing outcome as non-response, response, or remission. At each juncture, the PHQ score is used to indicate the need for assessment, treatment or referral, or adequacy of antidepressant therapy. The BHL is fully manualized with sections specific for implementation, documentation, assessment, interventions, and oversight. The structured assessments and scripted interventions for depression, anxiety, and at-risk drinking are fully adapted to telephone administration.


At-risk Drinking

Hospitalizations related to alcohol among older adults are nearly as frequent as those related to heart attack.22 At-risk alcohol use among older adults increases both medical complexity and costs to patients as well as their families and communities.23 However, existing services are not prepared to meet the needs of the projected 2-fold increase in alcohol- and substance-abusing older adults in the next 15 years.24 Using a nationally representative sample of 12,413 people from the Current Medicare Beneficiary Survey, Merrick and colleagues25 found unhealthy drinking patterns in 16% of men and 4% of women. Unhealthy drinking was defined either by >30 drinks in any month or >4 drinks in any single day during the last year. As operationalized by Merrick and colleagues25 in their Medicare Beneficiary Survey, respondents were considered to be at-risk or unhealthy if they either consumed as much as one drink daily for 30 days in any month during the last year or exceeded four drinks in any given day during the last year. This level of intake is slightly above what was recommended for screening in the Substance Abuse and Mental Health Services Administration’s (SAMHSA) Treatment Improvement Protocol26 for substance abuse among people ≥65 years of age; however, the level of intake is well below a score of ≥3 on the  Short Michigan Alcohol Screening Test-Geriatric Version employed by Oslin and colleagues’ Telephone Disease Management study of ambulatory care Veterans Administration patients.14,20

Numerous studies suggest that at-risk or unhealthy drinking can be reliably detected through telephone interviews and that interventions conducted by telephone can reduce the number of “risky drinking” days among people not seeking treatment for problem drinking.14,20,27-29 These data are further supported by the literature on brief interventions among primary care patients that reduce risky/harmful drinking without requiring lengthy or multiple counseling sessions to be effective.29 Approaching select patients during “teachable moment” following admission to the emergency department or discharge from hospital may heighten the probability of an alliance for change.17,30


Dementia Caregiver Burden

It is widely acknowledged that primary care settings are poorly designed and under-resourced to provide comprehensive care for dementia patients and their family caregivers.2,3,31 Even when routine primary care is augmented with improved access to dementia specialists, patients and families fare better from a collaborative care, disease management model similar to that used for chronic illnesses such as congestive heart failure or diabetes.2,3 In addition, disease management services provided to dementia care givers allow for cost savings.1 Given the increasing number of people with dementia, the need to find more efficient models of care is pressing. Estimates of the prevalence of memory problems or confusion in the National Health Interview representative survey32 of older community residents 65–85 years of age range from 7% to 20%, respectively. However these data are based on self-report or proxy respondents. In the Aging, Demographics, and Memory Study,33 in-home comprehensive assessments with diagnoses determined by expert consensus found dementia among 13.9% people ≥71 years of age.

Deficits in the cognitive domains of memory and executive function threaten the older adults’ capacity to adhere to medical therapy, avoid institutionalization, and survive in the community.34,35 However, screening for memory impairment to detect dementia in primary care settings remains controversial due to the confounding influence of physical illness, education, race and language on the screening test’s reliability.36,37 Moreover, evidence-based practices combining patient and caregiver interventions from mild cognitive impairment to end-of-life dementia care exceed the resources of most primary care practices.2,3,30 The critical period to screen for cognitive impairment may be immediately after hospital discharge when unrecognized persistent delirium or dementia places the patient at heightened risk for re-admission.

Brief screening measures for memory impairment and executive dysfunction have been validated for telephone administration by the Einstein Aging Study.38 More recent data suggest these measures, when used as part of a two-step screening procedure may represent an advance over the more commonly used Mini-Mental Status Examination in both distinguishing Alzheimer’s from vascular dementia and reducing the test’s sensitivity to education and race.37 Two separate studies listed in SAMHSA’s National Registry of Evidence-based Programs and Practices39 reduced depression among dementia caregivers of various racial and ethnic backgrounds.20,40,41 In addition, the Resources for Enhancing Alzheimer’s Caregiver Health II improved caregiver quality of life.41 The New York University Caregiver Intervention demonstrated superior health and perceived social support for caregivers as well as substantial delay in nursing home admissions for spouses with dementia.18,41 Although face-to-face counseling and peer support groups formed the bulk of the intervention, contact by telephone was included as well.

In contrast, two studies2,3 conducted in primary care sites used a disease management model with the care manager integrated into the primary care site or modified to include care mangers recruited from community based agencies. In the latter, caregiver interventions were conducted mainly by social workers via telephone following an in-home assessment. Outcomes for both patients and caregivers in the intervention groups were generally superior to enhanced routine care. Four of the studies cited suggest that some, if not all, of the caregiver intervention may be conducted by telephone. The potential of caregiver interventions to reduce costs1 and the detection of cognitive impairment to delay re-hospitalization warrant consideration.


Cultural Considerations and Issues with Access

Rather than presume that the communications between the patient and primary care provider are adequate, the Behavioral Health Manager can follow up by telephone to ensure that self-management and treatment adherence are optimized. Limited health literacy can be overcome with additional information regarding etiology, diagnosis, and treatment. Telephone-based depression care programs offer hope of reducing disparities in both access to and receipt of antidepressant treatment.42-45 Finally, although telephone interventions are limited to people without substantial hearing impairment, the capacity to provide behavioral health services by telephone is a marked advantage for individuals whose physical disability or geographic distance poses as barriers to more frequent office visits.



Depression, at-risk drinking, and caregiver burden are prevalent, and each is the subject of an emerging evidence-based practice incorporating interventions administered by telephone. Although the effectiveness and economic value of the interventions are yet to be established, their accessibility offers the hope of reducing behavioral health disparities among ethnic, minority, and physically disabled groups. If behavioral health interventions delivered by telephone reduce the costs of primary care or the risk of hospitalization, the Center for Medicare and Medicaid Services may be compelled to approve reimbursement. PP



1. Cohen JT, Neumann PJ, Weinstein MC. Does preventive care save money? Health economics and the presidential candidates. N Eng J Med. 2008;358(7):661-663.
2. Callahan CM, Boustani MA, Unverzagt FW, et al. Effectiveness of collaborative care for older adults with Alzheimer disease in primary care: a randomized controlled trial. JAMA. 2006;295(18):2148-2157.
3. Vickrey BG, Mittman BS, Connor KI, et al. The effect of a disease management intervention on quality and outcomes of dementia care: a randomized controlled trial. Ann Intern Med. 2006;145(10):713-726.
4. Gaugler JE, Roth DL, Haley WE, Mittelman MS. Can counseling and support reduce burden and depressive symptoms in caregivers of people with Alzheimer’s disease during the transition to institutionalization? Results from the New York University caregiver intervention study. J Am Geriatr Soc. 2008;56(3):421-428.
5. Nichols LO, Chang C, Lummus A, et al. The cost-effectiveness of a behavior intervention with caregivers of patients with Alzheimer’s disease. J Am Geriatr Soc. 2008;56(3):413-420.
6. Austrom MG, Damush TM, Hartwell CW, et al. Development and implementation of nonpharmacologic protocols for the management of patients with Alzheimer’s disease and their families in a multiracial primary care setting. Gerontologist. 2004;44(4):548–553.
7. Areán PA, Gum A. Selecting evidence-based practice. In: Levkoff SE, Chen H, McIntyre J, eds. Evidence-Based Behavioral Health Practices for Older Adults: A Guide to Implementation. 1st ed. New York, NY: Springer Publishing Company; 2006:1-13.
8. Badamgarav E, Weingarten SR, Henning JM, et al. Effectiveness of disease management programs in depression: a systematic review. Am J Psychiatry. 2003;160(12):2080-2090.
9. Oxman TE. Re-Engineering Systems for Primary Care Treatment of Depression; The Respect Depression Care Process Supervising Psychiatrist Manual. Hanover, New Hampshire: Trustees of Dartmouth College; 2003.
10. Bruce ML, Ten Have TR, Reynolds CF 3rd, et al. Reducing suicidal ideation and depressive symptoms in depressed older primary care patients: a randomized controlled trial. JAMA. 2004;291(9):1081-1091.
11. Unützer J, Tang L, Oishi S, et al. Reducing suicidal ideation in depressed older primary care patients. J Am Geriatr Soc. 2006;54(10):1550-1556.
12. Gilbody S, Bower P, Whitty P. Costs and consequences of enhanced care for depression: systematic review of randomized economic evaluations. Br J Psychiatry. 2006;189:297-308.
13. Datto CJ, Thompspn R, Horowitz D, Disbot M, Oslin DW. The pilot study of a telephone disease management program for depression. Gen Hosp Psychiatry. 2003;25(3):169-177.
14. Oslin DW, Sayers S, Ross J, et al. Disease management for depression and at-risk drinking via telephone in an older population of veterans. Psychosom Med. 2003;65(6):931-937.
15. Ludman EJ, Simon GE, Tutty S, Von Korff M. A randomized trial of telephone psychotherapy and pharmacotherapy for depression: continuation and durability of effects. J Consult Clin Psychol. 2007;75(2):257-266.
16. Ludman EJ, Simon GE, Grothaus LC, Luce C, Markley DK, Schaefer J. A pilot study of telephone care management and structured disease self-management groups for chronic depression. Psychiatric Serv. 2007;58(8):1065-1072.
17. Beckner V, Vella L, Howard I, Mohr DC. Alliance in two telephone-administered treatments: relationship with depression and health outcomes. J Consult Clin Psychol. 2007;75(3):508-512.
18. Katon W, Von Korff M, Lini E, et al. Improving primary care treatment of depression among patients with diabetes mellitus: the design of the pathways study. Gen Hosp Psychiatry. 2003;25(3):158-168.
19. Riegel B, Carlson B, Kpoo Z, LePetri B, Unger A. Effect of a standardized nurse case-management telephone intervention on resources use in patients with chronic heart failure. Arch Intern Med. 2002;162(6):705-712.
20. Zanjani F, Mavandadi S, TenHave T, et al. Longitudinal course of substance treatment benefits in older male veteran at-risk drinkers. J Gerontol A Biol Sci Med Sci. 2008;63(1):98-106.
21. Kennedy GJ. Telephone-facilitated treatment of depression in primary care using the PHQ-9. Primary Psychiatry. 2004;11(6):18-21.
22. Adams WI, Yuan Z, Barboriak J, et al. Alcohol-related hospitalizations of elderly people. JAMA. 1993;270(10):1222-1225.
23. Dyson J. Alcohol misuse and older people. Nurs Older People. 2006;18(7):32-35.
24. Gfroerer J, Penne M, Pemberton M, Folsom R. Substance abuse treatment need among older adults in 2020: the impact of the aging baby-boom cohort. Drug Alcohol Depend. 2003;69(2):127-135.
25. Merrick EL, Horgan CM, Hodgkin D, et al. Unhealthy drinking patterns in older adults: prevalence and associated characteristics. J Am Geriatr Soc. 2008;56(2):214-223.
26. Blow FC. Substance Abuse Among Older Adults Treatment Improvement Protocol (TIP) Series. Washington, DC: U.S. Department of Health and Human Services; 2004.
27. Brown RL, Saunders LA, Bobula JA, Mundt MP, Koch PE. Randomized-controlled trial of a telephone and mail intervention for alcohol use disorders: three-month drinking outcomes. Alcohol Clin Exp Res. 2007;31(8):1372-1379.
28. Bischof G, Grothues JM, Reinhardt S, Meyer C, John U, Rumpf HJ. Evaluation of a telephone-based stepped care intervention for alcohol-related disorders: a randomized controlled trial. Drug Alcohol Depend. 2008;93(3):244-251.
29. Whitlock EP, Polen MR, Green CA, et al. Behavioral counseling interventions in primary care to reduce risk/harmful alcohol use by adults: a summary of evidence for the U.S. Preventative Services Task Force. Ann Int Med. 2004;140(7):557-568.
30. Academic ED SBIRT Research Collaborative. The impact of screening, brief intervention, and referral for treatment on emergency department patients’ alcohol use. Ann Emerg Med. 2007;50(6):699-710.
31. Brayne C, Fox C, Boustani M. Dementai screening in primary care: is it time? JAMA. 2007;298(2):2409-2411.
32. Bernstein AB, Remsburg RE. Estimated prevalence of people with cognitive impairment: results from nationally representative community and institutional surveys. Gerontologist. 2007;47(3):350–354.
33. Plassman BL, Lnaga KM, Fisher GG, et al. Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology. 2007;29(1-2):125-132.
34. Cooney LM, Kennedy GJ, Hawkins KA, Hurme SB. Who can stay at home? Assessing the capacity to choose to live in the community. Arch Intern Med. 2004;164(4):357-360.
35. Kelman HR, Thomas C, Kennedy GJ, Cheng J. Cognitive impairment and mortality among older community residents. Am J Public Health. 1994;84(8):1255-1260.
36. Grober E, Hall C, Lipton RB, Teresi JA. Primary care screen for early dementia. J Am Geriatr Soc. 2008;56(2):199-205.
37. Grober E, Hall C, McGinn M, et al. Neuropsychological strategies for detecting early dementia. J Int Neuropsychol Soc. 2008;14(1):1-13.
38. Lipton RB, Katz MJ, Kuslansky G, et al. Screening for dementia by telephone using the memory impairment screen. J Am Geriatr Soc. 2003;51(10):1382–1390.
39. U.S. Department of Health and Human Services: Substance Abuse and Mental Health Services Administration (SAMSHA). Alcohol Use in Past Month by State Treatment Planning Area and Age Group. Available at: www.oas.samhsa.gov/subState2k6/ageAlc.htm. Accessed April 2, 2008.
40. Belle SH, Burgio L, Burns R, et al. Enhancing the quality of life of dementia caregivers from different ethnic or racial groups: a randomized, controlled trial. Ann Intern Med. 2006;145(10):727-738.
41. Mittelman MS, Roth DL, Clay OJ, Haley WE. Preserving health of Alzheimer caregivers: impact of a spouse caregiver intervention. Am J Geriatr Psychiatry. 2007;15(9):780-789.
42. Rivas A, Kennedy GJ, Woolis W, et al. Recruitment of disadvantaged minority groups for mental health services research is no greater a challenge than recruitment of their physicians. Poster presented at: The Annual Meeting of the American Association for Geriatric Psychiatry; March 1-4, 2007; New Orleans, LA.
43. Colemon YR, Kennedy GJ, Mudge R, Martinez-Kekenak M. Depression treatment of African American’s within a primary care setting. Poster presentation at: the Annual Meeting of the American Association for Geriatric Psychiatry; March 14-17, 2008; Orlando, FL.
44. Areán PA, Unützer J. Inequities in depression management in low-income, minority, and old-old adults: a matter of access to preferred treatments? J Am Geriatr Soc. 2003;51(12):1808-1809.
45. Fischer LR, Wei F, Solberg LI, Rush WA, Heinrich RL. Treatment of elderly and other adult patients for depression in primary care. J Am Geriatr Soc. 2003;51(11):1554-1562.

