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Norman Sussman, MD
Primary Psychiatry. 2007;14(3):15-16


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

Dr. Sussman is a consultant to and on the advisory boards of GlaxoSmithKline and Wyeth; and has received honoraria from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, and Wyeth.

In this month’s Primary Psychiatry, each feature article addresses an aspect of treatment involving complicated psychiatric disorders. Specifically, each article focuses on patients who do not respond to “first-line” interventions and sometimes do not respond to conventional treatments at all. In many of these cases, a therapeutic dilemma is whether to try a sequence of alternative therapies or use multiple agents, called drug cocktails. Treatment failure sometimes also leads patients to seek out alternative therapies, such as nutrients and vitamins, or procedures that have not been extensively studied for their efficacy and safety.

Given its prevalence, major depressive disorder (MDD) may be the “treatment resistant” psychiatric disorder seen most by primary care physicians and psychiatrists. Consistently, studies have shown that one third of patients fail to achieve complete resolution of their symptoms following initial antidepressant therapy for MDD, and there is no explanation for why these patients are resistant to medication. Recent evidence on the next step for clinicians after intial treatment failure has not shown that any strategy, such as switching or combining drugs, is better than any other. Nevertheless, there is a widely held belief that drugs with multiple neurotransmitter effects, such as the serotonin norepinephrine reuptake inhibitors (SNRIs), may be marginally superior to selective serotonin reuptake inhibitors (SSRIs) as “go to” drugs after initial treatment failure.

David L. Dunner, MD, provides a perspective on the available evidence for the efficacy of the SNRI venlafaxine in the treatment of unresolved depression symptoms following adequate antidepressant therapy. Dr. Dunner explains the implications of available data for achieving remission in patients with treatment-resistant depression. He concludes that, although comparative studies do not conclusively show venlafaxine to be superior to augmentation or switch strategies for patients who do not to respond to an SSRI there is suggestive evidence that venlafaxine may represent a better option than staying within class. If such an advantage does exist, the question that remains is whether response with venlafaxine is related to the drug’s dual mechanism of action, which is shared by the SNRI duloxetine.

Prior to reading the article by Allen Childs, MD, and Larry Price, PhD, describing the use of cranial electrotherapy stimulation (CES) to treat 48 chronically aggressive neuropsychiatric patients in a maximum security psychiatric hospital, I had been unaware that CES was a United States Food and Drug Administration approved treatment. The early focus of CES was as a treatment for sleep disorders and the therapy was known as electrosleep therapy. In fact, several types of CES units are certified as being effective for the treatment of anxiety, depression, insomnia, and pain. I am unsure why so little is published about this procedure; CES is not cited in standard psychiatric textbooks. Yet, case reports submitted by Childs and Price were accepted for publication in a major psychiatric journal.1 The robust antiaggressive effects of CES they report in chronically ill neuropsychiatric patients warrants publication of their findings. As in the case of electroconvulsive therapy, multiple treatments are typically needed to produce clinical effects. CES should not be confused with transcranial magnetic stimulation (TMS), an experimental procedure that is being tested at multiple academic centers. Far more research data about TMS have been published in scientific/medical journals than have the results of CES studies. Readers should keep in mind that the article by Childs and Price in this month’s issue contains case reports and not a controlled trial. Yet, given that CES is reported to be well tolerated—headache or skin irritation at the electrode site being the most common side effects—the possibility that it may be used to reduce aggression warrants further research. Aggression represents the most potentially serious behavioral consequence in neuropsychiatric patients.

Ruth E. Geller, MD, and Joseph F. Goldberg, MD, elaborate on the role of psychotherapy in the treatment of bipolar disorder in their article on psychotherapies for bipolar disorder. These psychotherapies, used as an adjunct to pharmacotherapy, include psychoeducation as well as cognitive-behavioral therapy, family-focused treatment, and interpersonal/social rhythm therapy. Geller and Goldberg note that these therapies may improve patients’ ability to cope with stress and improve insight into the reemergence of symptoms.

Bipolar disorder represents another common psychiatric disorder that is often difficult to treat. Often, it is possible to manage acute episodes of mania, hypomania, or bipolar depression but is difficult to maintain stability over time. Eduard Vieta, MD, PhD, presents an article examining the role of these newest type of drugs as mainstream mood stabilizers. All of the atypicals have been well-studied as treatments for acute mania and some are also indicated for mixed mood states, bipolar depression, or as maintenance treatment. Since bipolar disorder invariably requires long-term treatment, Vieta notes that there is a need for well-tolerated and clinically effective maintenance therapy. It remains to be seen whether atypical antipsychotics will fill this need for long-term therapy. However, this article discusses what is known about atypicals and other drugs used to treat biplar disorder in order to make clinicians aware of the relative risks and benefits of these interventions. In addition, the article mentions that medciation alone is not sufficient to provide optimal therapeutic outcomes and that psychotherapy and psychoeducation are important in improving adherence to treatment. PP


1. Childs A. Cranial electrotherapy stimulation reduces aggression in a violent retarded population: a preliminary report. J Neuropsychiatry Clin Neurosci. 2005;17(4):548-551.


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Serotonin Reuptake Inhibitors May be Associated with Increased Risk of Fracture in the Elderly

In the United States, approximately 10% of elderly primary care patients suffer from major depressive disorder (MDD) and other depressive disorders. Selective serotonin reuptake inhibitors (SSRIs) are the preferred pharmacologic treatment for MDD as they are associated with a lower incidence of adverse effects when compared to other antidepressants. However, a recent study shows a potential link between SSRI use and increased risk of fracture in the elderly population.

J. Brent Richards, MD, of the Division of Endocrinology and Metabolism at McGill University in Montreal, Quebec, and colleagues, evaluated 5,008 community-dwelling adults >50 years of age for 5 years in order to assess the incidence of fractures. Data were gathered on bone mineral density (BMD), falls, and medication use. Researchers also considered additional information, such as patient histories and demographic data, in the final assessment. One-hundred and thirty seven participants (mean age=65.1 years) reported daily use of SSRIs, including citalopram, fluoxetine, fluoxamine, paroxetine, and sertraline.

Richards and colleagues found a two-fold increase in the number of fractures, which most frequently occured in the forearm, ankle, and foot, for these patients. Also, there was a dose-dependent increase in the number of falls among patients using SSRIs daily as well as a decrease in BMD for this group. However, when data were adjusted to account for falls and diminished BMD, there remained a significant correlation between daily use of SSRIs and increased risk of fractures.

“SSRIs were chosen for this study because they have previously been shown to be associated with an increased risk of fracture,” Dr. Richards said. “Previous studies were limited in their ability to control for relevant confounding variables, such as falls and bone mineral density. Our study was novel in that we were able to control for multiple covariates including falls, BMD, and depressive symptoms.”

According to the National Institute of Mental Health, MDD and other depressive disorders affect approximately 26 million people in the US, including approximately 7 million individuals ≥65 years of age. Osteoperosis, a condition that causes brittle bones, is more common among older adults, afflicting >50% of adults >50 years of age. MDD has also been linked to low bone density, which can increase a patient’s risk of fracture, and could mediate study results.

Dr. Richards noted that “the risk attributable to SSRIs was similar to that attributed to corticosteroids, which are most commonly associated with an increased risk of osteoporotic fracture.”

The study authors concluded that clinicians should be aware of risks associated with SSRI use in the elderly population, and consider the association between medication and increased risk of fracture when determining how to treat MDD in elderly patients. Clinicians should also discuss the risks and benefits of using SSRIs with their patients. Richards and colleagues added that elderly patients treated with SSRIs should be encouraged to maintain good physical activity, eat a healthy diet including foods with vitamin D and calcium, and refrain from smoking.

Of note, one limitation of the study was its failure to account for the duration of SSRI use.

Funding for this research was provided by the Alliance for Better Bone Health, the Arthritis Society, the Canadian Institutes of Health Research, The Dairy Farmers of Canada, Eli Lilly, Merck, and Novartis. (Arch Intern Med. 2007;167(2):188-194.) —RS

Inflammatory Markers Incited by Cynic Distrust and Chronic Stress

Prior research has associated psychiatric disorders, such as major depressive disorder (MDD), with markers of artery inflammation, which is associated with greater risk of heart attack and other cardiovascular diseases, including atherosclerosis. However, a recent cross-sectional study found that a much wider range of psychosocial factors can influence the concentration of inflammatory markers.

Nalini Ranjit, PhD, of the Center for Social Epidemiology and Population Health at the University of Michigan in Ann Arbor, and colleagues, evaluated baseline data gathered by the Multi-Ethnic Study of Atherosclerosis (MESA) in order to examine the association between known psychosocial risk factors and cardiovascular diseases. Ranjit and collegues hypothesized that psychosocial risk factors would be positively associated with concentrations of inflammatory markers and analyzed associations between inflammatory markers and psychosocial risk factors. Results were also adjusted for the effect of body mass index (BMI), socioeconomic position, and diabetes.

MESA, a 10-year longitudinal study of 6,814 patients (45–84 years of age), measured cynical distrust, MDD, chronic stress, and the relationship of those factors to CVD. Cynical distrust was measured with an 8-item subset of the Cook-Medley Hostility Scale, depression was measured with the Center for Epidemiologic Studies-Depression Scale (CES-D), and chronic stress was measured with the 4-item Chronic Stress Scale, which measured in the domains of work, finances, and relationships, among others. Blood samples were also used to measure inflammatory markers, including interleukin-6 (IL-6), C-reactive protein, and fibrinogen.

Ranjit and collegues found that high levels of cynical distrust were associated with increased concentrations of inflammatory markers, and results were similar for chronic stress.

“We know that depression is associated with several cardiovascular risk factors,” Dr. Ranjit said. “But finding an association with cynical distrust and chronic stress was very surprising.”

Higher chronic stress levels were equivalent with higher concentrations of IL-6. Although there was no clear evidence of a threshold in the association of psychosocial factors and inflammatory markers, a CES-D score of 21 was associated with higher levels of all three inflammatory markers, however, IL-6 was the only statistically significant difference. After adjustment for behavioral factors, associations of psychosocial factors with inflammatory markers were reduced by 20% to 55%. Adjustment for BMI and diabetes decreased associations by 45% to 100%. The authors reported that, in all cases, associations were reduced after adjustment for behavioral factors.