To the Editor:                     February 16, 2008

Milton K. Erman, MD’s, critique of the popularity of trazodone and other non-benzodiazepine analogs for off-label use as soporifics1 fails to acknowledge some stark realities, namely, that trazodone is the most widely prescribed soporific because it works well and is very safe. Grasping for examples of the National Institutes of Health-cited “potentially significant adverse events” associated with trazodone, Erman is only able to come up with priapism, of which the risk is 1 in 6,000.2 Regarding cardiac arrhythmia, this risk is low when trazodone is prescribed at low, soporific doses rather than higher, antidepressant-range doses; the risk is further reduced with electrocardiogram monitoring for individuals with a history of arrhythmia or who are prescribed other arrhythmogenic medications.

The reason that there are no long-term studies on the use of trazodone for the treatment of insomnia, as Erman states,1 is that trazodone is a generic drug for which there is no financial incentive to fund the double-blind, placebo-controlled study needed to demonstrate what front-line prescribers already know. I did not wait for Food and Drug Administration on-label approval to offer divalproex to my patients for mood stabilization or quietapine for bipolar-spectrum depression. Likewise, I will not deny my patients the benefit of trazdodone which, when used appropriately, is a safe, effective, and non-addictive soporific with the potential to augment antidepressants in the treatment of depressive and anxiety disorders that are associated with insomnia.3

I know that I am not alone among my colleagues in being able to count on one hand the combined instances of trazodone-induced arrhythmia or priapism in my entire history of practice, whereas I have already a great deal of experience with the array of interesting side effects associated with the newer agents. Zolpidem, for example, has manifested as a robust inducer of parasomnias, including sleepwalking4 and amnestic nocturnal eating.5 There have additionally been reports of visual hallucinations6 and abuse.7 Regarding the latter, the World Health Organization Expert Committee on Drug Dependence in 2000 described “rates of actual abuse and dependence on zolpidem appear(ing) to be similar to those of other hypnotic benzodiazepines currently listed in Schedule IV…”8

I am in agreement with all that Erman says regarding ramelteon, another drug produced by one of his underwriters, including its remarkable safety profile and lack of abuse potential. Erman might concede another factor regarding ramelteon, that it is generally ineffective for insomnia.


Michael S. Hanau, MD, FAPA

Dr. Hanau is medical director of Community Counseling Services at Lawrence Memorial Hospital in Medford, Massachusetts.

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



1. Erman MK. Is it a sleeping pill? Primary Psychiatry. 2008;15(1)34-36.
2. Janicak PG, Davis JM, Preskorn SH, Ayd Jr FJ. Treatment with Antidepressants. Janicak PG, Davis JM, Preskorn SH, Ayd Jr FJ. Principles and Practice of Psychopharmacotherapy. 3rd ed, Chapt. 7, Philadelphia, PA: Lippincott Williams and Wilkins; 2001:295.
3. Fabre LF. Trazodone dosing regimen: experience with single daily administration. J Clin Psychiatry. 1990;51(suppl):23-26.
4. Sansone RA, Sansone LA. Zolpidem, somnambulism, and nocturnal eating. Gen Hosp Psychiatry. 2008;30(1):90-91.
5. Najjar M. Zolpidem and amnestic sleep related eating disorder. J Clin Sleep Med. 2007;3(6):637-638.
6. Tsai MJ, Huang YB, Wu PC. A novel clinical pattern of visual hallucination after zolpidem use. J Toxicol Clin Toxicol. 2003;41(6):869-872.
7. Victorri-Vigneau C, Dailly E, Veyrac G, Jolliet P. Evidence of zolpidem abuse and dependence: results of the French Centre for Evaluation and Information on Pharmacodependence (CEIP) network survey. Br J Clin Pharmacol. 2007;64(2):198-209.
8. WHO. World Health Organization Expert Committee on Drug Dependence. Thirty-second Report. Geneva: World Health Organization; 2001 (as cited in: The National Institute for Health and Clinical Excellence Assessment report: The clinical and cost-effectiveness of zaleplon, zolpidem and zopiclone for the management of insomnia (10/20/2003).



I thank Michael S. Hanau, MD, FAPA, for his observations. He notes that use of trazodone is very widespread; this was commented on (and supported by citations) in the opening paragraphs of my column.1-3

To paraphrase his argument, “Everybody is doing it, so it must be safe and effective.” The history of treatment in psychiatry is replete with examples of widespread prescribing practices (eg, rapid neurolepticization for acute psychosis, use of neuroleptics for management of dementia) later proven to be ineffective, risky, or both.

In support of use of trazodone for insomnia, Hanau cites Fabre’s 1990 review.4 This article reviewed the use of single daily dosing. The basic thrust of the article is that HS dosing is good for depressed patients, including depressed insomniacs. To support use for insomniacs without depression, Fabre cites a study by Montgomery and colleagues5 of “nine volunteers who were poor sleepers,” noting that it improved sleep quality. Interestingly, the title of the article is, “Trazodone enhances sleep in subjective quality but not in objective duration”; objective measures are the hallmark by which the Food and Drug Administration determines that drugs are worthy of approval.

With regard to published data on the efficacy of trazodone in treatment of insomnia, I would refer Hanau to the largest published data-set on the subject (of which I was a co-author), which involved a double-blind, placebo-controlled comparison of zolpidem 10 mg, trazodone 50 mg, and placebo in >300 adults diagnosed with primary insomnia.6 The study utilized subjective measures only; by the end of the second week of assessment, the trazodone group did not differ significantly from the placebo group with regard to reported sleep latency, sleep duration, sleep quality, wake after sleep onset, or number of awakenings demonstrated.

I did not need to “grasp” for examples of why trazodone is not a recommended treatment for insomnia; the National Institutes of Health (NIH) State of the Science Conference,7 a “blue ribbon” panel reviewing the published scientific literature with regard to treatment recommendations, stated quite directly (as I cited in the column) that “all antidepressants have potentially significant adverse events, raising concern about the risk-benefit ratio.”

Hanau states that, with regard to priapism, “the risk is 1 in 6,000.” This is a widely cited statistic, although in one series of 74 patients receiving trazodone in treatment of posttraumatic stress disorder, the reported incidence rate was 12%.8 Even accepting the rate of 1 in 6,000, this is not a trivial issue; usage rates suggest that the millions of patients currently receiving this medication in treatment of insomnia in this country are placed at risk. Other safety issues, including sedation and cardiac safety (eg, hypotension, orthostasis, ventricular arrhythmias) are explored by Mendelson.9

Regarding the safety of other agents (eg, zolpidem), I cited the NIH panel’s observation about the general safety of benzodiazepine receptor agonists. Case reports and case series have been published demonstrating amnestic behaviors of various types seen in association with several benzodiazepines and benzodiazepine-receptor agonists. Physicians should clearly consider issues of risk and benefit before prescribing any medication. With regard to the frequency of these problems occurring with zolpidem, sanofi-aventis noted in a press release in 2006 that zolpidem had a history of >14 billion nights of use worldwide.10 The number of amnestic events seen and reported worldwide should be considered using this number as the denominator in any fractional assessment of risk.


Milton K. Erman, MD

Dr. Erman is clinical professor in the Department of Psychiatry at the University of California, San Diego School of Medicine, a staff scientist for the Scripps Research Institute Department of Neuropharmacology, chief medical officer of Avastra USA, and author of the Primary Psychiatry bi-monthly column “Clinical Updates in Sleep Medicine.”

Disclosures: Dr. Erman is a consultant to Cephalon, Mallinckrodt, Neurocrine, sanofi-aventis, and Takeda; is on the speaker’s bureaus of Forest, sanofi-aventis, and Takeda; is on the advisory boards of Cephalon, Neurocrine, sanofi-aventis, and Takeda; has received grant/research support from Arena, Cephalon, Eli Lilly, GlaxoSmithKline, Mallinckrodt, Merck, Organon, Pfizer, Pharmacia, ResMed, sanofi-aventis, Schwarz Pharma, and Takeda; and owns stock in Cephalon, Forest, Merck, Neurocrine, Pfizer, sanofi-aventis, and Sepracor.



1. Erman MK. Is it a sleeping pill? Primary Psychiatry. 2008;15(1)34-36.
2. Walsh JK, Schweitzer PK. Ten-year trends in the pharmacological treatment of insomnia. Sleep. 1999;22(3):371-375.
3. Walsh JK. Drugs used to treat insomnia in 2002: regulatory-based rather than evidence-based medicine. Sleep. 2004;27(8):1441-1442.
4. Fabre LF. Trazodone dosing regimen: experience with single daily administration. J Clin Psychiatry. 1990;51(suppl):23-26.
5. Montgomery I, Oswald I, Morgan K, Adam K. Trazodone enhances sleep in subjective quality but not in objective duration. Br J Clin Pharmacol. 1983;16(2):139-144.
6. Walsh J, Erman M, Erwin M, et al. Subjective hypnotic efficacy of trazodone and zolpidem in DSM-III-R primary insomnia. Hum Psychopharmacol. 1998;13(3):191-198.
7. NIH State of the Science Conference statement on Manifestations and Management of Chronic Insomnia in Adults. J Clin Sleep Med. 2005;1(4):412-421.
8. Warner M, Dorn M, Peabody C. Survey on the usefulness of trazodone in patients with PTSD with insomnia or nightmares. Pharmacopsychiatry. 2001;34(4):128-131.
9. Mendelson W. A review of the evidence for the safety and efficacy of trazodone in insomnia. J Clin Psychiatry. 2005;66(4):469-476.
10. Statement Responding to Recent Media Reports Regarding Appropriate Use of AMBIEN(R) (zolpidem tartrate) CIV in the US. Bridgewater, NJ. March 20, 2006. Available at: http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/03-20-2006/0004323684&EDATE. Accessed March 24, 2008.

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



Dr. Zammit is president and CEO of Clinilabs, director of the Sleep Disorders Institute, and clinical associate professor at the Columbia University College of Physicians and Surgeons in New York City.

Disclosure: Dr. Zammit is a consultant to Boehringer-Ingelheim, sanofi-aventis, Sepracor, and Takeda; receives research support from Forest, GlaxoSmithKline, Pfizer, sanofi-aventis, Sepracor, Takeda Pharmaceuticals North America, Transcept, and Wyeth; and receives honoraria from Takeda.

Acknowledgments: The author would like to thank Ms. Bridget Banas for her assistance in the preparation of this manuscript.

Please direct all correspondence to: Gary Zammit, PhD, Clinilabs, Inc, 423 W.  55th St, 4th Floor, New York, NY 10019; Tel: 212-994-4560; Fax: 212-523-1704; E-mail: gzammit@clinilabs.com; Website: www.clinilabs.com.




Mood disorders and insomnia are often comorbid conditions, sharing a complex and bi-directional relationship. Complicating the situation, mood stabilizers can disrupt sleep in a variety of different ways depending on a drug’s mechanism of action, dosage level, and timing of administration. The treatment of comorbid depression and insomnia can be achieved through the use of a sedating antidepressant, a combination of two antidepressants, or a combination of an antidepressant in conjunction with a hypnotic. Common practices typically include the concomitant use of an alerting and a sedating antidepressant. However, the empirical evidence supporting this approach is limited, and there are few indicators that sedating antidepressants are efficacious in the treatment of primary insomnia. This article examines the evidence supporting the efficacy and safety of mood stabilizers in the treatment of comorbid and primary insomnia.



Psychiatric disorders and chronic insomnia are often comorbid with each other. The presence of insomnia symptoms in individuals with a current episode of major depressve disprder (MDD) has been shown to approach 80% to 90%.1-4 The incidence of comorbid insomnia is higher when anxiety complicates the clinical presentation, affecting approximately 90% with a concurrent anxiety disorder.1 Furthermore, mood disorder symptoms are typically more pronounced in people with insomnia symptoms.5-10

Insomnia is often a precursor to depression. Several longitudinal studies have examined the incidence of psychiatric disorders over periods ranging from 1–40 years following the initial diagnosis of insomnia.11-17 In every study completed to date, insomnia has been found to be a significant risk factor for the subsequent onset of depression, with a greater incidence of affective disorder found in people with insomnia. These findings do not suggest that insomnia is merely part of a prodrome that occurs in close temporal association with affective disorders, as depression may first appear several years after the initial diagnosis of insomnia. In addition to these findings, it has been shown that insomnia is a precursor to the recurrence of depression in patients in remission,18,19 and that persistent sleep disturbance is associated with non-response to antidepressant therapy.20

While insomnia often precedes the onset of affective illness, symptoms of depression and insomnia may be concurrent. Complicating this picture is the fact that many antidepressants used to treat depression disturb sleep, potentially exacerbating the relationship between the two disorders. The type of sleep disturbance produced by depression pharmacotherapy varies based on the compound’s mechanism of action and the dosage employed. Effects may include decrements in rapid eye movement (REM) sleep, a lengthening of the time to sleep onset, and an increase in nocturnal arousals (Table 1).24,86-88 This article reviews the effectiveness and safety of several treatment options for comorbid depression and insomnia.



Prescribing Patterns

Between 1987 and 1996, the pharmacologic treatment of insomnia decreased markedly. A recent review21 covering this period found that drug mentions (ie, patient contact that resulted in drug therapy or a mention of drug therapy) fell by >50% for hypnotics, and were down approximately 25% for all forms of insomnia pharmacotherapy combined. Antidepressants used for the treatment of insomnia were the only drug category showing signs of growth—tripling in drug mentions over this period.

In 1996, the two drugs mentioned most frequently for the treatment of insomnia were trazodone, a sedating tricyclic antidepressant (TCA), and zolpidem, a non-benzodiazepine hypnotic. Trazodone is indicated for the treatment of depression, but not specifically labeled for use as a hypnotic. Over the 10-year period examined, the total number of trazodone mentions was steady.21 However, mentions associated with antidepressant action fell from >70% of all occurrences in 1987 to only 31% in 1996. In contrast, the number of mentions associated with insomnia rose from only 6.5% to almost 42% over the same period.

The conclusion that the use of sedating antidepressants for the treatment of insomnia rose between 1987 and 1996 was based on reported medication doses. The therapeutic daily dosage of trazodone for depression therapy is 150–600 mg/day. Doses below this level may provide sedative effects but are not expected to combat the symptoms of depression. By 1996, two-thirds of all trazodone mentions were associated with a daily dose of ≤100 mg—strongly suggesting that antidepressant effects were not the intended results. Furthermore, almost 40% of treatment mentions in 1996 were concomitant with the mention of another antidepressant. This analysis is consistent with a more recent survey of psychiatrists’ prescribing practices.22 The survey was conducted at a psychopharmacology review course to investigate the management of antidepressant-induced side effects. Almost 80% of the survey respondents indicated that they would prescribe trazodone to address selective serotonin reuptake inhibitor (SSRI)-induced insomnia.


Treatment Options

In light of the common use of trazodone as adjunctive insomnia therapy in depressed patients, it is important to remember that several treatment approaches are available. Insomnia comorbid with depression may be treated using a single hypnotic, a single antidepressant, a combination of two antidepressants, and a combination of one antidepressant and one hypnotic.23


Option 1: A Single Hypnotic

There is no evidence to support the treatment of patients with MDD and comorbid insomnia with a hypnotic medication alone. Even though these medications are highly efficacious in ameliorating sleep disturbances in a wide range of patient populations, neither the older benzodiazepine nor the newer non-benzodiazepine hypnotics have been shown to be effective therapy for MDD.


Option 2: A Single Antidepressant

A single, sedating antidepressant can be employed as a treatment for both insomnia and depression. Candidates for this therapeutic approach include the TCAs and several atypical antidepressants.23 Most of these TCAs inhibit the reuptake of noradrenaline and serotonin and block histamine (H)1 receptors and α1-adrenoceptors.24 Amitriptyline and trimipramine, both particularly associated with sedation, also block serotonin (5-HT)2 action.24 Trazodone is an antagonist at the α1-adrenoceptors, 5-HT1A, and 5-HT2 receptors.24 Nefazodone has strong 5-HT2 antagonist properties and mild serotonin reuptake-blocking effects.24 Finally, mirtazapine blocks 5-HT2 receptors, H1 receptors, and α2-adrenoceptors.24

Some practitioners use a single, sedating antidepressant to treat comorbid depression and insomnia. When administered at therapeutic doses for depression, these medications are known to produce sedative side-effects that may be exploited in an effort to treat insomnia and to provide relief from depression. This approach has intuitive appeal, as the use of one medication to treat multiple disorders has the advantage of minimizing the risks associated with drug-drug interactions and may make patient compliance easier. However, the utility of this approach may be limited by current treatment guidelines and safety concerns.


Option 3: A Combination of Two Antidepressants

This approach typically involves employing a therapeutic dose of a non-sedating antidepressant (eg, SSRIs, monoamine oxidase inhibitors [MAOIs]) to treat depression, and a lower, non-therapeutic dose of a sedating antidepressant to treat insomnia. While this strategy has been used with some popularity, there are relatively few data demonstrating the safety and efficacy of this approach.23,25,26


Option 4: A Combination of One Antidepressant and One Hypnotic

This treatment approach enables clinicians to decouple the treatment for depression from the treatment of insomnia. This approach represents an important treatment option because it is often necessary to experiment with different antidepressants, titrate dosage levels, and modify dose timing to find the most appropriate therapy for an individual with MDD. Employing a hypnotic as an adjunctive treatment enables the clinician to directly and immediately address a patient’s insomnia symptoms while still making necessary adjustments to the pharmacotherapeutic used to treat depression. When present, antidepressant-induced insomnia typically occurs during the first 3–4 weeks of treatment.27 Therefore, addressing sleep complaints early may provide rapid relief to the patient and may also contribute to compliance with depression therapy.


Evidence Supporting the Use of a Single Antidepressant


The SSRIs and MAOIs are generally alerting; these drugs tend to exacerbate existing insomnia symptoms or produce treatment-related insomnia (Table 1). As such, they are not considered appropriate for addressing insomnia symptoms in depressed patients as monotherapy.

In contrast, the TCAs commonly produce sedation as a side effect, even though they also tend to suppress REM sleep like the SSRIs and MAOIs. Three TCAs appear to offer the greatest potential for combining both antidepressant and hypnotic effects,24 namely, amitriptyline,28,29 doxepin,28 and trimipramine. Improvements were seen in depressed patients treated with amitriptyline in measures of early morning awakenings,20 nocturnal waking,20 and sleep latency30 as compared to the results produced by imipramine or fluoxetine. Doxepin has been shown to significantly improve Hamilton Rating Scale for Depression (HAM-D) sleep scores as compared to placebo31 and bupropion.32 Trimipramine has been reported to improve sleep efficiency, increase sleep time, and reduce nocturnal awakenings as compared to both fluoxetine33 and imipramine.34

The atypical antidepressants most often used to treat depression and comorbid insomnia are mirtazapine, nefazodone, and trazodone.24 Mirtazapine has been shown to produce a range of effects on sleep in depressed patients. Rapid improvements on quality of sleep and other subjective sleep assessments have been seen with mirtazapine as compared to citalopram,35 while improvements in sleep efficiency and nocturnal distress have been seen relative to both fluoxetine36 or paroxetine treatment.37 It is of interest that HAM-D sleep item scores have been shown to improve more when patients are treated with mirtazapine than with either venlafaxine38 or paroxetine.39 Nefazodone has also been shown to improve HAM-D sleep item scores relative to treatment with placebo.40 It also produces less nocturnal disturbance than either fluoxetine41 or paroxetine.42

Trazodone’s effects on sleep in depressed patients are perhaps better characterized than that of any other sedating antidepressant. Two studies have found that, relative to placebo, trazodone objectively increases total sleep time, sleep efficiency, and slow wave sleep (SWS) with limited next-day sedative effects.43,44 It has also been shown that trazodone 75 mg results in increases in SWS and improvements in HAM-D scores and subjective assessments of daytime alertness.45 Higher doses of trazodone also appear to have effects on depression and sleep. Trazodone (150–400 mg) produces significant improvement in symptoms of depression and changes in objective measures of sleep architecture.46 Specifically, sleep latency declined, and total sleep time, SWS, and sleep efficiency increased following active treatment. Doses of 400–600 mg produce significant improvements in Montgomery-Asberg Depression Rating Scale (MADRS) scores (>60% reduction), reduce sleep latency, and increase total sleep time and SWS.47



Employing a sedating antidepressant to treat both depression and comorbid insomnia is appealing because of the reduced opportunity for drug-drug interactions and the potential increase in patient compliance due to a less complex treatment regimen. However, the available literature suggests caution should be exercised when considering this approach. A recent conference that reviewed the evidence supporting the use of both TCAs and SSRIs resulted in a published statement suggesting that TCAs are no longer justified as first-line antidepressant therapy in most situations.48 This position reflects concerns about the differential efficacy and safety profiles of the TCAs relative to newer therapies.