“The study results suggest that psychosocial factors may act through increasing obesity and unhealthy practices like smoking,” Dr. Ranjit said. “Primary care practitioners should be on the lookout for unhealthy practices among patients with high levels of psychosocial risk factors.”

Funding for this research was provided by the National Heart, Lung, and Blood Institute and the National Institute of Child Health and Human Development. (Arch Intern Med. 2007;167:174-181.) —LS

Cognitive-Behavioral Therapy Demonstrates Efficacy Superior to Other Psychotherapies in Generalized Anxiety Disorder

According to the National Institute of Mental Health, generalized anxiety disorder (GAD), which is characterized by chronic anxiety often due to common or non-existent problems and life situations, affects approximately 6.8 million adults in the United States in a given year. Affecting women more than men, GAD develops gradually and can affect patients of any age. In addition to worry and tension, GAD symptoms can be manifested as physical symptoms, including headaches, trembling and twitching, sweating, fatigue, muscle aches, and irritability, which can lead to reduced quality of life.

While antidepressants have been evaluated in prior studies and shown to be efficacious in GAD treatment, there have been few studies comparing the ability of different psychotherapies to treat the disorder. Vivien Hunot, PhD, of the Institute of Psychiatry in London, England, and colleagues, sought to determine the efficacy of three psychotherapies as treatments for GAD: cognitive-behavioral therapy (CBT), psychodynamic therapy, and supportive therapy.

In reviewing 25 studies with 1,305 patients, Hunot and colleagues compared within the various psychotherapies and against patients on a treatment waiting list or usual treatment. Usual treatment was defined as any appropriate medical care delivered during the study period, including use of medication with or without concurrent therapy. CBT involved patients recognizing destructive thought and reaction patterns and modifying or replacing these patterns with realistic ones, psychodynamic therapy examined patients’ childhood experiences for underlying issues, and supportive therapy utilized patient skills to resolve problems.

Included studies were randomized and quasi-randomized controlled trials conducted in non-inpatient settings that involved adults 18–75 years of age with a primary GAD diagnosis. Treatment response was indicated by anxiety reduction as measured by screening tools of the reviewed studies.

Hunot and colleagues found that patients who received CBT showed the greatest reduction in GAD symptoms over patients receiving other therapies or usual treatment groups. Forty-six percent of patients assigned to CBT showed a response after treatment in contrast to the 14% of patients on a waiting list or receiving usual treatment. Also, patients who completed CBT sessions showed increased reductions in worry, anxiety, and depression symptoms.

“This review provides robust evidence that psychological therapy using a CBT approach is an effective short-term treatment for patients with GAD,” Dr. Hunot said. “The findings may be regarded as highly applicable in primary care practice, since primary care patients tend to prefer psychological therapies to pharmacologic interventions as a treatment for common mental disorders.”

When compared to supportive therapies in six studies, patients receiving CBT showed a non-significant difference in anxiety measures. Hunot and colleagues attribute this finding to the limited number of studies available for comparison, which was not expected by the researchers.

“However, the small number of studies and significant heterogeneity, partly explained by the number of therapy sessions, precludes the ability to draw conclusions on whether or not CBT and supportive therapy are of comparable effectiveness in treating GAD,” Dr. Hunot said. “Given that psychodynamic and supportive therapies are commonly used in primary care clinical practice, the most surprising finding in this review was the lack of currently available evidence to support their use.”

The authors concluded that while CBT is effective when compared to usual treatment, more studies are needed that compare CBT directly to other psychotherapies in the treatment of GAD. Therefore, clinicians should carefully consider utilizing CBT for GAD treatment. Reviewed studies also did not compare CBT to treatment with antidepressants or other medications.

“Naturalistic concurrent prescribing of medications was a common feature of studies included in the review,” Dr. Hunot added. “However, the comparative effectiveness of treatments other than psychological therapies was not investigated.”

Hunot and colleagues also found that patients receiving CBT in group therapy settings had an increased likelihood to dropout of treatment, when compared to patients on a waiting list or those receiving usual care, and GAD patients receiving CBT in individual settings (patient and clinician) were less likely to end treatment. The authors stated that while dropout reasons could have been underreported, the finding may point to a tendency of patients to prefer individual treatment. (Cochrane Database Syst Rev. 2007;(1):CD001848.) —CP

Posttraumatic Stress Disorder Linked to Reported Health Problems in Iraq War Soldiers

Characterized by chronic distressful recollections of traumatic events and psychological upset, posttraumatic stress disorder (PTSD) affects approximately 5 million adults 18–54 years of age in the United States, according to the National Institute of Mental Health, and often occurs comorbid with other anxiety disorders, major depressive disorder (MDD), and substance abuse. While various traumatic events can lead to PTSD—including motor vehicle accidents, natural disasters, child abuse, and witnessing or being involved in a violent crime—warfare and military combat were among the earliest and most prominent causes for PTSD, and were commonly linked to physical health problems for past veterans. Although the ongoing war in Iraq has been identified as a PTSD risk for active soldiers and military personnel, there have been few studies on a potential link between PTSD and physical health problems for these soldiers.

Charles W. Hoge, MD, of the Department of Psychiatry and Behavioral Sciences at the Walter Reed Army Institute of Research in Silver Spring, Maryland, and colleagues, studied PTSD and health problem prevalence in 2,863 soldiers who had returned from combat duty in Iraq 1 year prior to the beginning of the study. Hoge and colleagues sought to find an association between PTSD and increased complaints of health problems by recently returned soldiers.

Study participants, who were from four U.S. Army combat infantry brigades, completed the 17-item National Center for PTSD Checklist, the 9-item Patient Health Questionnaire Depression Scale, and an alcohol screening test. The 15-item Patient Health Questionnaire was also used to evaluate somatic symptoms. Soldiers responded to the standardized self-administered screening measures anonymously, and were also asked the frequency of their sick or missed days at work. Ninety-seven percent of study participants were male, 80% were <30 years of age, 56% were enlisted personnel, and 17% were injured.

Overall, Hoge and colleagues found that 16.6% of study participants met screening criteria for PTSD, as compared to the 5% of soldiers from a comparable group who met PTSD screening criteria prior to their deployment to Iraq. Of the study participants who had been wounded or injured in ≥1 circumstance during their tour, Hoge and colleagues found a 31.8% prevalence of PTSD, as compared to the 13.6% PTSD prevalence for unwounded participants.

Regarding self-reported health measures, the researchers found that soldiers with PTSD had poorer health ratings (47% rated health as poor or fair compared to 20% of soldiers without PTSD), had called in sick or missed days at work ≥2 times in 1 year, had more physical symptoms, and showed higher somatic symptom severity. This finding was also apparent after researchers controlled for combat injuries. Soldiers with PTSD also more frequently reported having sleep problems (71%) as compared to those without PTSD (26%).

The authors concluded that these findings show that PTSD has a close association with the indication of physical symptoms in soldiers 1 year after returning from Iraq, regardless of incidents of injury on duty. Hoge and colleagues suggest that soldiers who have served in Iraq and show symptoms of PTSD, should be evaluated for other physical symptoms and vice versa. Study limitations include a reliance on self-report measures rather than clinician interviews, lack of randomization, and the exclusion of hospitalized soldiers or those in medical care during the study period. (Am J Psychiatry. 2007;164(1):150-153.) —CP

Bipolar Smokers Show Higher Rates of suicide and Psychiatric comorbidity Than Non-Smokers

Previous research has found a higher prevalence of smoking among patients with bipolar disorder compared to the general population. Michael J. Ostacher, MD, MPH, of Massachusetts General Hospital in Boston, and colleagues, reviewed the medical records of 399 outpatients treated at a bipolar specialty clinic over a 5-year span in order to determine the implications of smoking on the disorder.

Ostacher and colleagues evaluated each patient’s records and noted mood state, course of illness, functioning, and psychiatric comorbidities using the Affective Disorders Evaluation and the Mini-International Neuropsychiatric Interview. Their goal was to determine the relationship between smoking, bipolar disorder severity, and suicidal behavior as well as psychiatric and substance use disorder comorbidity.

The authors found that approximately 39% of patients in the study had a history of daily smoking. In addition, bipolar patients who smoked had a greater severity of symptoms, poorer overall functioning, a history of suicide attempts, and lifetime history of comorbid anxiety and substance use disorders. Ostacher and colleagues also found that 47% of bipolar disorder patients who smoked had a lifetime history of a suicide attempt compared to 25% of patients who never smoked. Patients who smoked also had an earlier age of onset of their first depressive and manic episode. A history of comorbid anxiety disorders as well as alcohol and substance abuse and dependence were also found in patients who smoked.

Study limitations included its retrospective nature, that nicotine intake was self-reported rather than diagnosed by a physician, and that researchers had little or no knowledge of factors leading up to the suicide attempts were made.

The authors believe future research is necessary to explore the relationship between smoking, impulsive behavior, and mood. (J Clin Psych. 2006;67(122):1907-1911.) —CN

Psychiatric Dispatches is written by Christopher Naccari, Carlos Perkins, Jr., Lonnie Stoltzfoos, and Rebecca Sussman.


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In Session with Charles H. Kellner, MD: Current Developments
in Electroconvulsive Therapy

Charles H. Kellner, MD, interviewed by Norman Sussman, MD

Primary Psychiatry. 2007;14(3):34-37

This interview was conducted by Norman Sussman, MD, on December 15, 2006.

Disclosure: Dr. Kellner receives grant support from the National Center for Complementary and Alternative Medicine and the National Institute of Mental Health.

This interview is also available as an audio PsychCastTM at

If you have any questions and/or comments regarding the interview with Charles H. Kellner, MD, please submit a “Letter to the Editor” to Norman Sussman, MD, at

Dr. Kellner is professor and chair of the Department of Psychiatry, and assistant dean for clinical research at the University of Medicine and Dentistry of New Jersey in Newark. He is also co-director of the electroconvulsive therapy (ECT) service at The University Hospital in Newark with George Petrides, MD, and was editor of The Journal of ECT from 1994–2004. Dr. Kellner’s ongoing research includes studies comparing different ECT types and methods for optimizing maintenance ECT.


What typical procedures are involved in electroconvulsive therapy (ECT)?

Performed in a modern hospital setting, ECT is a series of treatments in which patients receive general anesthesia and a muscle relaxant followed by a small amount of electrical current to induce a seizure that typically lasts 1 minute. Each procedure takes approximately 15 minutes. The patient is under anesthesia and feels no pain or discomfort.

How many treatments are typically needed before patients show a response?