Two of the three sedating atypical antidepressants reviewed here are also of questionable value as first-line treatment. First, mirtazapine is indicated for the treatment of depression but often is used as an alternative or augmentation therapy for depression rather than a first-line monotherapy.49 Second, sales of nefazodone have been discontinued in several countries including the United States (branded version) due to concerns of liver toxicity.

The process of elimination leaves trazodone as the most likely candidate for monotherapy in depression with comorbid insomnia. However, while trazodone is considered to be safer than the TCAs, it remains associated with a series of significant side effects. The most common adverse events seen with trazodone at doses of ≥75 mg/day are drowsiness, dizziness, dry mouth, nausea, vomiting, constipation, headache, hypotension, and blurred vision.50 A review of published data from controlled trials in depressed patients found that 25% to 30% of patients experienced some treatment-emergent adverse event attributed to trazodone.51 Reported discontinuation rates from clinical trials were relatively high (25% to 60%), with 25% to 50% specifically attributable to adverse events.50 Most importantly, a recent literature review identified a sizable number of reports of treatment-emergent cardiac events.52 Adverse events noted in clinical studies and case reports include hypotension, ventricular arrhythmias, cardiac conduction disturbances, and exacerbation of ischemic attacks. Torsades de pointes, a prolongation of the QTc interval, and other cardiac arrhythmias, have been observed in patients treated with trazodone.53-57 Finally, a review of psychotropics and priapism found that almost 80% of cases reviewed were associated with trazodone, while the balance was associated with antipsychotics.58


Evidence Supporting the Use of a Combination of Two Antidepressants


Trazodone is the most widely used sedating antidepressant used as adjunctive therapy to other antidepressants. Given the frequency with which this treatment course is pursued, it is remarkable that the combination of trazodone and other antidepressants has not been ardently investigated. Of the studies that have been conducted, almost all have employed small samples and, therefore, may be of limited applicability to the general population of patients with depression.

In one study,59 trazodone 100 mg or placebo was given to patients (N=12) stable on different SSRIs for a period of 7 days. At the end of this period, trazodone co-therapy significantly increased total sleep time and  SWS, and reduced the number of awakenings seen on polysomnography. Another study60 examined the impact of prescribing trazodone for patients (N=17) with an incomplete response to fluoxetine or bupropion. In this evaluation, trazodone produced significantly more improvement than placebo in several subjective measures of sleep.

Trazodone has been added to fluoxetine in one study of a group of depressed patients (N=8) for the purposes of either improving sleep or as a possible antidepressant potentiator.61 Three of the eight patients experienced improvements in both sleep and depression symptoms. A second group of patients on fluoxetine (N=16) was given adjunctive trazodone for complaints of insomnia.62 All patients had a positive hypnotic response, but five discontinued trazodone due to excessive sedation.

Trazodone was compared to placebo in depressed patients (N=7) who developed insomnia while treated with the MAOI brofaromine.63 Trazodone increased SWS and was associated with subjective reports of better and deeper sleep. A review of MAOI-induced insomnia treated with trazodone found 13 case-studies.64 Twelve reported an initial positive response to co-therapy while only nine were able to continue treatment without intolerable side effects.

Depressed patients (N=50) participated in a 4-week study of the atypical antidepressant venlafaxine with adjunctive trazodone, as needed, for the development of comorbid insomnia.65 The timing and dosage of trazodone was left to the discretion of the clinicians to simulate a naturalistic setting. Patients who received adjunctive trazodone had a lower response to venlafaxine monotherapy on MADRS measures of insomnia and inner tension. Once trazodone was introduced, these patients showed improvements in insomnia symptoms but not in other measures of depression.

Other Antidepressants
Aside from trazodone, very little information is available about the impact on sleep parameters of sedating antidepressants used as adjunctive therapy to any of the alerting SSRIs or MAOIs.



In one study of trazodone as adjunctive therapy for fluoxetine, five of eight patients were unaffected by the addition of trazodone to fluoxetine or had intolerable adverse drug reactions.61 In a second study62 of trazodone-fluoxetine co-therapy, all patients reported marked daytime sedation with five of 16 discontinuing trazodone as a consequence. The implications of these case reports suggest that the utility of the combination of fluoxetine and trazodone may be limited by adverse effects.

Co-administration of trazodone and brofaromine produced few adverse events and was well tolerated by study participants.63 A review of several case studies of trazodone-MAOI co-therapy found that one of 13 patients was unable to tolerate the combination initially and another three discontinued this course of treatment due to side effects over a longer period of time.64

Serotonin syndrome has been described when trazodone was prescribed in combination with nefazodone.66 Serotonin syndrome has also been reported following the use of venlafaxine and fluoxetine.67

Other Sedating Antidepressants
Co-administration of the atypical antidepressant venlafaxine and the TCAs clomipramine or imipramine has been well tolerated.68 Venlafaxine has been used as adjunctive therapy when patients have realized only partial response to the TCA. However, no effects on sleep parameters were reviewed.

Adjunctive paroxetine has been employed to increase the effectiveness of TCAs (amitriptyline and imipramine) in patients who had not sufficiently responded after 3 weeks of monotherapy.69 This combination increased TCA serum levels as intended and was well tolerated. Effects on sleep were not reviewed.

When used in combination, the SSRI fluoxetine was shown to increase TCA plasma levels for several members of this class of antidepressants.70 This increase was highest with clomipramine and imipramine and less notable with amitriptyline. These pharmacokinetic changes did not induce side effects in the patients evaluated. The effects on sleep were not reviewed.


Evidence Supporting the Use of a Combination of One Antidepressant and One Hypnotic


Although numerous drug-drug interaction studies have been conducted to evaluate the interaction between hypnotics and antidepressants, efforts to evaluate the effectiveness of co-administration of these treatments on comorbid depression and insomnia are still in the early stages.

The use of zolpidem was examined in SSRI-treated patients with persistent comorbid insomnia.71 Patients who participated in this study were diagnosed with depression, treated stably with the SSRIs fluoxetine, sertaline, or paroxetine, and complained of sleep onset difficulty or too-short sleep time at least 3 nights a week and associated with daytime impairment. Over a 4-week period, treatment with zolpidem 10 mg lengthened sleep time, improved sleep quality, reduced the number of awakenings, and improved multiple measures of daytime functioning as compared to placebo.

A recent study evaluated the co-administration of eszopiclone 3 mg with the SSRI fluoxetine in patients with MDD over an 8-week period.72 Compared to fluoxetine alone, the fluoxetine-eszopiclone group demonstrated statistically significant improvements in all sleep parameters evaluated at all time points. Measures included sleep latency, wake time after sleep onset, total sleep time, sleep quality, and depth of sleep. Importantly, eszopiclone also resulted in a greater treatment response to fluoxetine as measured by improvements on the 17-item HAM-D, Clinical Global Impression (CGI) Improvement scale, and CGI Severity scale. Furthermore, a significantly greater percentage of individuals in the co-therapy group were classified as responders (59% versus 48%) and remitters (42% versus 33%) at the end of the study.



In the zolpidem-SSRI-induced insomnia study, adverse events were similar between the placebo and zolpidem groups.71 There was no evidence of dependence or withdrawal from zolpidem during the placebo substitution period at the conclusion of the study.

Zolpidem drug-drug interaction studies have been conducted with two TCAs and two SSRIs.73 Co-administration of zolpidem and imipramine produced a 20% decrease in peak levels of imipramine and an additive effect of decreased alertness. Chlorpromazine in combination with zolpidem produced no pharmacokinetic interactions; however, decreases in alertness and psychomotor performance were potentiated. Both of these studies evaluated single-dose interactions in healthy volunteers. Thus, the results may not be predictive for chronic administration in depressed patients.

Zolpidem-fluoxetine interactions were examined in both single-dose and multiple-dose studies. A single-dose study in male volunteers with zolpidem 10 mg and fluoxetine 20 mg at steady-state levels did not find any clinically significant pharmacokinetic or pharmacodynamic interactions.73,74 Healthy females participated in a multiple-dose study of zolpidem and fluoxetine at steady-state concentrations.73 The only significant change in this evaluation was a 17% increase in the half-life of zolpidem. No changes in psychomotor performance were seen.

Healthy female volunteers were dosed with sertraline 50 mg for 17 days. Once steady-state levels were reached, subjects were dosed for 5 consecutive nights with zolpidem 10 mg. The pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem, but zolpidem Cmax was significantly higher (43%) and Tmax was significantly decreased (53%).

Adverse events and dropout rates were similar between the placebo and eszopiclone groups in the 8-week eszopiclone-fluoxetine MDD study.72 The frequency of adverse events continued to be similar between both groups during the placebo washout period at the conclusion of study.75 No evidence of withdrawal effects, rebound insomnia, or rebound depression was observed. A single-dose study of co-administration of eszopiclone 3 mg with paroxetine 20 mg (7 days) found no pharmacokinetic or pharmacodynamic interactions.73

Zaleplon was evaluated in three single-dose antidepressant drug interaction studies.73 Zaleplon 20 mg co-administered with the TCA imipramine 75 mg potentiated decrements in next-day alertness and psychomotor performance as compared to either compound administered alone. There was no alteration of the pharmacokinetics of either drug. In two separate studies, neither co-administration of zaleplon with the SSRI paroxetine 20 mg (7 days) or with the atypical antidepressant venlafaxine 150 mg resulted in any pharmacokinetic or pharmacodynamic changes to either zaleplon or the antidepressant.

Ramelteon is the newest hypnotic approved for the treatment of insomnia in the US. It has been evaluated for use in conjunction with two SSRIs. A single-dose of ramelteon 16 mg was co-administered with fluvoxamine 100 mg (3 days).73 This combination increased the area under the curve (AUC)0-inf of ramelteon by approximately 190-fold, and the Cmax by approximately 70-fold. This effect appeared to be specific to fluvoxamine and cytochrome P450 1A2 inhibitors rather than being a class effect which could be expected to occur with other SSRIs.

A multiple dose study of co-administration of ramelteon and sertraline was conducted.76 Ramelteon had no effect on the systemic availability of sertraline. Decreases in ramelteon AUC and Cmax (23% and 43%, respectively) were deemed clinically irrelevant due to ramelteon’s highly variable inter-subject pharmacokinetic profile.



Antidepressants and Non-Depressed Patients

A small number of studies have evaluated the efficacy of antidepressants in non-depressed, primary insomnia patients. The extremely limited nature of this evidence and the small scale of most of these studies strongly argues against the use of antidepressants as hypnotics in non-depressed patients.

The largest study (N=306) reported to date has been the only placebo-controlled study of trazodone in insomnia patients.77 Over a 2-week period, trazodone improved sleep latency and total sleep time relative to placebo during the first week of treatment only. The loss of efficacy during the second week suggests that trazodone is not an appropriate insomnia treatment choice for non-depressed patients. No other trazodone studies have been reported in primary insomnia patients.

A low-dose formulation of doxepin is currently in development as a hypnotic. Three published studies have examined doxepin’s effects in primary insomnia patients. A placebo-controlled, 4-week study of doxepin 25–50 mg (N=47) found that active treatment improved sleep efficiency and sleep quality over the entire treatment period.78 Notably, more rebound insomnia was observed in the doxepin treatment group during the placebo run-out period. Adverse effects were comparable between the two groups, but two doxepin patients discontinued due to adverse effects. In the second study, patients (N=10) were treated with placebo for 1 night and doxepin 25 mg for 3 weeks.79 Relative to placebo, sleep was improved after one dose of doxepin during the double-blind phase of the trial. At the end of 3 weeks of open-label treatment, doxepin also improved sleep relative to baseline values. Adverse events and rebound insomnia remained a concern in some patients. Finally, a 2-night cross-over study80 (N=67) was employed to evaluate doxepin 1–6 mg. All three doses improved wake time during sleep, total sleep time, and sleep efficiency relative to placebo. The safety profile of doxepin was similar to that of placebo with no evidence of anticholinergic effects, memory impairment, or significant hangover/next-day residual effects.

Two studies evaluated paroxetine in primary insomnia patients. Fifteen insomnia patients were treated for 6 weeks with a flexible dose of paroxetine (median dose=20 mg).81 At the end of the treatment period, 11 patients had improved and seven no longer met the diagnostic criteria for insomnia. Subjective measures of sleep quality and daytime function were significantly improved, but neither objective nor subjective measures of sleep quantity were consistently changed with treatment. One participant dropped out due to adverse side effects. A double-blind comparison82 of paroxetine and placebo in older adults (N=27) found improvements in subjective sleep quality and several measures of daytime function. Sleep efficiency, sleep latency, and wake time appeared to be unaffected by active treatment. Both evaluations suggest that paroxetine is ineffective for treating primary insomnia.

Trimipramine was studied in two groups of primary insomnia patients.83 It was shown to produce significant improvements in sleep efficiency, total sleep time, wake time after sleep onset, sleep quality, and next-day well-being in 19 primary insomnia patients (mean dose=166 mg ). Side effects included dry mouth and the anticholinergic properties of the drug. No rebound insomnia was observed at either 4 or 14 days following drug discontinuation. A 4-week study84 of trimipramine (mean dose=100 mg) in 55 insomnia patients found significant improvements in sleep efficiency but no impact on total sleep time. Adverse effects were deemed minimal and no rebound insomnia was observed.

One open label study85 of nefazodone in primary insomnia has been reported. Patients (N=32) were treated with 100 mg nefazodone at bedtime. Over the 4-week period evaluated, this dose could be titrated up to 400 mg depending on treatment response. At the end of the treatment period sleep latency was prolonged and there was less SWS relative to baseline values. The duration of REM sleep was greater and improvements were seen in subjective Pittsburgh Sleep Quality Index scores, but overall sleep effects were decidedly mixed. Furthermore, 12 of 32 participants dropped out of the study citing either lack of efficacy or intolerable side effects.



Mood disorders are frequently comorbid with insomnia. Treatment options to address both conditions simultaneously include the use of a sedating antidepressant, two antidepressants (one sedating), or an antidepressant in conjunction with a hypnotic. Although the simultaneous use of two antidepressants is perhaps the most common course of action, it has not been well studied and is associated with significant safety concerns. Recent studies suggest that combining an antidepressant with a hypnotic may be a more promising, efficacious, and safe strategy for the treatment of comorbid mood disorders and insomnia. PP



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86.    Sharpley AL, Cowen PJ. Effect of pharmacologic treatments on the sleep of depressed patients. Biol Psychiatry. 1995;37(2):85-98.
87.    Antai-Otong D. Antidepressant-induced insomnia: treatment options. Perspect Psychiatr Care. 2004;40(1):29-33.
88.    Clark NA, Alexander B. Increased rate of trazodone prescribing with bupropion and selective serotonin-reuptake inhibitors versus tricyclic antidepressants. Ann Pharmacother. 2000;34(9):1007-1012.


This interview took place on January 17, 2008, and was conducted by Norman Sussman, MD.


This interview is also available as an audio PsychCastTM at http://psychcast.mblcommunications.com.

Disclosure: Dr. Diem receives grant support from Eli Lilly, the National Institutes of Health, and Pfizer.


Dr. Diem is assistant professor of medicine at the University of Minnesota. She is a general internist, epidemiologist, and clinical trialist of women’s health. In addition, her clinical practice is primarily focused on perimenopausal and postmenopausal women. Dr. Diem is co-investigator on the Study of Osteoporotic Fractures, a prospective cohort study funded by the National Institutes of Health that examines the risk factors for osteoporosis and fractures in postmenopausal women.


What did your study on the use of antidepressants and rates of hip bone loss in older women reveal?

Using data collected over a 4.5 year period in the Study of Osteoporotic Fractures,1 we compared the rate of bone loss in older women who use selective serotonin reuptake inhibitors (SSRIs) to the rate of bone loss in older women who do not use SSRIs. We found that the women taking SSRIs had a bone loss rate of approximately 0.8% per year while the women not taking SSRIs had a bone loss rate of approximately 0.5% per year.

There are several differences between women who take SSRIs and women who do not take SSRIs and these differences can influence bone density.

As an observational study, it was important for us to have measures for those differences. The study was adjusted for these potential confounders that influence bone density (ie, differences in physical activity, health conditions, and depression).


Are the findings statistically significant?

Of the 2,600 women involved in the study, 198 of them used SSRIs during the 4.5-year period. The difference in the rate of bone loss between the two groups was statistically significant. However, there is some question over whether that difference in the rate of bone loss translates into an increased risk of fracture in the long run.

The companion study2 that looked at men >65 years of age was slightly different. It used cross-sectional analyses to compare the average bone density in men using SSRIs to the average bone density in men not using SSRIs. That study only looked at the average bone density at a particular point in time because follow-up bone density data was not yet available. However, the study found that bone density at the hip and spine in men who used SSRIs was lower than that in men who did not use SSRIs even when factors such as age, physical activity, health status, and smoking status were controlled.


What were the major confounders in these studies?

There were several potentially important confounders in these studies. One important issue is that of confounding by indication; SSRIs are typically prescribed for depression, and there is evidence that depression itself may have negative effects on bone.3-5 As a result, it is difficult to verify whether this lower bone density and higher rate of bone loss is due either to the medications or to the underlying condition for which the drugs are being prescribed. In addition, although these studies had measures for comorbid conditions, physical activity, and other confounders, those measures are not perfect. Differences in diet, sunlight exposure, and exercise among people who take SSRIs and people who do not take SSRIs could also be potential explanations for the differences observed in bone loss. Thus, the results of these studies must be considered preliminary.

Are follow-up studies being conducted to verify bone loss as an effect related either to the disorder or to the intake of SSRIs?
There is an interest in trying to replicate these analyses in other groups, especially in younger cohorts. The women in our study were on average 78 years of age, and whether or not the results from that study are generalizable to younger groups is debateable. People are certainly interested in trying to repeat these analyses in other cohorts. However, any observational study is going to be limited by the fact that they are observational and therefore subject to similar issues of confounding. Cohorts that have better measures of depression than we had in our study would be ideal for replicating these analyses.


What led you to conduct these studies?

A fair amount of previous work has reported an association between SSRI use and hip fracture. However, the mechanism of that association remains unclear. SSRIs have been associated with an increased risk of falls, and they are likely prescribed to people who are sicker and therefore at risk for fractures because of their other illnesses. However, it has remained unclear whether we have a full understanding of the reasons for the association between SSRI use and fractures.

More recently, serotonin receptors and transporter systems have been described in bone cells, which has raised the possibility that blockade of these transporters could have an effect on bone metabolism. There have been animal data suggesting a possible negative effect of administration of SSRIs on bone, which then prompted us to try to take a look at the data we had in this large cohort study.


What findings are there in terms of animal data?

Evidence from animal studies to date has been mixed, with some studies suggesting that blockade of the serotonin transporter may be beneficial to bone and others suggesting a negative effect on bone health. It is unclear what the explanation is for these discrepant results. However, it is clear that more work is needed to try to clarify the effects of inhibition of serotonin transporters on bone. One study6 involved female mice with and without ovaries that underwent fluoxetine treatment. The research reported that the fluoxetine treatment increased volume in the vertebral trabecular bone. However, this beneficial effect of SSRI administration was found only in the female mice with ovaries. The fluoxetine-treated mice that underwent ovariectomy were not protected against bone loss, which suggests some interplay among estrogen, serotonin transport inhibition, and bone. More research is needed to clarify the effects of inhibition of serotonin transporters on bone loss.


Should people who take SSRIs use supplementary medications specifically for the prevention of bone loss?

I cannot make blanket recommendations for all patients taking SSRIs because I think the literature is still too preliminary. Recommendations for calcium supplements and for other anti-osteoporosis drugs should be based on current indications. Calcium supplements are a relatively benign intervention, and I generally have a low threshold for suggesting them. For example, most guidelines suggest consideration of calcium supplementation for peri- and postmenopausal women. I think that is a relatively simple thing to do. However, I am not yet convinced that the existing literature about SSRIs justifies having everyone on an SSRI be told they should take calcium supplements.


Is additional research being conducted in this field?

Given the widespread use of these medications, there is growing interest in further exploring and better understanding any possible effects of SSRIs on bone health. We are conducting analyses in a younger cohorts of women in a perimenopausal age group. In addition, we are using data from the Study of Osteoporotic Fractures to look at SSRI use and risk of fracture in older women. Other research is exploring the basic science issues in animal models more in depth as well.


How will this study affect clinical practice?

In my opinion, the only change the current literature might justify would be related to decisions on screening for low bone density. The current recommendations for ordering a bone mineral density test are based on known risk factors for fracture and osteoporosis, including age, menopausal status, family history, history of previous fracture, and smoking. If a patient has borderline indications for a bone mineral density test, but that patient has depression or is receiving active treatment with an SSRI, then the current literature might suggest that it would be reasonable to obtain the bone density test. I do not think that the current literature should lead to patients and doctors stopping treatment with SSRIs out of concern for bone health because the current literature regarding SSRIs and bone is too preliminary. Depression is a serious illness with significant morbidity and discontinuing a treatment for depression based on our existing understanding of SSRIs and their possible effect on bone would be premature. PP



1.    Diem SJ, Blackwell TL, Stone KL, et al. Use of antidepressant and rates of hip bone loss in older women: the study of osteoporotic fractures. Arch Intern Med. 2007;167(12):1240-1245.
2.    Haney EM, Chan BK, Diem SJ, et al. Association of low bone mineral density with selective serotonin reuptake iInhibitor use by older men. Arch Intern Med. 2007;167(12):1246-1251.
3.    Diem SJ, Blackwell TL, Stone KL, et al. Depressive symptoms and rates of bone loss at the hip in older women. J Am Geriatr Soc. 2007;55(6):824-831.
4.    Michelson D, Stratakis C, Hill L, et al. Bone mineral density in women with depression. N Engl J Med. 1996;335(16):1176-1181.
5.    Robbins J, Hirsch C, Whitmer R, Cauley J, Harris T. The association of bone mineral density and depression in an older population. J Am Geriatr Soc. 2001;49(6):732-736.
6.    Battaglino R, Vokes M, Schulze-Spate U, et al. Fluoxetine treatment increases trabecular bone formation in mice. J Cell Biochem. 2007;100(6):1387-1394.

Needs Assessment:
When patients present with a major depressive episode, one of the challenges inherent to current pharmacotherapy options is that medications often take several weeks to exert their antidepressant effects. A well-known anesthetic and analgesic medication, ketamine, has shown potential for providing a much more rapid relief of symptoms.

Learning Objectives:
• Summarize the evidence for a role of the glutamate system in major depressive disorder.
• List the most common acute adverse effects of intravenous ketamine infusion.
• Identify the main reasons why the antidepressant efficacy of ketamine is still considered preliminary.

Target Audience: Primary care physicians and psychiatrists.

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

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

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

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: March 19th, 2008.