While there is some variability, most patients with major depressive disorder (MDD) and other depressive disorders will typically remit with an acute ECT course of 6–10 treatments. Some patients achieve remission with fewer than six treatments and some patients will need more than 10 treatments.

From the early days of its application, clinicians saw remarkable results with ECT. It continues to be the most effective treatment available for MDD. However, we are still unsure as to why ECT works.

What are current indications for ECT versus drug therapy?

The most important use of ECT is in patients with MDD who have not responded to medication. Approximately 80% of all patients who receive ECT have very severe depression, either in the context of unipolar or bipolar disorder, which has not responded to several trials of medication.

In some situations, a patient has such a severe case of MDD that medication is not used. Rather, ECT is indicated as a first-line treatment. Such patients would include those who are severely suicidal, extremely psychotic, extremely agitated, or so depressed that self-care is declining and impairing their health through dehydration or malnourishment. Thus, there are some acute situations where ECT is a primary treatment. However, the majority of patients will have received several medication trials. If those medications are not adequately effective in relieving MDD symptoms, ECT is an appropriate choice.

In addition to its antidepressant effects, ECT acts as a mood stabilizer and is effective in both poles of bipolar disorder. Although it is also an acute anti-manic treatment, ECT is not used much for that purpose because most manic patients do respond to medication. For the small subset of patients who do not respond to medication, ECT is an effective anti-manic treatment.

ECT also has a limited but critical role in the treatment of schizophrenia. While ECT does not treat the underlying illness, it treats the positive symptoms of schizophrenia. Thus, ECT can be helpful in treating hallucinations, delusions, and agitation, particularly early in the course of schizophrenia, and should not be overlooked as a treatment for that illness.

In addition, we have found that patients with comorbid MDD and Parkinson’s disease have had beneficial results after ECT, both in terms of improvement in the motor systems of Parkinson’s disease as well as depression. ECT is also a good anti-catatonia treatment, whether catatonia occurs in the context of bipolar disorder, schizophrenia, or, more rarely, other medical illnesses. ECT has the potential to bring a patient out of a catatonic state.

Does the memory impairment acutely associated with ECT persist over time?

ECT causes three types of memory impairment: an acute-confusional state, anterograde amnesia, and retrograde amnesia. The acute-confusional state is characterized by patient confusion due to the seizure and general anesthesia. That impairment typically lasts 20–30 minutes and subsides by the time patients leave the hospital. Patients are brought to a recovery room in order to wake up in an unstimulating environment because of this impairment. Anterograde amnesia is the disruption of memory function during the course of ECT treatment. If, for example, patients are receiving ECT three times a week for 3 weeks of treatment, they will have difficulty remembering and recording memories during that time. Anterograde amnesia dissipates over approximately 1–2 weeks after the end of the ECT course with memory functioning returning to normal. For that reason, patients cannot drive for approximately 1 week after their course of ECT, and certainly not during ECT treatment. Retrograde amnesia is the erasure of a portion of memory around the time of the treatment course, and is probably the most anxiety-producing type of memory problem caused by ECT. It is the only type of memory impairment that can have a long duration. Many memories can return, but some can be erased permanently.

There are reports of more extensive memory problems with ECT and, in rare cases, ECT has the theoretical potential to cause more severe memory impairment.1 Memory impairment was more common in the past when ECT techniques were not as sophisticated as they are currently. Many refinements of ECT technique have occurred over the last 25 years and have served to minimize the amount of retrograde memory impairment caused by ECT.

Is ECT ever indicated for someone who has previously failed a course of ECT?

It is possible that a patient who did not respond during a particular episode could respond in a subsequent episode. Clinicians should carefully review how ECT was performed and patient circumstances. In situations where patients may have had adverse effects from ECT, clinicians should be careful about using the treatment again, particularly if patients have had more cognitive effects than predicted.

Sometimes, ECT is not effective because patients have not received a sufficient number of treatments. In research studies, 10 treatments are conducted before declaring that a patient is a nonresponder.2 Clinicians should take all patient information into account, but 10–12 or more treatments is not unusual. If a patient is not responding in the middle of an ECT course, the practitioner should review the patient diagnosis and ensure that patients are not taking any concomitant medications that may be interfering with ECT efficacy. Clinicians should ensure that the technical parameters of treatment are optimized for each patient.

Should antidepressants or mood stabilizers be stopped during treatment?

Years ago, clinicians used to stop all medications while patients received ECT. However, most antidepressants can be safely continued during ECT. There is some developing evidence that medication may be beneficial in terms of efficacy and in preventing relapse after ECT.3 In addition, commonly-used antidepressants are now much less cardiotoxic than older tricyclic antidepressants, and we often co-administer them with ECT.

Some medications are contraindicated in ECT. Anticonvulsants interfere with seizure production, which is the therapeutic agent of ECT. Antiepileptic mood stabilizers should be tapered and stopped before ECT. Benzodiazepines should only be given in small doses concurrently with ECT because they are potently anticonvulsant. Monoamine oxidase inhibitors (MAOIs)—a class of antidepressants used in the 1960s and 70s that is experiencing a resurgence—can also be safely co-administered with ECT. There are two methods of working with MAOIs when patients receive ECT. It is most conservative to stop MAOIs for 10–14 days prior to treatment. However, if patients are receiving benefit, MAOIs can often be safely continued during the course of ECT. The anesthesiologist and psychiatrist should be aware of potential problems and have the ability to treat the problems if they do occur. Antipsychotics, which are often co-administered in patients with psychotic depression, schizophrenia, and anxiety, can be safely co-administered with ECT as well.

Does ECT ever convert medication nonresponders to responders?

We do not know. It is theoretically possible, but that is a very hard occurrence to study. Another possibility is that patients can partially respond to antidepressants and ECT can help them achieve remission. Continuing antidepressant use has beneficial effect in preventing relapse once patients achieve remission.

Are there any strategies for extending the benefit of an ECT treatment course?

There are two shortcomings of ECT. The first is memory impairment. The second is that there is a high relapse rate in the first 6–12 months if clinicians do not aggressively treat patients who have had successful ECT. Researchers and clinicians are addressing that shortcoming in several ways. First, we are more prone to utilize tapered courses of ECT, also referred to as continuation ECT. In the past, patients may have received treatments three times a week and then stopped abruptly. Now, patients are treated until symptom remission and receive treatments on a lengthened schedule over the next several weeks. A patient may receive treatments three times a week and return for additional treatments at 1-week intervals and later at 2-week intervals. In addition, we are more liberal in co-prescribing antidepressants during the acute course of ECT. This method may have the benefit of ensuring that patients have a therapeutic level of antidepressants when ECT is stopped. In the past, if patients had an acute course of ECT on no medication and started antidepressants after the treatment course, they may not have a therapeutic blood level of the antidepressant for another 1–2 weeks, which would leave them at risk for relapse.

In addition, if a patient has a serious history of recurrent episodes of mood disorder, they can be considered for maintenance ECT, which is an extended course of ECT past the continuation period. The patient would receive a single treatment on an outpatient basis approximately one time per month, although there is flexibility in that schedule. The goal is for patients to receive ECT, even if they are well, about once a month as a prophylactic treatment to prevent a subsequent episode of mood disorder.

Is there evidence that repeated ECT causes brain damage?

There is much evidence that ECT does no structural damage to the brain.4 There are a number of well-designed studies that show ECT does not cause brain damage and numerous reports of patients who have received a large number of treatments over their lifetime and have suffered no significant problems due to ECT.5 In fact, there is evidence that ECT may cause the release of trophic chemicals from neurons that may actually protect the brain. This effect has been shown in animal studies in which ECT induces sprouting of neurons in the hippocampus and may cause increased proliferation of neurons.6 Rather than cause brain damage, there is evidence that ECT may reverse some of the damaging effects of serious psychiatric illness. Several magnetic resonance imaging studies have demonstrated that there is no evidence of structural brain damage due to ECT.7

What are the prevailing theories as to how ECT works?

ECT is a powerful treatment that affects multiple brain systems. While researchers understand the action of ECT on the brain, because it effects many brain regions simultaneously, we have not yet been able to determine which effect or multiple effects causes the antidepressant or antipsychotic effects of ECT. There are theories suggesting that ECT and antidepressant medication action act similarly, each releasing neurotransmitters that are deficient in depressed states. However, ECT acts on a more powerful scale.

Over the last 20 years, we have observed that, parodoxically, ECT is an anticonvulsant treatment. When clinicians induce a series of seizures, they are teaching the brain to recruit anticonvulsant mechanisms to end the seizures. Researchers in psychopharmacology know that one of the most important advances in the treatment of mood disorders in the last 20 years was the introduction of the anticonvulsant mood stabilizers.

There is reason to believe that the anticonvulsant property of ECT may be related to its antidepressant effect. Other theories include one called the neuroendocrine theory, which states that ECT causes the release of peptides that are beneficial in restoring appropriate mood. There is also evidence that ECT corrects the main neuroendocrine abnormality in MDD, which is disregulation of the hypothalamic pituitary adrenal axis. This result was shown in work with the dexamethasone suppression test. In these studies, patients successfully treated with ECT showed normalization of their dexamethasone suppression test.8

There are also many attempts to refine ECT, prevent relapse, and uncover the mechanism of ECT action. Regarding relapse prevention, there are studies now looking at combining maintenance ECT with pharmacotherapy to prevent relapse.

There are ongoing studies examining the best technical methods to perform ECT.9 Three techniques in performing ECT are bilateral (also called bitemporal) electrode placement, right unilateral electrode placement, and the more recent bifrontal placement. Studies are looking at the relative efficacy and the cognitive side-effect profile of each of these three electrode placements. These are attempts to make treatment as effective as possible while limiting cognitive side effects.

Should clinicians begin ECT treatment sooner than previously thought or utilize implanted vagus nerve stimulation (VNS)?

In many situations, it is appropriate to consider ECT earlier rather than later. Modern ECT is a benign procedure. Thus, I believe it is a clinical mistake to allow a patient to remain severely ill and subjected to many antidepressant trials before offering ECT. The application of ECT should be determined by the severity of the patient’s illness. For those patients who are most severely symptomatic with typical MDD symptoms, clinicians should consider ECT among the treatment options. Unfortunately, many clinicians are reluctant to consider ECT sooner. This is a prejudice that should be overcome.