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

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by April 1, 2010 to be eligible for credit. Release date: April 1, 2008. Termination date: April 30, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. aan het Rot is postdoctoral fellow in the Department of Psychiatry; Dr. Charney is dean and Anne and Joel Ehrenkranz Professor in the Departments of Psychiatry, Neuroscience, and Pharmacology and Systems Therapeutics; and Dr. Mathew is assistant professor in the Department of Psychiatry, all at the Mount Sinai School of Medicine in New York City.

Disclosure: Dr. aan het Rot reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Drs. Charney and Mathew receive grant support from the General Clinical Research Center, the National Alliance for Research on Schizophrenia and Depression, and the National Institute of Mental Health. Drs. Charney and Mathew have been named as inventors on a use-patent of ketamine for the treatment of depression. If ketamine were shown to be effective in the treatment of depression and received approval from the Food and Drug Administration for this indication, Drs. Charney and Mathew could benefit financially.

Acknowledgments: The authors acknowledge the valuable contributions of David L. Reich, MD, Andrew M. Perez, MD, Richard M. Lewis, MD, James W. Murrough, MD, Katherine A. Collins, MSW, and the New York Mood Disorders Support Group.

Please direct all correspondence to: Sanjay J. Mathew, MD, Mount Sinai School of Medicine, 1468 Madison Ave, Annenberg 21, Room 90, One Gustave L. Levy Place, Box 1217, New York, NY 10029; Tel: 212-241-4480; Fax: 212-241-7973; E-mail: Sanjay.Mathew@MSSM.edu; Website: www.mssm.edu/psychiatry/map.




Conventional pharmacologic treatments for major depressive disorder (MDD) generally take several weeks to several months to have a clinically meaningful effect. This time lag to response constitutes a major burden for patients and contributes to increased morbidity and mortality. Two published studies in patients with MDD have now provided evidence for rapid and robust antidepressant efficacy of a single intravenous (IV) infusion with a sub-anesthetic dose of ketamine hydrochloride compared with an infusion of saline. In the approximately 60% of patients who responded, ketamine’s acute antidepressant effects were maintained for at least several days and up to 2 weeks. This article reviews the pathophysiologic rationale underlying this approach, the clinical evidence for the use of IV ketamine for treatment of MDD, ketamine’s safety profile, and areas of uncertainty to be explored in future studies.



The United States National Comorbidity Survey Replication recently estimated the lifetime prevalence of major depressive disorder (MDD) to be approximately 17%.1 The occurrence of a major depressive episode (MDE) is often associated with significant impairment in multiple areas, including functioning in school or at work and interaction with family and friends. This may negatively impact patient outcomes long after the MDE has been resolved and may increase risk of recurrence or relapse.2 The clinical availability of therapeutic interventions with rapid onset of action may help reduce or even prevent the long-term effects of an MDE.

However, most existing pharmacologic treatments for MDD take several weeks to months to achieve their full clinical effects. This constitutes a major burden for patients, contributes to significant morbidity, and increases risk for suicide. The delay in onset of action that is typical of currently available antidepressants may exist because these medications exert their pharmacologic effects on systems upstream from the core pathophysiology of MDD.3 Thus, the interaction of these medications with their corresponding binding molecules (eg, receptors, transporters) activates intracellular signaling cascades that only in turn lead to changes in the expression and sensitivity of downstream neurotransmission molecules that are part of MDD pathophysiology. Most notable in this respect has been the recent accumulation of data indicating that antidepressants impact pathways that regulate cellular plasticity and survival in brain regions involved in mood regulation.4 In keeping with this are studies demonstrating atrophy and cell death in subgroups of patients with MDD.5-7

Plasticity and survival of brain cells involve multiple actions of the excitatory amino acid neurotransmitter glutamate.4 It is not surprising that there is an increasing interest in the use of glutamate system modulators for treatment of MDD.8,9 The potential efficacy of the high-affinity N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, in particular, has received attention both in the scientific community and from the general public.10 This article reviews two published placebo-controlled studies in which ketamine was given intravenously to patients with MDD. A single dose of ketamine (0.5 mg/kg) infused over 40 minutes had robust antidepressant effects that appeared after only a few hours.11,12 In light of these two promising initial reports, ketamine may have potential as a novel antidepressant with rapid onset of action, which is essential for minimizing the long-term effects of an MDE.


Depression Pathophysiology and Effect of Treatment

Rational drug development for treatment of MDD should be guided by a solid pathophysiologic model derived from both preclinical data and clinical observations. One such model focuses on the role of stressful experiences on glutamate function.13 The behavioral stress response involves multiple brain systems including not only activation of the hypothalamic-pituitary-adrenocortical axis but also initiation of complex cascades of reactions mediated by several neurotransmitters, including release of the excitatory amino acid neurotransmitter glutamate.14 When a stressor is acute and mild, the stress response helps an organism adapt and cope. However, when the stressor is chronic and severe, and especially when it is considered uncontrollable and inescapable, it may have pathologic consequences, including MDD.15,16 Preclinical studies have found that chronic stress may lead to excessive extrasynaptic accumulation of glutamate.17 In addition, chronic stress induces changes at the level of the glutamatergic NMDA receptor.18 Over time, this persistent hyperactivity of the stress system may contribute to glutamate-mediated excitotoxicity leading ultimately to cell death in brain areas such as the hippocampus.19,20 In addition, accumulating evidence from post-mortem and brain imaging indicates that glutamate metabolism is altered in individuals who are depressed compared to those who are well.21-24

Preclinical data on the involvement of the glutamate system in the mechanism of action of conventional antidepressants go back many years.8 For example, monoaminergic antidepressants have multiple effects on glutamate receptor function.25-27 In addition, there is abundant evidence of the positive effects of glutamatergic drugs in animal models of depression.8 These include antagonists at the NMDA receptor.28-31 Most relevant for this review are animal studies of ketamine, which in glutamatergic pathways works as a high-affinity NMDA antagonist.32 In rats ketamine induces antidepressant-like effects in the forced swimming test and in the learned helplessness model of depression.33-35 These effects may be mediated by regulating the functional interplay between NMDA and non-NMDA ionotropic glutamate receptors, especially α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptors.36


Clinical Evidence for Ketamine

Though compelling, it was not the preclinical data that sparked interest in the potential use of ketamine as an antidepressant treatment. Instead, it was an experimental study in patients with MDD that originally aimed to characterize the psychotomimetic effects of a subanesthetic intravenous (IV) dose of ketamine in this population. In 2000, Berman and colleagues11 at Yale University reported on the effects of ketamine 0.5 mg/kg and saline infusions on mood in nine drug-free symptomatic inpatients with recurrent MDD. Mood change following each of the two 40-minute infusions was measured using the 25-item Hamilton Rating Scale for Depression (HAM-D25) and the Beck Depression Inventory, both acutely (40–230 minutes after the start of the infusion) and sub-acutely (1–3 days post-infusion). Treatment order was randomized across patients. The two infusions were separated by ≥1 week. HAM-D25 scores were virtually unchanged in the saline condition. In contrast, a significant ketamine-induced reduction in HAM-D25 scores was first seen after 230 minutes and continued to develop over time. Three days post-ketamine, HAM-D25 scores were reduced by an average of 48%. In four of the eight patients who received ketamine, the HAM-D25 reduction was ≥50% (one patient dropped out after having received saline during the first infusion). Within 1–2 weeks post-ketamine, all patients but one (who started antidepressants after responding to ketamine and never completed the saline condition) had relapsed.

Zarate and colleagues12 replicated this study in a larger sample using an inpatient protocol at the National Institutes of Health which involved administration of IV ketamine (0.5 mg/kg) and IV saline in a randomized order 1 week apart. All 18 patients had a diagnosis of recurrent MDD and a HAM-D21 score ≥18 at baseline. They had responded insufficiently to ≥2 adequate antidepressant trials in their lifetime and were therefore considered to be treatment resistant. Participants were rated 40–230 minutes after the start of the infusion and 1–7 days post-infusion. A significant ketamine-induced reduction in HAM-D21 scores was first seen after 110 minutes. One day post-infusion, HAM-D21 scores were significantly reduced in the ketamine condition (-56%) but not in the saline condition (-10%). At this point, 71% of patients reported ≥50% decreases in HAM-D21 scores following ketamine, versus 0% following saline. After 1 week, these percentages were 34% and 0%, respectively. Notably, whereas 17 patients received the ketamine infusion, only 14 patients received the saline infusion, because four patients who received ketamine first maintained the antidepressant response for >1 week.

These two studies11,12 suggest that IV ketamine can have a robust (large effect size) and rapid (within 2 hours) antidepressant effect in patients with MDD. A recent third study,37 also conducted at Yale University and presented in abstract form at the 2007 Society for Biological Psychiatry Annual Meeting, again replicated the acute response to ketamine in an additional 10 patients (Table 1).11,12,37,38


Importantly, although neither study included patients who were actively suicidal, both Berman and colleagues11 and Zarate and colleagues12 observed meaningful reductions in suicidal ideation. Patients who responded acutely subsequently remained well for several days. The authors of this article and several other groups are currently conducting follow-up studies in order to develop adequate continuation treatment, with the goal of sustaining the acute ketamine response for longer time periods. For example, a recent report of two patients with treatment-resistant depression (TRD) who received one or more continuous ketamine infusions of approximately 0.3 mg/kg/h for 5 days found that the patients remained well for >1 year.39 However, another case study in a patient with TRD and comorbid alcohol and benzodiazepine dependence found that the antidepressant effect of a second 0.5 mg/kg ketamine infusion was reduced compared to the first infusion.40 Berman and colleagues11 and Zarate and colleagues12 excluded patients with recent alcohol and drug use disorders. It remains to be seen if including such patients will alter the antidepressant efficacy of IV ketamine in a placebo-controlled study.


Clinical Use

While the interest in ketamine as an antidepressant developed fairly recently, its use in anesthesia and sedation in both adults and children goes back many years.41,42 Surgical anesthesia is typically produced by IV doses of approximately 1–3 mg/kg.43,44 The efficacy of ketamine as an analgesic agent is also well documented and may outlast that of anesthesia.41,42 Treatment at sub-anesthetic doses may in fact be sufficient for long-term therapeutic benefit in patients with chronic pain.45,46 Notably, a 2005 study in 40 patients with complex regional pain syndrome (CRPS) who had previously insufficiently responded to conventional treatments found that the effects of 10 open-label ketamine infusions (of up to 20 mg/hour infused over 4-hour periods, or 40–80 mg per infusion) included not only a decrease in subjective pain intensity scores and an increase in mobility, but also a reduced need for antidepressants.47 These benefits lasted for periods lasting from 2 weeks to 15 months.