More evidence is needed on the efficacy of VNS as a treatment before it is given widespread use. Data on VNS efficacy are emerging. While evidence is encouraging, it is premature to conclude that it will be an important treatment in our field. PP


1. Sackeim HA. Memory and ECT: from polarization to reconciliation. J ECT. 2000;16(2):87-96.

2. Kellner CH, Knapp RG, Petrides G, et al. Continuation electroconvulsive therapy vs pharmacotherapy for relapse prevention in major depression: a multisite study from the Consortium for Research in Electroconvulsive Therapy (CORE). Arch Gen Psychiatry. 2006;63(12):1337-1344.

3. Sackeim HA, Haskett RF, Mulsant BH, et al. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. JAMA. 2001;285(10):1299-1307.

4. Weiner RD. Does electroconvulsive therapy cause brain damage? Behav Brain Sci. 1984;7(1):1-22.

5. Devanand DP, Verma AK, Tirumalasetti F, Sackeim HA. Absence of cognitive impairment after more than 100 lifetime ECT treatments. Am J Psychiatry. 1991;148(7):929-932.

6. Duman RS, Vaidya VA. Molecular and cellular actions of chronic electroconvulsive seizures. J ECT. 1998;14(3):181-193.

7. Coffey CE, Weiner RD, Djang WT, et al. Brain anatomic effects of electroconvulsive therapy. A prospective magnetic resonance imaging study. Arch Gen Psychiatry. 1991;48(11):1013-1021.

8. Swartz CM, Saheba NC. Dose effect on dexamethasone suppression testing with ECT. Ann Clin Psychiatry. 1990;(2):183-188.

9. Kellner CH, Knapp R, Petrides G, et al. Bifrontal stimulation: where are we right now? J ECT. 2006;22(1):78.


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James L. Levenson, MD

Primary Psychiatry. 2007;14(3):25-28

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.

Chronic pulmonary diseases are a global health problem and the number of patients being treated in primary care settings is increasing. The prevalence of a life-time diagnosis of asthma has increased in all age groups. Drug use for obstructive diseases of the airways have shown a sharp increase over the past decade. Acute exacerbations are a characteristic clinical expression of asthma and chronic obstructive pulmonary disease (COPD) and account for a significant amount of health care costs. This column reviews psychiatric issues in pulmonary disorders, including asthma, cystic fibrosis, COPD, and sarcoidosis, as well as psychopharmacology in patients with pulmonary disease. More comprehensive review of these and other lung diseases can be found elsewhere.1


Comorbidity With Psychiatric Disorders

After hypertension, asthma is the most common chronic disease in the United States, affecting 5% to 7% of the population. Psychiatric disorders, especially anxiety disorders, are very common in patients with asthma. Both adults, children, and adolescents with asthma have a high prevalence of anxiety disorders. In children and adolescents with asthma, up to 33% may meet criteria for comorbid anxiety disorders. In adult populations with asthma, the estimated rate of panic disorder ranges from 6.5% to 24%.2 In a large population-based sample of adults, asthma was associated with a significantly increased likelihood of anxiety disorders (especially panic, generalized anxiety disorder, and phobias) and affective disorders.3 There are a number of reasons for this frequent comorbidity. Anxiety increases risk for asthma, and asthma increases risk for anxiety. Anxiety is increased by asthma attacks, chronic sensations of breathlessness, and anticipation of attacks in response to certain triggers. Respiratory distress causes a wide array of anxiety symptoms (eg, panic attacks, generalized and anticipatory anxiety, phobic avoidance), and audible wheezing aggravates social anxiety. Prospective epidemiologic studies indicate the primary risk factor for development of panic disorder in young adulthood is history of asthma as a child.4 A recent study even found a significant relationship between asthma and dental anxiety.5 An additional cause of frequent anxiety is that many drugs used to treat asthma have anxiety as a potential side effect.1

Asthma may sometimes be mistakenly diagnosed as an anxiety disorder, especially panic disorder, and some anxiety disorders (eg, panic, social anxiety) may be mislabeled as asthma. This differentiation can be difficult because shortness of breath, palpitations, sweating, chest pain, lightheadedness, fear of losing control, and even fear of dying can represent either asthma or panic anxiety. Of course, as noted above, patients can and often do have both asthma and an anxiety disorder.

Depressive symptoms are also very common in asthma. Severe asthma can be very demoralizing and lead to learned helplessness. Furthermore, higher dosage of oral or parenteral corticosteroids may cause secondary depression.

Psychological Factors in Asthma

Asthma was once regarded as a classic psychosomatic disorder, positing a central conflict revolving around unconscious dependency needs and fear of separation; however, this theory has had little empirical support. No particular personality type is more susceptible to development of asthma, but asthmatics have a tendency to hold catastrophic beliefs.6

Asthma is currently viewed as a primary respiratory disease with varying immunologic and autonomic pathophysiologic changes, but many physicians still believe that psychological factors play an important role in the precipitation and aggravation of asthma, particularly anxiety. Brittle asthmatic patients, like brittle diabetic patients, are more likely to have current or past psychiatric disorders than are other asthmatic individuals, but it is not clear whether the psychopathology is the cause or the result of more refractoy disease. Anxiety and depression are associated in asthmatic patients with more respiratory symptom complaints, but not with differences in objective measures of respiratory function.7 Asthma symptom severity increased in New York City following the terrorist attacks on September 11, 2001, and posttraumatic stress disorder was a significant predictor of the increase.8

In difficult asthmatics, there is a high prevalence of undiagnosed psychiatric morbidity, with depression being particularly prevalent. Asthma and depression have additive adverse effects on health-related quality of life. As with anxiety, depression is more strongly associated with increases in subjective measures of asthma severity than objective measures, but some investigators have found impaired pulmonary function (eg, first-second forced expiratory volume [FEV1]).9 It has been demonstrated that sadness and depression can produce respiratory effects consistent with asthma exacerbations.10 Depression is also associated with poorer adherence with asthma treatment.

In one study, psychological factors and psychosocial problems in hospitalized asthmatics were a more powerful predictor of which ones required intubation than any of the examined medical variables.11 Psychological morbidity is associated with high levels of denial and delays in seeking medical care, which may be life-threatening in severe asthma, as well as less medication adherence and consequently poorer control of asthma.12 Not surprisingly, psychopathology in severe asthmatics is associated with increased healthcare utilization, including hospitalizations as well as outpatient and emergency room visits, independent of asthma severity.13 Since psychiatric disorders are prevalent among asthmatics and are associated with worse asthma control and quality of life,14 mental health intervention deserves serious consideration as part of the regular armamentarium in asthma treatment.

Interventions with Asthma Patients

Adjuvant forms of treatment for asthma may involve psychological interventions such as biofeedback, education programs, hypnosis, stress management, symptom perception, and yoga.1 Recent small randomized, double-blind, controlled trials of progressive muscle relaxation have shown physical and psychological benefits in adolescent females15 and in pregnant women.16 There have also been several beneficial small trials of cognitive-behavioral therapy in asthma. The most systematic and up-to-date review of randomized controlled trials testing the efficacy of psychological interventions in adults with asthma found some promising results from meta-analysis but concluded that “due to heterogeneity and the low quality of included studies, this review was unable to draw firm conclusions for the role of psychological interventions in asthma.”17

Asthma in Children and Adolescents

Asthma is the most common pediatric chronic illness. More than 33% of asthmatic children have anxiety disorders.18 Comorbid psychiatric disorders may reduce adherence with treatment, impair daily functioning, and adversely affect pulmonary function. Moderate-to-severe asthma appear to be associated with a higher risk for anxiety disorders compared to mild disease. The presence of an anxiety or depressive disorder is highly associated with increased asthma symptom burden for young people with asthma.19

Posttraumatic stress symptoms are common in adolescents and their parents who have experienced a life-threatening asthma event.20 Asthma can increase family burden, and having depressed primary caretakers increases the risk of poorer treatment adherence. Despite frequent psychiatric comorbidity in asthma, rates of recognition of comorbid anxiety and depressive disorders are low in youths with asthma. Few youths with asthma and comorbid anxiety and depression receive adequate mental health treatment.21

Standard pharmacologic and psychological treatments for anxiety and depression in children are applicable to those with asthma. Family therapy may be a useful adjunct to medication to improve asthma management in children with this illness.22

Cystic Fibrosis

Cystic fibrosis affects approximately 30,000 children and adults in the US and is the most common hereditary disease in white children.18 With progress in treatment, lifespan in cystic fibrosis has significantly increased. Nearly 40% of those with cystic fibrosis are adults. Despite the severity of this disease, rates of psychiatric disorders among those with cystic fibrosis have been reported to be no greater than in the general population in children,23 adolescents,24 and adults,25 though this is probably not true in those with a severe form of the disease.26 Nevertheless, psychological factors are important in cystic fibrosis. Separation, autonomy, sexuality, and adherence are all important issues in cystic fibrosis. In adults, depression, but not FEV1, predicted whether a patient was employed.27 There are no apparent contraindications for standard treatment approaches for psychiatric disorders in those with cystic fibrosis.

Chronic Obstructive Pulmonary Disease

COPD results in progressive declines in arterial oxygen, with carbon dioxide increasing late in the course of the disease. Hypoxia causes confusion, disorientation, altered consciousness, muscle twitching, tremor, and seizures. Mild hypoxia may result in irritability, mental slowing, and impairment of memory and other cognitive functions. Prolonged hypoxia in COPD can cause permanent cognitive deficits and even dementia. Patients with hypercapnea may be lethargic and have auditory and visual hallucinations.1

Comorbidity With Psychiatric Disorders

Nicotine dependence is the most commonly associated psychiatric condition in COPD patients. Anxiety and depressive symptoms are common in patients with COPD, even when their disease is mild.28 Major depressive disorder (MDD) is very common in patients with COPD, partly due to an increased prevalence of depression in smokers. However, only a small fraction of COPD patients with MDD are treated with antidepressants. Anxiety is also common in COPD and is related to some of the same factors described for asthma including the psychological response to the experience of breathlessness as well as side effects of b-agonists. Sexual dysfunction is also common in COPD, as well as cognitive dysfunction, which is improved by supplemental oxygen.

Psychological Factors in COPD

Depression and anxiety in COPD patients have led to lower exercise tolerance, greater difficulty in stopping smoking, noncompliance with treatment, poorer health-related quality-of-life, and increased disability.1 Anxiety and depression predict a greater likelihood of relapse and rehospitalization.1,29 Depression in out-patients suffering from COPD appears to be an independent predictor of mortality.30 Chronic corticosteroid use may also exacerbate depression, emotional lability, or irritability.

Interventions with COPD Patients

Psychotherapeutic, psychopharmacologic, and rehabilitation intervention trials in COPD are reviewed in detail elsewhere.31 The first priority in the rehabilitation of patients with COPD is smoking cessation. The goals of rehabilitation treatment are to relieve symptoms, improve physical functioning, and improve patients’ coping skills.1 Patients with chronic dyspnea may avoid all activity and become home-bound and almost agoraphobic. A review of 25 published studies of psychological treatments for reduction of anxiety in patients with COPD found insufficient evidence to recommend a specific psychological treatment for anxiety in COPD,32 though relaxation techniques are useful in motivated patients.


Sarcoidosis is characterized by noncaseating granulomas in lymph nodes, lungs, and other tissues. Onset of the illness is usually between 20 and 40 years of age. The most common symptoms are dry cough, shortness of breath, fatigue, and weight loss. The disease often follows a relapsing and remitting course, and many patients are asymptomatic. However, a minority of patients die of progressive respiratory impairment, infection, cardiac disease, or renal failure. Sarcoidosis may affect the central nervous system in approximately 5% of patients. Neurosarcoidosis can manifest as cranial or peripheral neuropathies, cognitive dysfunction, psychosis, and seizures. Most such symptoms rapidly remit with steroids. Pituitary or hypothalamic sarcoidosis may cause diabetes insipidus, the syndrome of inappropriate antidiuretic hormone secretion, hyperprolactinemia, menstrual cycle changes, or hypogonadism.1

Few studies examine psychological factors in sarcoidosis. Stress levels are high in patients with symptomatic sarcoidosis,33 and one small study found that increased life stress appeared to predict subsequent impairment of lung function.34

Psychopharmacology in Pulmonary Disease

Anxiety in pulmonary patients may be caused by breathlessness, bronchospasm, excessive secretions, or hypoxia, so the first step in treatment of anxiety is optimization of management of the patient’s respiratory illness. Many drugs used to treat pulmonary disease may cause anxiety. Theophylline can cause anxiety, nausea, tremor, and restlessness, especially at higher doses. b-adrenergic bronchodilators can cause anxiety, tachycardia, and tremor, particularly in patients who overuse their inhalers. Nonprescription asthma preparations contain nonselective sympathomimetics, which are even more likely to cause anxiety, tachycardia, and tremor, and can result in tachyphylaxis leading to very high doses, which can cause psychosis and seizures.

The respiratory depressant effects of benzodiazepines can significantly reduce the ventilatory response to hypoxia. This may precipitate respiratory failure in a patient with marginal respiratory reserve and contraindicates their use in patients with carbon dioxide retention. However, benzodiazepines are not contraindicated for use in all patients with COPD and asthma. Anxiety can often reduce respiratory efficiency, and benzodiazepines may actually improve respiratory status in some patients, especially in those with asthma or emphysema (“pink puffers”). Patients with severe bronchitis (“blue bloaters”), severe restrictive lung disease, and sleep apnea are the most vulnerable to the adverse effects of benzodiazepines. In elderly patients, shorter-acting benzodiazepines with no active metabolites, such as lorazepam and oxazepam, are preferred. While buspirone does not adversely affect pulmonary function, its limitations are its potency and delayed therapeutic effect. Antipsychotics are safer than benzodiazepines for treating acute anxiety in COPD, but rarely have caused laryngeal dystonia. Benzodiazepines should be avoided in obstructive sleep apnea. Zolpidem does not alter respiratory drive in COPD patients but may cause rebound insomnia. Selective serotonin reuptake inhibitors (SSRIs) may also be helpful in treating panic symptoms and do not have pulmonary side effects. b-blockers should not be used to treat anxiety in patients with reactive airway disease because of resulting bronchoconstriction.

When choosing an antidepressant, the side-effect profile and cytochrome P450 (CYP) interactions with pulmonary drugs should be considered. Antidepressants have little or no effect on respiratory function. Generally, SSRIs other than fluvoxamine have few drug interactions that are problematic in pulmonary patients. One exception is the antituberculosis drug rifampin. Rifampin is a CYP 3A4 substrate and may compete with many psychotropic drugs, including the antidepressants amitriptyline, imipramine, fluoxetine, sertraline, bupropion, venlafaxine, and trazodone. Rifampin may compete through the same site with anticonvulsants (eg, carbamazepine, tiagabine, and valproate) and with benzodiazepines, zolpidem, and haloperidol.

Most pulmonary medications do not affect lithium levels, but theophylline can lower lithium levels by 20% to 30%. Cholinesterase inhibitors should be prescribed cautiously in patients with asthma or COPD since acetylcholine is a potent mediator of bronchoconstriction. PP


1. Coffman K, Levenson JL. Lung disease. In: Levenson JL, ed. Essentials of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2007:35-54.

2. Katon WJ, Richardson L, Lozano P, McCauley E. The relationship of asthma and anxiety disorders. Psychosom Med. 2004;66(3):349-355.

3. Goodwin RD, Jacobi F, Thefeld W. Mental disorders and asthma in the community. Arch Gen Psychiatry. 2003;60(11):1125-1130.

4. Goodwin RD, Pine DS, Hoven CW. Asthma and panic attacks among youth in the community. J Asthma. 2003;40(2):139-145.

5. Russell L. Dental anxiety, dental health attitudes, and bodily symptoms as correlates of asthma symptoms in adult dental patients with asthma. J Dent Hyg. 2004;78(3):3.

6. Giardino ND, Schmaling KB, Afari N. Relationship satisfaction moderates the association between catastrophic cognitions and asthma symptoms. J Asthma. 2002;39(8):749-756.

7. Rietveld S, van Beest I, Everaerd W. Stress-induced breathlessness in asthma. Psychol Med. 1999;29(6):1359-1366.

8. Fagan J, Galea S, Ahern J, Bonner S, Vlahov D. Relationship of self-reported asthma severity and urgent health care utilization to psychological sequelae of the September 11, 2001 terrorist attacks on the World Trade Center among New York City area residents. Psychosom Med. 2003;65(6):993-996.

9. Krommydas GC, Gourgoulianis KI, Angelopoulos NV, Kotrotsiou E, Raftopoulos V, Molyvdas PA. Depression and pulmonary function in outpatients with asthma. Respir Med. 2004;98(3):220-224.

10. Opolski M, Wilson I. Asthma and depression: a pragmatic review of the literature and recommendations for future research. Clin Pract Epidemol Ment Health. 2005;1:18.

11. LeSon S, Gershwin ME. Risk factors for asthmatic patients requiring intubation. J Asthma. 1996;33(1):27-35.

12. Cluley S, Cochrane GM. Psychological disorder in asthma is associated with poor control and poor adherence to inhaled steroids. Respir Med. 2001;95(1):37-39.

13. ten Brinke A, Ouwerkerk ME, Zwinderman AH, Spinhoven P, Bel EH. Psychopathology in patients with severe asthma is associated with increased health care utilization. Am J Respir Crit Care Med. 2001;163(5):1093-1096.

14. Lavoie KL, Cartier A, Labrecque M, et al. Are psychiatric disorders associated with worse asthma control and quality of life in asthma patients? Respir Med. 2005;99(10):1249-1257.

15. Nickel C, Kettler C, Muehlbacher M, et al. Effect of progressive muscle relaxation in adolescent female bronchial asthma patients: a randomized, double-blind, controlled study. J Psychosom Res. 2005;59(6):393-398.

16. Nickel C, Lahmann C, Muehlbacher M, et al. Pregnant women with bronchial asthma benefit from progressive muscle relaxation: a randomized, prospective, controlled trial. Psychother Psychosom. 2006;75(4):237-243.

17. Yorke J, Fleming SL, Shuldham C. Psychological interventions for adults with asthma: a systematic review. Respir Med. 2007;101(1):1-14.

18. Bursch B, Stuber. Pediatrics. In: Levenson JL, ed. Essentials of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2007:375-404.

19. Richardson LP, Lozano P, Russo J, McCauley E, Bush T, Katon W. Asthma symptom burden: relationship to asthma severity and anxiety and depression symptoms. Pediatrics. 2006;118(3):1042-1051.

20. Kean EM, Kelsay K, Wamboldt F, et al. Posttraumatic stress in adolescents with asthma and their parents. J Am Acad Child Adolesc Psychiatry. 2006;45(1):78-86.

21. Katon WJ, Richardson L, Russo J, Lozano P, McCauley E. Quality of mental health care for youth with asthma and comorbid anxiety and depression. Med Care. 2006;44(12):1064-1072.

22. Yorke J, Shuldham C. Family therapy for chronic asthma in children. Cochrane Database Syst Rev. 2005;(2):CD000089.

23. Kashani JH, Barbero GJ, Wilfley DE, Morris DA, Shepperd JA. Psychological concomitants of cystic fibrosis in children and adolescents. Adolescence. 1988;23(92):873-880.

24. Szyndler JE, Towns SJ, van Asperen PP, McKay KO. Psychological and family functioning and quality of life in adolescents with cystic fibrosis. J Cyst Fibros. 2005;4(2):135-144.

25. Anderson DL, Flume PA, Hardy KK. Psychological functioning of adults with cystic fibrosis. Chest. 2001;119(4):1079-1084.

26. Pfeffer PE, Pfeffer JM, Hodson ME. The psychosocial and psychiatric side of cystic fibrosis in adolescents and adults. J Cyst Fibros. 2003;2(2):61-68.

27. Burker EJ, Sedway J, Carone S. Psychological and educational factors: better predictors of work status than FEV1 in adults with cystic fibrosis. Pediatr Pulmonol. 2004;38(5):413-418.

28. Di Marco F, Verga M, Reggente M, et al. Anxiety and depression in COPD patients: The roles of gender and disease severity. Respir Med. 2006;100(10):1767-1774.

29. Gudmundsson G, Gislason T, Janson C, et al. Risk factors for rehospitalisation in COPD: role of health status, anxiety and depression. Eur Respir J. 2005;26(3):414-419.

30. Stage KB, Middelboe T, Pisinger C. Depression and chronic obstructive pulmonary disease (COPD). Impact on survival. Acta Psychiatr Scand. 2005;111(4):320-323.

31. Brenes GA. Anxiety and chronic obstructive pulmonary disease: prevalence, impact, and treatment. Psychosom Med. 2003;65(6):963-970.