Adverse Effects

Based on an extensive anesthesia literature, ketamine may be considered a very safe drug. Its sympathomimetic effects generally include mild-to-moderate increases in heart rate, blood pressure, and cardiac output.41-43,48 Ketamine produces no or only a mild respiratory depression.41,42 Unless patients present with cardiovascular disease and/or uncontrolled hypertension, acute risks associated with IV ketamine administration are therefore regarded as minimal.48 Other adverse effects may include perceptual disturbances, which usually manifest as floating-in-space sensations and/or out-of-body experiences, but in rare events might also include visual or auditory hallucinations.41 While some patients describe these dissociative experiences as pleasurable, joyful, and fascinating (in 1999 ketamine was placed in Schedule 3 of the Controlled Substance Act), others find them bizarre or frightening.48 The perceptual disturbances are usually mild and do not last long beyond ketamine administration.42 Several studies have addressed the question of prolonged psychological effects of ketamine in the general population, secondary to its anesthetic use, and concluded that ketamine does not place patients at a greater risk than do other anesthetics.49,50 Perceptual disturbances following ketamine may be more common and last longer in individuals with preexisting psychosis.48,49,51 However, an investigation of patients with schizophrenia who received a sub-anesthetic dose of IV ketamine in experimental studies found no evidence of enduring adverse effects and distress at follow-up 8 months later.52

Consistent with ketamine’s acute effects on perception, both Berman and colleagues11 and Zarate and colleagues12 found that, 40–45 minutes after the start of the ketamine infusion, patients reported more positive symptoms on the Brief Psychiatric Rating Scale (BPRS) than at baseline. Ketamine administration was also associated with a significant increase in subjective “high” and in scores on item 1 of the Young Mania Rating Scale (elevated mood).11,12 However, none of these effects were seen beyond 80 minutes. The authors of this article are currently investigating methods to attenuate the acute psychotomimetic and dissociative effects of ketamine. They are also carefully characterizing ketamine’s acute side effect profile in patients with TRD using validated measures for adverse event reporting. A report on data from 295 healthy volunteers who were repeatedly administered ketamine (at the dose found to have antidepressant effects in patients with MDD) revealed no increase in positive symptoms, subjective “high,” and perceptual alterations between the first and subsequent exposures.53

Several experimental studies in healthy volunteers have found acute effects of ketamine on neuropsychological test performance. Ketamine impairs performance on tests of attention (eg, trail making, Stroop color-word test, continuous performance), memory (eg, immediate and delayed, verbal and non-verbal recall) and executive function (eg, word list generation fluency, Wisconsin card sorting).54-57 It has been argued that these acute impairments in cognition may have a long-term impact.10 However, studies investigating cognition in recreational ketamine users are confounded by several factors, including comorbid substance abuse.58 Very few prospective controlled studies have addressed this critical issue, but a recent study in patients with treatment-resistant CRPS found no adverse neuropsychological effects of extended ketamine treatment at relatively high doses of 3–7 mg/(kg*h).59

The absence of enduring adverse effects and behavioral sensitization following administration of a subanesthetic dose of IV ketamine also argues against the idea that its antidepressant effects may be offset by possible glutamate-mediated toxicity and cell death.10 This is corroborated by recent findings from preclinical studies36 of increases in glutamatergic AMPA throughput in response to a subanesthetic dose of IV ketamine. It is likely that any toxicity precipitated by ketamine is dose dependent. Thus, the authors of this article hypothesize that, at the relatively low single dose required to achieve a therapeutic effect on mood, ketamine does not cause the cell death that may result from higher doses and more prolonged courses of treatment. Medications with similar pharmacologic properties, the glutamate receptor modulators riluzole and memantine, have been found to have neuroprotective effects in neurodegenerative disorders (amyotrophic lateral sclerosis and Alzheimer’s disease, respectively).9,60-62


Areas of Uncertainty

Despite evidence from two published studies,11,12 ketamine’s effectiveness in relief of MDD symptoms must still be considered a preliminary finding. Drawing conclusions on the effectiveness of ketamine is hindered by the fact that both studies used saline as the placebo control. The acute effects of ketamine and the acute effects (or lack thereof) of saline were likely to be readily distinguishable, which means it was impossible to maintain the integrity of the blind (in both patients and clinicians). The problem is illustrated by the fact that not all study participants received both IV ketamine and IV saline. In the study by Zarate and colleagues,12 crossing participants over from one treatment to another after 1 week was problematic in patients who were administered ketamine on the first infusion day and showed an antidepressant response that lasted longer than 1 week. These patients never received the subsequent saline infusion. A longer inter-treatment interval might be one possible solution for future studies employing a within-group crossover design. Berman and colleagues11 separated the two infusions by up to 2 weeks such that patients who had received ketamine on the first infusion day and showed an antidepressant response had relapsed, except for one patient who initiated continuation treatment following ketamine-induced mood improvement and never completed the saline infusion. A between-groups study may be preferable to ensure that patients complete the placebo condition.

The lack of a placebo control that maintains integrity of the blind in both patients and clinicians during the infusions may also explain why in one of the studies12 the magnitude of psychotomimetic effects during ketamine infusion (ie, increase in BPRS positive symptoms) was correlated with the mood improvement at day 1 (ie, decrease in HAM-D scores). Neither study has reported if the elevated mood reported by patients 40–80 minutes after the start of the ketamine infusion was associated with the observed change in HAM-D scores at later time points.10 Such an association would call into question to what extent ketamine’s antidepressant effects may have been based on patients’ expectations derived from its acute effects. This issue of unmasking participants would remain even if ketamine was compared with saline in a between-groups study. To circumvent this, future studies should therefore consider the use of an active placebo control instead of, or in addition to, saline. The active control should have subjective effects similar to those of ketamine during the infusion but not have any known antidepressant effects after the infusion. A 2002 study63 in medicated depressed patients undergoing surgery has found that those induced with propofol, fentanyl, and ketamine reported improved mood and reduced subjective pain 2–4 days post-surgery, whereas no such changes were seen in patients induced with propofol and fentanyl alone. It is unlikely that patients were unblinded to the different treatments during the procedure, given that post-surgery confusion scores were similar across the two groups. This study provides some evidence that IV ketamine can have an antidepressant effect even when patients are masked to the treatment they are receiving.

The route of drug administration may have influenced the speed of ketamine’s antidepressant response. IV administration bypasses first-pass metabolism and results in higher plasma concentrations than oral administration. Some studies have demonstrated a rapid response to IV administration of conventional antidepressants.64,65 Other studies reported no difference between IV and oral administration in the speed of onset of action of these drugs.66,67 From the point of view of patient convenience, oral administration of antidepressants is usually the preferred route. It remains to be seen if ketamine will have rapid antidepressant properties when administered orally or in other formulations (eg, intramuscularly, intranasally, transdermally). The current data on the efficacy of other glutamate-modulating medications available for oral administration in patients with MDD are mixed. Oral administration of riluzole may improve mood in patients with TRD.68,69 Oral administration of memantine had no significant antidepressant effects in a recent study in patients with MDD.70 However, memantine has significantly lower affinity for the NMDA receptor than ketamine.71

Other areas of uncertainty include the relative effectiveness of the two optical enantiomers, S- and R-ketamine, and the role of neurotransmitters other than glutamate in ketamine’s antidepressant effects. Ketamine is approved by the US Food and Drug Administration only as a racemic mixture of both enantiomers. The more active enantiomer, S-ketamine, has approximately 4–5 times greater affinity for the NMDA receptor than R-ketamine.72 In healthy volunteers, S-ketamine was found to produce emotional disturbances, cognitive impairments, and dissociative experiences, whereas R-ketamine induced a state of relaxation.73 S-ketamine has been approved in some European countries based on evidence that it has more potent anesthetic and analgesic effects such that it can be used in smaller doses and therefore possibly decrease recovery time.74 There is also some indication that the psychotomimetic or unpleasant effects of S-ketamine may be less pronounced than those of the racemic mixture.75 S-ketamine–induced decreases in binding potential of the dopamine-2 receptor antagonist raclopride, measured using positron emission tomography in the striatum and surrounding brain areas, have been shown to correlate with subjective euphoria; this suggests that dopamine may play a role in its acute mood-elevating effects.76 Most experimental studies that administered single subanesthetic IV doses of racemic ketamine to humans have also found that ketamine has effects on dopamine receptors.77-80 These studies have also implicated a role for mu opioid receptors.81 In summary, ketamine has a complex pharmacologic profile, with its actions on the glutamate system and NMDA receptors being only one of multiple pathways that together are responsible for its diverse effects.

Other currently unresolved issues with ketamine include the following. First, the dose used thus far (0.5 mg/kg) may not be the optimal dose for induction and mainte­nance of the mood response. Second, it is unknown which medications are viable continuation treatment options in patients who show an initial favorable response (eg, repeated ketamine administration, use of another glutamatergic drug such as riluzole or memantine, or other more traditional approaches). Third, although there is no current evidence of addiction potential in controlled studies performed to date, the potential of ketamine abuse must continue to be consid­ered. Finally, future studies should more closely measure the acute and longer-term side effects of ketamine at multiple time points following its administration.


Comparison with Existing Rapid Antidepressant Treatments

Current treatments for MDD can be divided into “acute” interventions and continuation/maintenance strategies. However, besides ketamine only sleep deprivation produces antidepressant responses within 24 hours (Table 2). Sleep deprivation has a long-known rapid and robust efficacy in approximately 60% of patients with MDD.82 The magnitude of improvement is often equivalent to that observed after 6 weeks of antidepressant treatment. Hence, the acute therapeutic response to sleep deprivation must be mediated by mechanisms different from those mediating the gradual improvement obtained with antidepressants.83 Functional brain imaging studies are highly suggestive of an association between clinical improvement and increased activity in the ventral anterior cingulate cortex.84 Advantages of sleep deprivation include its noninvasive nature and safe use in pregnant and breastfeeding women. However, most patients relapse after one subsequent night of sleep regardless of medication status,82 which may explain why sleep deprivation is rarely administered by clinicians in the US. Nevertheless, sleep deprivation has been successfully used to hasten the onset of action of antidepressants.85 


Bright light therapy (BLT) can also be administered safely in pregnant and breastfeeding women. Like sleep deprivation, it is non-invasive. However, compliance may be difficult for some, as patients are usually required to self-administer bright light in the early morning.86 BLT reportedly has a response rate of approximately 60%. The effect size may be larger in patients with seasonal affective disorder (SAD) versus non-seasonal MDD.87 Like sleep deprivation, BLT has been successfully used as an adjunct to conventional antidepressant treatment in order to speed up its antidepressant effect.88 While BLT efficacy has mostly been studied over time periods in the range from weeks to months, at least two studies89,90 in patients with SAD are indicative that its onset of action may be faster than that of the commonly prescribed selective serotonin reuptake inhibitor, fluoxetine. Anecdotally, clinically meaningful mood changes have been found to occur even after time periods of 2–3 days.91,92 A 2004 Cochrane review of BLT studies in patients with non-seasonal MDD showed significant benefit in studies of up to a week, but no significant benefit in longer and better-controlled studies.93 However, a 2005 controlled trial reported significant benefit of BLT in approximately 50% of patients with non-seasonal chronic MDD.94

Electroconvulsive therapy (ECT) is usually administered to patients with TRD and generally involves three sessions per week, with most individuals requiring at least 6 treatments to achieve a response. ECT is considered the most effective antidepressant treatment, especially for patients with psychotic, melancholic, or bipolar depression.95 It is considered another rapid antidepressant treatment, although onset of action is rarely achieved during the first treatment session (Table 2). Interestingly, a recent case report in a patient with severe, recurrent MDD showed that intramuscular administration of 100 mg of ketamine in combination with a single session of ECT resulted in marked clinical improvement within 8 hours of treatment which continued at least until the next ECT session 3 days later.96 Disadvantages to ECT include its invasive nature, including the requirement of general anesthesia and the risk of significant retrograde amnesia, which in some patients may be irreversible.97 Without continuation treatment, the majority of patients will relapse within 6 months.98



The development of a rapid antidepressant strategy which is effective within 24 hours and can be sustained is an important therapeutic goal in psychiatry. Studies on the antidepressant effects of ketamine are a work in progress. This article has presented the currently available data, with the intention to stimulate future research.

As of yet, there are no established guidelines for ketamine administration in patients with MDD. Berman and colleagues11 and Zarate and colleagues12 have administered ketamine on an inpatient basis. Ongoing studies by the authors of this article and elsewhere also use this approach. Patients are monitored by an anesthesiologist during infusion, are continuously observed by nursing staff, and remain in the inpatient setting for 24 hours post-infusion to ensure safety. Acutely, ketamine’s potential side effects include respiratory or circulatory problems, especially in patients with lung disease and uncontrolled hypertension, respectively. Studies thus far have not encountered these problems; however, patient selection procedures actively excluded patients with known risk factors. At present, the use of ketamine for treatment of TRD in uncontrolled settings is discouraged by the authors of this article.