32. Rose C, Wallace L, Dickson R, et al. The most effective psychologically-based treatments to reduce anxiety and panic in patients with chronic obstructive pulmonary disease (COPD): a systematic review. Patient Educ Couns. 2002;47(4):311-318.

33. De Vries J, Drent M. Relationship between perceived stress and sarcoidosis in a Dutch patient population. Sarcoidosis Vasc Diffuse Lung Dis. 2004;21(1):57-63.

34. Klonoff EA, Kleinhenz ME. Psychological factors in sarcoidosis: the relationship between life stress and pulmonary function. Sarcoidosis. 1993;10(2):118-124.

Journal CMEs

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Current Approaches to the Treatment of Bipolar Disorder
With Atypical Antipsychotics

Eduard Vieta, MD, PhD

Needs Assessment: This article deals with the availability of novel therapies for the long-term treatment of bipolar disorder, and whether atypical antipsychotics have mood-stabilizing properties. Recent data suggest that atypical antipsychotics may play a role in the long-term management of bipolar illness, particularly when used in combination with other medications and psychoeducation.

Learning Objectives:

Recognize unmet needs in the treatment of bipoar disorder.


Discuss limitations of the currently available maintenance treatments for bipolar disorder.


Assess the use of atypical antipsychotics in the long-term treatment of bipolar disorder.


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 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: February 13, 2007.


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


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

Primary Psychiatry. 2007:14(3):70-76

Dr. Vieta is director of the Bipolar Disorders Program at the Hospital Clinic of the University of Barcelona and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) in Barcelona, Spain.


Disclosure: Dr. Vieta is a consultant to AstraZeneca, Bial, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck, Merck, Novartis, Organon, Otsuka, Pfizer, sanofi-aventis, Servier, and UCB Pharma; on the speaker’s bureaus of AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Otsuka, Pfizer, sanofi-aventis, and Servier; and receives grant support from AstraZeneca, Bial, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Otsuka, Pfizer, sanofi-aventis, Servier, the Spanish Ministry of Health, REM-TAP Network, and the Stanley Foundation.        


Please direct all correspondence to: Eduard Vieta, MD, PhD, Director, Bipolar Disorders Program, Hospital Clinic, University of Barcelona, IDIBAPS, Villarroel 170, 08036 Barcelona, Spain; Tel: 34-932-275-401;
Fax: 34-932-275-477; E-mail:



Bipolar disorder has an episodic and chronic nature that requires long-term treatment in all patients. There is an unmet need for well-tolerated and clinically effective maintenance therapy with enhanced patient adherence. Few well-tolerated treatment options are available that are effective in all phases of bipolar disorder and prevent episode recurrence. Lithium has established efficacy in the prevention of further manic episodes and may also be effective in the prevention of depression and suicide. Safety is a concern due to a narrow therapeutic window. For valproate and carbamazepine, data appear much less compelling. Lamotrigine has been shown to be effective for long-term prevention of depressive episodes, but is not effective in acute episodes. Controlled studies suggest that some atypical antipsychotics may also have mood-stabilizing properties and may become standard for long-term therapy. The role of psychoeducation in improving adherence to medication in long-term treatment and patient outcomes is also emphasized. 



Bipolar disorder is an episodic, chronic, and progressive illness that usually requires long-term treatment in most, if not all, patients.1-3 Although treatment may resolve symptoms during episodes, impaired functioning may persist for many patients.4,5 Maintenance therapy is necessary in order to maintain and develop initial success of treatment. Maintenance therapy aims to prevent relapses as well as reduce subthreshold symptoms, risk of suicide, cycle frequency, and mood instability.6 Long-term or even life-long therapy is usually required to improve functioning and maintain quality of life.


Identifying clinically effective maintenance therapy treatments for bipolar disorder has been a significant challenge. An ideal long-term treatment or mood stabilizer would effectively treat episodes of mania and depression as well as prevent relapses. In addition, such treatment should be well tolerated and have few side effects. In the absence of an ideal mood stabilizer, lithium has been the recommended treatment for maintenance therapy.7,8 Some randomized, controlled studies suggest that lithium, carbamazepine, divalproex, and lamotrigine may be clinically useful as maintenance treatment for bipolar disorder.2,9-11


Nevertheless, a substantial number of patients with bipolar disorder do not respond, suffer recurrence, or cannot tolerate side effects of these agents. Intolerance to side effects and inadequate long-term adherence to treatment potentially translates into poor treatment outcomes. Although few adequately designed long-term maintenance studies have been conducted, emerging data suggest that certain atypical antipsychotics may be effective in maintenance therapy for patients with bipolar disorder. Recent evidence for long-term therapies in bipolar disorder is reviewed in this article with particular emphasis on the long-term use of atypical antipsychotics.


Early research has shown that lithium is a standard choice for the long-term treatment of bipolar disorder. However, this research has been criticized due to methodological limitations. Moreover, naturalistic studies, which more closely approximate clinical practice, have shown less activity with lithium maintenance therapy.12 In addition, many bipolar disorder patients have some residual illness with lithium maintenance treatment as well as with other treatment modalities.13 Due to this effect, most patients are treated with combinations of several drugs. Clinicians also accept that abrupt withdrawal from lithium can induce a manic episode.


In addition to these limitations, some patient subsets are intolerant to lithium or are unable to achieve adequate efficacy and/or adherence at serum levels necessary for symptom remission.14 Results from a double-blind, prospective maintenance trial in which bipolar disorder patients were randomly assigned to therapy targeting either standard (0.8–1.0 mmol/L) or low (0.4–0.6 mmol/L) serum lithium levels, showed that higher serum lithium levels were associated with a higher rate of side effects and lower rate of adherence.14 A post-hoc re-analysis of the data—which accounted for baseline lithium levels—showed that patients with standard serum lithium levels at baseline who were randomized to the low range had the highest risk of recurrence.15


However, recent trials have provided further support to the long-term efficacy of lithium, including lamotrigine long-term studies. Furthermore, studies find that lithium may have specific anti-suicidal effects,16 which has only also been shown for clozapine in schizophrenia.17


Lamotrigine is an anticonvulsant with limited efficacy during acute episodes, no efficacy for mania, and some efficacy for depression. However, it has proven effectiveness in the long-term treatment of bipolar disorder.11 A main concern during lamotrigine treatment is emergence of skin rash. Two 18-month, randomized, double-blind trials compared lamotrigine, lithium, and placebo as maintenance treatment in a total of 1,315 recently manic or depressed patients with bipolar I disorder.11,18 Individual and combined study analyses showed that both lamotrigine and lithium significantly prolonged the time to intervention for any mood episode compared with placebo (Figure 1). Despite the enriched design for lamotrigine responders, lithium prevented manic episodes more effectively than lamotrigine and placebo.19 Lamotrigine was particularly efficacious in the prevention of depressive episodes, which is the primary use of the drug in bipolar disorder.


Only one randomized, placebo-controlled study has assessed divalproex in comparison with placebo for maintenance therapy in bipolar disorder patients.9 Divalproex, lithium, or placebo were given to 372 patients and time to relapse of any mood episode during the 1-year treatment period was determined. There was no significant difference between treatments (Figure 2), although a post-hoc analysis showed that patients who had already began divalproex prior to randomization and were receiving divalproex in the study had significantly fewer relapses than those receiving placebo.20


Prior studies of carbamazepine for the long-term treatment of bipolar disorder have shown the drug is not efficacious.21 Lithium (n=74) and carbamazepine (n=70) were compared in a randomized study of 144 bipolar disorder patients followed for 2.5 years.21 Patients treated with carbamazepine had significantly more recurrences and use of concomitant medication (P=.041) and/or adverse events (P=.007) compared with lithium.


In a smaller double-blind study, 52 bipolar disorder patients were randomly assigned to 1 year of treatment with lithium or carbamazepine, then treated with the opposite drug for 1 year, and additionally treated with a combination of the two drugs for 1 year.22 More patients treated with carbamazepine (37.1%) failed to complete the first full year of treatment due to lack of efficacy compared with those treated with lithium (31%). With the combination treatment, 24.1% of patients withdrew from the study due to lack of efficacy.


Another study randomized 94 patients in remission to double-blind treatment with lithium (n=44) or carbamazepine (n=50) for 2 years.23 The frequency of mood episodes and the proportion of patients exiting the study were higher with carbamazepine treatment than with lithium, with a completion rate of 32% and 36% respectively.


Nevertheless, data suggest that some efficacy in prevention of relapse and recurrence of manic or mixed episodes can be demonstrated for an extended-release formulation of carbamazepine.24 Patients (N=92) in a 3-week double-blind study of carbamazepine or placebo were assigned to 6 months of further open-label treatment with carbamazepine. The estimated mean time to relapse was 141.8 days, standard deviation (SD)=5.6 days, and 14.3% patients relapsed during the study. Patients who had previously received carbamazepine in the 3-week treatment period maintained their improvement and those who had received placebo demonstrated significant improvements in manic symptoms. The most common adverse events with carbamazepine were headache, dizziness, and rash. These results indicate that further studies to determine the role of carbamazepine in the long-term treatment of patients with bipolar disorder are warranted.


Atypical Antipsychotics as Maintenance Therapy


Due to their superior tolerability profile regarding extrapyramidal symptoms and tardive dyskinesia liability compared with conventional antipsychotics, atypical antipsychotics are increasingly being used for bipolar disorder treatment. Olanzapine, quetiapine, risperidone, ziprasidone, and aripiprazole have demonstrated efficacy in the treatment of bipolar mania in 3-week studies as monotherapy.25 When used in combination with lithium, divalproex, and other traditional mood stabilizers, olanzapine, risperidone, and quetiapine also proved to be more efficacious than lithium or valproate monotherapy.25 Evidence also suggests that some atypical antipsychotics are effective in the treatment of bipolar depression.26,27 Data indicating the efficacy in long-term treatment of bipolar disorder for each of these agents are reviewed in this article.




Several studies have addressed the efficacy of olanzapine as long-term therapy in bipolar disorder.28-30 Data from a study in which a 6–12-week phase of open-label olanzapine and lithium combination therapy was followed by 52 weeks of double-blind olanzapine or lithium monotherapy found that the prevention of depressive relapse—which was indicated by maintaining a 21-item Hamilton Rating Scale for Depression (HAM-D)21 score of £15—was quite similar with both agents. However, in the study, olanzapine was superior to lithium (P<.001) in reducing the incidence of manic relapse, which was indicated by an increase in Young Mania Rating Scale (YMRS) scores to ≥15.30


The efficacy of olanzapine in manic and depressive episodes and maintenance of remission has also been corroborated in a comparative study against divalproex.28 In this investigation, 251 adult patients with a bipolar I disorder, manic or mixed, according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), criteria were randomly assigned to olanzapine (5–20 mg/day) or divalproex (500–2,500 mg/day) during a 3-week, randomized, double-blind phase followed by a double-blind continuation phase of 44 weeks.28


Olanzapine was significantly superior to divalproex in mean improvement in YMRS total scores from baseline to endpoint (last observation carried forward to week 47; P=.03). A numerical but not significant difference was also observed in mean improvement of HAM-D21 scores in all patients and in those with moderate-to-severe depressive symptoms (HAM-D21 20 at baseline).28 The median time to symptomatic remission of mania (YMRS £12) was significantly shorter for olanzapine (14 days) than for divalproex (62 days) (P=.05),28 although there was no significant difference between groups in mania remission rates and subsequent relapse into mania or depression. Treatment with olanzapine was associated with somnolence, increased appetite, and weight gain more frequently (P<.05) than divalproex.28


In another study, bipolar disorder patients who had previously received open-label treatment with olanzapine, were randomized to double-blind treatment for up to 52 weeks. Olanzapine was shown to be associated with lower rates of relapse and a longer time to relapse compared with placebo (P<.001).31


Olanzapine added to lithium or valproate has been evaluated in an 18-month study for prevention of relapse.29 Patients achieving syndromic remission after 6 weeks of treatment with olanzapine and lithium or valproate were randomized to further treatment with olanzapine (n=51) or placebo (n=48) in addition to lithium or valproate. At the end of the treatment period, symptomatic (using the total score on the YMRS and HAM-D21) but not syndromic relapse (meeting DSM-IV criteria for a manic, mixed, or depressive episode), was significantly different in patients treated with olanzapine and lithium or valproate compared with the group treated with placebo and lithium or valproate (P=.023).


Concerns raised by olanzapine as a long-term therapy for bipolar patients are related to weight gain and metabolic syndrome.


Quetiapine monotherapy has been shown to be superior to placebo in the improvement of mania and associated symptoms as well as the maintenance of response and remission rates in two double-blind, 3-month studies of bipolar disorder patients.32,33 In one study, patients were randomized to quetiapine (n=107), lithium (n=98), or placebo (n=95). Both quetiapine and lithium decreased YMRS scores significantly more than placebo at 3 weeks (P<.001) and this difference was maintained to week 12 (P<.001).32 Another study found a similar improvement in YMRS scores in patients treated with quetiapine or haloperidol versus placebo. The response (≥50% reduction in YMRS scores) and remission (YMRS £12) rates in the quetiapine-treated group were significantly greater than placebo at week 3 and week 12. Haloperidol was more efficacious than quetiapine at week 3, but not at week 12.33 A combined analysis of these two studies indicated that the majority of patients who responded by week 3 maintained their response through the end of the 3-month study period. Of the proportion of patients who did not respond by week 3 and who had a further assessment, 72% of quetiapine-treated versus 41% of placebo-treated patients responded by the end of the study. Similarly, remission rates in the quetiapine group were maintained to the end of treatment. Compared with placebo, a significantly greater proportion of patients in the quetiapine group met all clinical remission/euthymia criteria (YMRS £12 or YMRS £2 + MADRS £10 or YMRS £12 + Montgomery-Asberg Depression Rating Scale [MADRS] £8) by the primary endpoint (day 21; P<.01) and rates of remission/euthymia continued to improve to the end of the 3-month treatment period (P<.001).34 The results from these controlled studies show that the early treatment effect of quetiapine was maintained over a period of 3 months in patients with bipolar mania, but no controlled trials are available for quetiapine beyond 3-month follow-up.


Quetiapine has also been shown to have benefits as long-term therapy in two prospective, open-label studies of patients with rapid cycling.35,36 One study assessed 14 patients with rapid cycling, according to DSM-IV criteria (manic, hypomanic, mixed, depressive, or euthymic), treated with quetiapine, which was initiated at 50 mg/day and dosed according to tolerability and clinical response in combination with ongoing psychotropic medication for 112 days (SD=33 days).35 The Clinical Global Impressions for Bipolar Disorder (CGI-BP), YMRS, and HAM-D17 rating scales were included in efficacy assessments (Figure 3).

Although controlled maintenance studies are necessary, findings from these naturalistic, open-label investigations suggest that quetiapine may be clinically effective in the long-term treatment of rapid-cycling bipolar disorder. The main safety and tolerability concerns with the drug are related to sedation and weight gain liability.


No controlled trials are available with risperidone beyond 12 weeks. A 6-month, open-label study suggests that monotherapy or combination therapy with risperidone may maintain the improvement of manic and depressive symptoms in patients with bipolar disorder over time.37 Forty-four patients who met DSM-IV criteria for bipolar II with a current hypomanic episode and a YMRS score >7 showed a significant reduction from baseline in YMRS score (P<.001) by the first week of risperidone treatment (Figure 4).37 This improvement in manic symptoms was maintained throughout the 6-month study period. There was no significant difference in the rate of improvement between patients receiving combination therapy or monotherapy with risperidone.37 Seventy-three percent of patients found a 50% reduction in YMRS scores from baseline and were considered responders. Risperidone treatment also significantly reduced HAM-D17 scores by week 1 (P<.001) and until the end of the 6-month treatment period (P<.001).37

Study data were included in an analysis involving patients with different index episodes, including manic, hypomanic, mixed, or depressive episodes, as well as those with schizoaffective disorder, bipolar type.38 In this heterogeneous sample (n=541), significant reductions in mean YMRS score occurred by week 1 and continued for 6 months (P£.001 versus baseline) for all groups except patients with depression (P<.05 versus baseline).38 Risperidone, either in combination with mood stabilizers or as monotherapy, was well tolerated in bipolar II patients with little evidence of tardive dyskinesia or extrapyramidal symptoms related adverse events emerging over a 6-month period.37 Double-blind controlled studies in patients with bipolar disorder are needed to confirm the findings from these open-label studies. Safety and tolerability concerns about risperidone in bipolar disorder included EPS liability, hyperprolactinemia, and weight gain.


There is evidence that suggests clozapine is effective against mood and psychotic symptoms in patients with schizoaffective disorder, bipolar type, and bipolar I disorder. In addition, results from an open study in patients (n=38) who met DSM-IV criteria for treatment-resistant schizoaffective or bipolar disorder suggest that clozapine may have utility as maintenance treatment.39 Patients in this study were randomly assigned to clozapine add-on treatment or treatment without clozapine and evaluated for 1 year. The CGI, HAM-D24, Brief Psychiatric Rating Scale (BPRS), and Bech-Rafaelsen Mania scales were included in the monthly assessments.39


Significant advantages across all measures, except the HAM-D24, were observed with clozapine versus treatment as usual.39 In particular, clozapine was a strong anti-manic and anti-mood lability agent. The decrease in the mean rate of change in BPRS score over 1 year or until last visit in the clozapine group revealed significant improvement, whereas there was worsening in the treatment-as-usual group (-3.68% versus 2.51% respectively; P=.001). Sixty-five percent of patients taking clozapine met the criteria for response—30% improvement in BPRS from baseline—by 3 months and 82% by 6 months.


Patients who were switched from treatment-as-usual to clozapine also benefitted. The nine patients (seven with bipolar I disorder) who had clozapine substituted for treatment-as-usual showed significant improvement in BPRS score (P<.05) over 1 year compared with scores at the termination of usual treatment.39 Overall, findings suggest that clozapine may have a role for bipolar disorder patients who do not respond to standard treatments but this should be confirmed in larger controlled studies. The safety profile of clozapine appeared to be worse than other atypical antipsychotics with side effects noted throughout the study.39 Somatic complaints increased relative to baseline in clozapine-treated patients and were more severe than in the treatment-as-usual group. No patient developed agranulocytosis but this side effect is a known concern in the use of clozapine,40 besides weight gain and metabolic effects.


One randomized, double-blind study has compared aripiprazole versus placebo in the maintenance treatment of bipolar disorder patients.41 Patients (n=161) who had recently experienced a manic episode or who had just completed an aripiprazole acute mania study were assigned to aripiprazole or placebo for 26 weeks. Time to relapse of symptoms and total number of relapses (P=.013) significantly decreased in patients treated with aripiprazole versus those treated with placebo. No effect was seen in prevention of depression or mixed episodes. Adverse events >10% in the aripiprazole group included anxiety, insomnia, depression, and nervousness.


There is little evidence on the use of amisulpride in bipolar disorder,42 and even less on its long-term use. Carta and colleagues43 reported an open-label study suggesting effective long-term prevention of mania with amisulpride.


Role of Psychoeducation in Long-Term Treatment


Concomitant psychosocial intervention during bipolar maintenance treatment is increasingly recognized as an important tool to enhance treatment adherence and other aspects of illness management.6 Supporting benefits of psychoeducation in the maintenance setting are findings from a study of bipolar I and II outpatients who were all receiving a standard pharmacologic treatment that showed concomitant group psychoeducation produces significantly more stable lithium levels over time (P£.05 at 6, 16, and 24 months) than nonstructured group meetings.44 Stable lithium levels most likely reflect enhanced long-term adherence to treatment.


Furthermore, intervention with psychoeducation translated into improved outcomes in a study that consisted of a 21-week, single-blind, randomized treatment phase and 2-year follow-up (Figure 5).45 At the follow-up period end, group psychoeducation significantly reduced the number of relapsed patients (P<.001 psychoeducation versus control) and increased the time to any recurrence (P<.001) including depressive (HAM-D17 ≥17), mixed (YMRS ≥20; HAM-D17 ≥12), and manic (YMRS ≥20) or hypomanic (YMRS ≥12) episodes.45 The number and length of hospitalizations per patient were also lower in those who received psychoeducation (P<.05). Despite the benefits of psychoeducation, however, >50% of patients receiving group psychoeducation and standard pharmacologic treatment had relapsed by the end of the 2-year follow-up period.