Nevertheless, in the future ketamine may offer the clinician a potentially efficacious and rapidly acting medication, especially for patients with TRD. As the therapeutic lag time inherent to currently available treatments for MDD is suboptimal, this and similar approaches are worthy of further investigation.



Ketamine is a well-known FDA-approved anesthetic and analgesic medication. In at least two placebo-controlled studies in patients with MDD,11,12 one of which included patients with TRD, ketamine has shown additional potential as a rapid and robust antidepressant. There was some evidence of a decrease in suicidality as part of the overall rapid clinical improvement. The acute antidepressant effects of a single ketamine infusion lasted up to 2 weeks. It remains to be seen if ketamine, in combination with existing or future continuation therapies, can be developed as a safe and effective treatment option for patients with an acute MDE. The development of a new pharmacologic intervention with acute and sustained antidepressant effects could have a significant impact on public health. PP



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



Today’s patient has likely researched his or her condition on the Internet before even stepping into a doctor’s office for the first time. Some patients have even read articles from scientific journals and have asked physicians about their opinion on that type of treatment option. Although the Internet has made a wealth of information available to patients, there is still a significant amount of conflicting information even in the medical journals, and even more so on the Internet. This column reviews the trends in patient health information access and discusses strategies for physicians on how to navigate and negotiate with patients surfing for information.



In the past, patients relied mostly on their physicians to have the expertise to manage the majority of their health issues, and oftentimes did not question the validity of recommendations. The advent of the Internet has ushered in the “information overload” age with health information as one of the most popular destinations. In the 2002 Pew Internet and American Life Project report,1 it was estimated that 52 million American adults, or 55% of those with Internet access, have used the Internet to get health/medical information. This report indicated that patients went online at least once a month to get health information, and that the information they find has a direct effect on decisions regarding healthcare and interactions with doctors. Specifically, 70% of patients indicated that the health information on the Internet influenced their decision about how to treat an illness or condition. Fifty percent of patients said that information on the Internet led them to ask their doctor new questions or seek a second opinion from another doctor, while 48% indicated that Internet-based health information has helped them take care of themselves.

Kaplan and Brennan2 described the beginning trend of consumer health informatics, an area regarding the growth of the organization and delivery of health care and changing roles of patient and provider. At the Spring 2000 Congress of the American Medical Informatics Association, three panels examined the trend of health information, patient participation, shared decision making, and clinician responses in the context of the Internet.2 Several themes emerged, including the change in roles of consumers and providers, support for patient-provider-information technology partnership, virtual structure for health care and health information delivery, and health care as an integrated part of each person’s life. Patients clearly wanted more personalized relationships with their providers as well as interactive tools to help manage their health and diseases.


Website Certifications

In the early years of the Internet, it was simple enough for patients and providers alike to determine the potential bias and usefulness of a Website by examining the URL for its domain (either .net, .com, .edu, or .org). It was at that time relatively safe to assume that “.edu” and “.org” were non-profit sites of educational institutions and organizations; therefore. any Website content would not be biased or commercial in nature. Over the years, domain names became a “commodity,” which could demand high prices in the competitive open market. Domain name “squatters” rushed to register the names first or took advantage if registrants who failed to renew their domain in a timely manner. Now, there are numerous additional domain appellations such as “.biz,” “.info,” and even “.md.” To add even more confusion, many Website URLs are actually referrer domain names, which then send the visitor to another site or same site. One example, www.physician.md,3 actually sends visitors to the National Institutes of Health Website, which is normally accessed at www.nih.gov.4 Nowadays, the inherent nature of a Website is no longer predetermined by its domain name. The Mayo Clinic operates three sites, MayoClinic.com5 for health information, MayoClinic.org6 for health services, and Mayo.edu7 for education and research.

One way to help patients determine the relative usefulness and reliability of health information on the Internet is for the site to have accreditation. The Health on the Net (HON) Foundation is a not-for-profit and private Swiss foundation which has been granted non-governmental organization status by the Economic and Social Council of the United Nations.8 It serves to accredit Websites that have fulfilled the eight ethical principles of the HON code of conduct (Table). In addition to accreditation, HON also offers MedHunt, a specialized search engine geared toward the public and designed to find health information on the Internet. HONselect is a meta-search engine that offers medical terms, corresponding pictures, bibliographic references, news, and Websites that adhere to the HON code of conduct.


Another accreditation organization is the Utilization Review Accreditation Commission (URAC).9 This organization accredits many types of healthcare organizations. In particular, URAC provides oversight on how an accredited health Website is operated. URAC Health Web Site Accreditation ensures that the site is supervised by clinically trained staff, discloses key information about how the Website operates, and limits how personal health information is used or disclosed to third parties. There are >50 URAC health Website standards, which were developed in conjunction with healthcare providers, consumers, and health Website companies.


Online Tools

As indicated in the Pew Internet Report, patients seek information on the Internet because it is convenient and relatively anonymous, especially on sensitive topics, which may include mental health. A previous Tech Advisor10 discussed how Internet-based assessment tools can be used to help patients check for various conditions. Healthplace.com11 has created a collection of links to other Websites that have screening tools for a variety of psychological disorders, encompassing both free and commercial tools. Organizations, such as the Mental Health Association of America, often sponsor free screening tools to encourage patients to discuss matters with their health provider (eg, Depression-Screening.org).12

Today’s patients are quite savvy and are often appropriately concerned about medications and drug-drug interactions. Numerous Websites offer drug information and drug-drug interaction tools, such as DoublecheckMD,13 Drugs.com,14 and Medscape.15 These Websites are fairly easy to use. However, they can create confusion for the patient and some consternation for the practitioner. In a simple check of drug interactions between risperidone and escitalopram, both DoublecheckMD and Drugs.com indicate a potential for central nervous system depression, whereas Medscape indicates that there are no drug interactions at all. Epocrates Online,16 which has been traditionally used by medical professionals but can be used by patients, indicates that the drug-drug interaction can cause potential increased risperidone levels due to inhibition of hepatic metabolism. One advantage for patients using DoublecheckMD is that its explanation of the risks uses less medical jargon. Drugs.com offers a pill identification wizard and will store lists of drugs and interactions once patients register at the Website. Much of the discrepancy of the interaction checks is based on the drug database employed by the Website and its editorial board.


Online Forums

Online health information comes from a variety of sources, traditionally from textbooks and journal articles that are edited and distilled but delivered via the interface of the Internet. Patients usually rely on Websites such as WebMD,17 RevolutionHealth,18 and the National Institute of Mental Health19 to find general information on various health conditions. A new trend has been the shift toward online support groups. Patients and family members can log in and read other patients’ experiences with medications and treatment in order to attain a better understanding of symptoms and disease course. DailyStrength.org20 has numerous discussion forums where patients share their thoughts and provide support. Furthermore, it has a specific “advice” column where patients explicitly offer each other advice on how to cope, and “recommendations” where patients recommend books and videos. PatientsLikeMe21 takes the sharing of patient experiences further. Although the Website focuses right now on Parkinson’s disease, multiple sclerosis, HIV/AIDS, and amyotropic lateral sclerosis, patients share their symptoms and treatment, which are tabulated in a running total. Patients track their outcomes, treatment, and symptoms over time, which are nicely plotted in a graphical view. At MedHelp.org,22 patients not only get information and support from one another on forums, but they can also get advice from members and medical professionals who are responsible for answering questions posted on the forum. Yahoo Health23 takes patient sharing a step further by providing inspirational stories from patients as well as video posts from patients. It also offers an amalgam of information including expert opinion from various providers.


Health Search Engines

Finding relevant information on the Internet has helped Google24 achieve its marketshare and financial success, but one search engine cannot find everything relevant. Specific health search engines, such as Healia,25 Medstory,26 and Healthline,27 do a better job finding useful information by searching the Internet, ClinicalTrials.gov,28 and Pubmed29 using health-related taxonomies compared to traditional search engines. Healia offers filters such as information based on ethnicity, HON- and URAC-accredited sites, and whether information is easy or harder to read. Medstory also filters information based on keywords identified during the search. For example, upon searching for negative symptoms of schizophrenia, topics such as drugs, procedures, conditions, and personal health can refine the search. A helpful feature is that once the search has been created, an really simple syndication (RSS) feed can be created so any new content can be updated in an RSS reader. Healthline offers information both from its own content as well as the Internet, and the HealthMap creates a flowchart for patients to find new information as well as understand its relevancy.



Soon enough, it will be commonplace for every patient coming into the health practitioner’s office to bring information discovered on the Internet. Patients may even begin to “tag” Websites and articles using services such as Digg30 and Del.ici.ous,31 to be shared with their doctor for further discussion. Although it is impossible for all providers to learn in advance what types of information is on the Internet for their patients, they should be prepared to help patients navigate such information because personal relevancy and medical advice is still in the domain of medical practice. PP



1.    Fox S, Rainie L, Horrigan J, et al. The online health care revolution: how the web helps Americans take better care of themselves. Available at: www.pewinternet.org/PPF/r/26/report_display.asp. Accessed March 1, 2008.
2.    Kaplan B, Brennan PF. Consumer informatics supporting patients as co-producers of quality. J Am Med Inform Assoc. 2001;8(4):309-316.
3.    National Institutes of Health. Available at: www.physician.md. Accessed March 1, 2008.
4.    National Institutes of Health.  Available at: www.nih.gov. Accessed March 12, 2008.
5.    MayoClinic.com. Available at: www.mayoclinic.com. Accessed March 1, 2008.
6.    MayoClinic.org. Available at: www.mayoclinic.org. Accessed March 1, 2008.
7.    Mayo.edu. Available at: www.mayo.edu. Accessed March 1, 2008.
8.    Health on the Net Foundation. Available at: www.hon.ch. Accessed March 3, 2008.
9.    URAC. Available at: www.urac.org. Accessed March 3, 2008.
10.    Luo J. Computerized medicine. Primary Psychiatry. 2006;13(9):20-22.
11.    HealthyPlace.com: Online Psychological Tests. Available at: www.healthyplace.com/site/tests/psychological.asp. Accessed March 12, 2008.
12.    Depression-Screening.org. Available at: http://depression-screening.org. Accessed March 5, 2008.
13.    DoublecheckMD. Available at: www.doublecheckmd.com. Accessed March 5, 2008.
14.    Drugs.com Drug Interaction Checker. Available at: www.drugs.com/drug_interactions.html. Accessed March 5, 2008.
15.    Medscape Drug Interaction Checker. Available at: www.medscape.com/druginfo/druginterchecker. Accessed March 5, 2008.
16.    Epocrates Online. Available at: http://online.epocrates.com. Accessed March 5, 2008.
17.    WebMD. Available at: www.webmd.com. Accessed March 10, 2008.
18.    Revolution Health. Available at: www.revolutionhealth.com. Accessed March 10, 2008.
19.    National Institute of Mental Health. Available at: www.nihm.nih.gov. Accessed March 10, 2008.
20.    DailyStrength.org. Available at: www.dailystrength.org. Accessed March 11, 2008.
21.    PatientsLikeMe. Available at: www.patientslikeme.com. Accessed March 11, 2008.
22.    MedHelp. Available at: www.medhelp.org. Accessed March 11, 2008.
23.    Yahoo Health. Available at: http://health.yahoo.com. Accessed March 11, 2008.
24.    Google. Available at: www.google.com. Accessed March 12, 2008.
25.    Healia. Available at: www.healia.com. Accessed March 11, 2008.
26.    Medstory. Available at: www.medstory.com. Accessed March 11, 2008.
27.    Healthline. Available at: www.healthline.com. Accessed March 11, 2008.
28.    ClinicalTrials.gov. Available at: www.clinicaltrials.gov. Accessed March 11, 2008.
29.    Pubmed. Available at: www.ncbi.nlm.nih.gov/PubMed/. Accessed March 11, 2008.
30.    Digg. Available at: www.digg.com. Accessed March 12, 2008.
31.    Delicious. Available at: http://del.icio.us. Accessed March 12, 2008.