The treatment of patients with bipolar disorder remains a challenge for clinicians. Effective therapeutic approaches are required for the management of acute and chronic symptoms as well as prophylaxis against future episodes. In addition to lithium and certain anticonvulsants, atypical antipsychotics have shown promising results in bipolar disorder maintenance therapy but concerns about weight gain and metabolic syndrome are increasing. Strategies, such as psychoeducation in combination with effective drug therapy, may also improve bipolar disorder maintenance therapy. In the future, supplementary interventions, such as cognitive rehabilitation, may help reduce the gap between symptomatic recovery and functional recovery. PP


1. Mendlewicz J, Souery D, Rivelli SK. Short-term and long-term treatment for bipolar patients: beyond the guidelines. J Affect Disord. 1999;55(1):79-85.


2. Bowden CL, Lecrubier Y, Bauer M, et al. Maintenance therapies for classic and other forms of bipolar disorder. J Affect Disord. 2000;59(suppl 1):S57-S67.


3. Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59(6):530-537.


4. Tohen M, Jacobs TG, Feldman PD. Onset of action of antipsychotics in the treatment of mania. Bipolar Disord. 2000;2(3 pt. 2):261-268.


5. Martinez-Aran A, Vieta E, Colom F, et al. Cognitive impairment in euthymic bipolar patients: implications for clinical and functional outcome. Bipolar Disord. 2004:6(3):224-232.


6. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 159(4 suppl):1-50.


7. Sachs GS, Printz DJ, Kahn DA, Carpenter D, Docherty JP. The Expert Consensus Guideline Series: Medication Treatment of Bipolar Disorder 2000. Postgrad Med. 2000;(special issue):1-104.


8. Goodwin GM, Geddes JR. Latest maintenance data on lithium in bipolar disorder. Eur Neuropsychopharmacol. 13(suppl 2):S51-S55.


9. Bowden CL, Calabrese JR, McElroy SL, et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Arch Gen Psychiatry. 2000;57(5):481-489.


10. Keck PE Jr, McElroy SL. Carbamazepine and valproate in the maintenance treatment of bipolar disorder. J Clin Psychiatry. 2002;63(suppl 10):13-17.


11. Calabrese JR, Vieta E, Shelton MD. Latest maintenance data on lamotrigine in bipolar disorder. Eur Neuropsychopharmacol. 2003;13(suppl 2):S57-S66.


12. Rybakowski JK, Cholpocka-Wozniak M, Suwalska A. The prophylactic effect of long-term lithium administration in bipolar patients entering treatment in the 1970s and 1980s. Bipolar Disord. 2001;3(2):63-67.


13. Baldessarini RJ, Tondo L. Does lithium treatment still work? Evidence of stable responses over three decades. Arch Gen Psychiatry. 2000;57(2):187-190.


14. Gelenberg AJ, Kane JM, Keller MB, et al. Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. N Engl J Med. 1989;321(22):1489-1493.


15. Sachs GS, Thase ME. Bipolar disorder therapeutics: maintenance treatment. Biol Psychiatry. 2000;48(6):573-581.


16. Gonzalez-Pinto A, Mosquera F, Alonso M, et al. Suicidal risk in bipolar I disorder patients and adherence to long-term lithium treatment. Bipolar Disord. 2006;8(5 pt. 2):618-624.


17. Meltzer HY, Alphs L, Green AI, et al, and the International Suicide Prevention Trial Study Group. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003;60(1):82-91.


18. Bowden CL, Calabrese JR, Sachs G, et al, and the Lamictal 606 Study Group. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry. 2003;60(4):392-400.


19. Goodwin GM, Bowden CL, Calabrese JR, et al. A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. J Clin Psychiatry. 2004;65(3):432-441.


20. Gyulai L, Bowden CL, McElroy SL, et al. Maintenance efficacy of divalproex in the prevention of bipolar depression. Neuropsychopharmacology. 2003;28(7):1374-1382.


21. Greil W, Ludwig-Mayerhofer W, Erazo N, et al. Lithium versus carbamazepine in the maintenance treatment of bipolar disorders–a randomised study. J Affect Disord. 1997;43(2):151-161.


22. Denicoff KD, Smith-Jackson EE, Disney ER, Ali SO, Leverich GS, Post RM. Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder. J Clin Psychiatry. 1997;58(11):470-478.


23. Hartong EG, Moleman P, Hoogduin CA, Broekman TG, Nolen WA, and the LitCar Group. Prophylactic efficacy of lithium versus carbamazepine in treatment-naive bipolar patients. J Clin Psychiatry. 2003;64(2):144-151.


24. Ketter TA, Kalali AH, Weisler RH, and the SPD417 Study Group. A 6-month, multicenter, open-label evaluation of beaded, extended-release carbamazepine capsule monotherapy in bipolar disorder patients with manic or mixed episodes. J Clin Psychiatry. 2004;65(5):668-673.


25. Vieta E, Goikolea JM. Atypical antipsychotics: newer options for mania and maintenance therapy. Bipolar Disord. 2005;7(suppl 4):21-33.              


26. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60(11):1079-1088.


27. Calabrese JR, Keck PE, Jr, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162(7):1351-1360.


28. Tohen M, Ketter TA, Zarate CA, et al. Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: a 47-week study. Am J Psychiatry. 2003;160(7):1263-1271.


29. Tohen M, Chengappa KN, Suppes T, et al. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. Br J Psychiatry. 2004;184:337-345.


30. Tohen M, Greil W, Calabrese JR, et al. Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomized, double-blind, controlled clinical trial. Am J Psychiatry. 2005;162(7):1281-1290.


31. Tohen M, Bowden C, Calabrese J, et al. Olanzapine’s efficacy for relapse prevention in bipolar disorder: a randomized double-blind placebo-controlled 12-month clinical trial. Eur Neuropsychopharmacol. 2003;13(suppl 4):S212.


32. Bowden CL, Grunze H, Mullen J, et al. A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. J Clin Psychiatry. 2005;66(1):111-121.


33. McIntyre RS, Brecher M, Paulsson B, Huizar K, Mullen J. Quetiapine or haloperidol as monotherapy for bipolar mania–a 12-week, double-blind, randomised, parallel-group, placebo-controlled trial. Eur Neuropsychopharmacol. 2005;15(5):573-585.


34. Vieta E, Mullen J, Brecher M, Paulsson B, Jones M. Quetiapine monotherapy for mania associated with bipolar disorder: combined analysis of two international, double-blind, randomised, placebo-controlled studies. Curr Med Res Opin. 2005;21(6):923-934.


35. Vieta E, Parramon G, Padrell E, et al. Quetiapine in the treatment of rapid cycling bipolar disorder. Bipolar Disord. 2002;4(5):335-340.


36. Ghaemi SN, Goldberg JF, Henry CA, et al. Quetiapine for rapid-cycling bipolar disorder: a long-term follow-up study. Bipolar Disord. 2003;5(suppl 1):50.           


37. Vieta E, Gasto C, Colom F, et al. Role of risperidone in bipolar II: an open 6-month study. J Affect Disord. 2001;67(1-3):213-219.     


38. Vieta E, Goikola JM, Corbella B, et al, and the Group for the Study of Risperidone in Affective Disorders (GSRAD). Risperidone safety and efficacy in the treatment of bipolar and schizoaffective disorders: results from a 6-month, multicenter, open study. J Clin Psychiatry. 2001;62(10):818-825.


39. Suppes T, Webb A, Paul B, Carmody T, Kraemer H, Rush AJ. Clinical outcome in a randomized 1-year trial of clozapine versus treatment as usual for patients with treatment-resistant illness and a history of mania. Am J Psychiatry. 1999;156(8):1164-1169.   


40. Ertugrul A, Meltzer HY. Antipsychotic drugs in bipolar disorder. Int J Neuropsychopharmacol. 2003;6(3):277-284.


41. Keck PE Jr, Calabrese JR, McQuade RD, et al, and the Aripiprazole Study Group. A randomized, double-blind, placebo-controlled 26-week trial of aripiprazole in recently manic patients with bipolar I disorder. J Clin Psychiatry. 2006;67(4):626-637.


42. Vieta E, Ros S, Goikolea JM, et al. An open-label study of amisulpride in the treatment of mania. J Clin Psychiatry. 2005;66(5):575-578.


43. Carta MG, Zairo F, Mellino G, Hardoy MC, Vieta E. An open label follow-up study on amisulpride in the add-on treatment of bipolar I patients. Clin Pract Epidemol Ment Health. 2006;2:19.                


44. Colom F, Vieta E, Reinares M, Martinez-Aran A, Sanchez-Moreno J, Torrent C. Group psychoeducation enhances serum lithium levels stability. Bipolar Disord. 2003;5(suppl 1):40-41.         


45. Colom F, Vieta E, Martinez-Aran A, et al. A randomized trial on the efficacy of group psychoeducation in the prophylaxis of recurrences in bipolar patients whose disease is in remission. Arch Gen Psychiatry. 2003;60(4):402-407.


Journal CMEs

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David L. Dunner, MD, FACPsych

Needs Assessment: Various strategies are used to address the treatment of unresolved symptoms of depression. A vigorous approach to management of unresolved symptoms may help clinicians and patients overcome treatment-resistant depression. This literature review describes the efficacy of venlafaxine, an agent with one of the largest evidence bases of studies in patients with unresolved symptoms of depression following initial antidepressant treatment.


Learning Objectives:
Describe treatment-resistant depression (TRD) and its clinical implications.

Discuss evidence for the efficacy of venlafaxine in the treatment of unresolved symptoms of depression following adequate antidepressant therapy.

Explain the implications of these data for achieving remission in patients with TRD.


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 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: February 13, 2007.


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


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

Primary Psychiatry. 2007:14(3):39-49

Dr. Dunner is director of the Center for Anxiety and Depression in Mercer Island, Washington, and professor emeritus in the Department of Psychiatry and Behavioral Sciences at the University of Washington in Seattle.


Disclosure: Dr. Dunner is a consultant to Bristol-Myers Squibb, Corcept, Cypress, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Otsuka, Pfizer, Roche Diagnostics, Shire, Somerset, and Wyeth; is on the speaker’s bureaus of Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Organon, Pfizer, and Wyeth; and receives grant support from Cyberonics, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Pfizer, and Wyeth.


Acknowledgments: Dr. Dunner would like to thank Trish Bakos, MS, RD, Lorraine M. Sweeney, and Jennifer B. Hutcheson, of Medesta Publications, for their writing and editorial assistance.


Please direct all correspondence to: David L. Dunner, MD, FACPsych, Director, Center for Anxiety and Depression, 7525 SE 24th St, Suite 400, Mercer Island, WA 98040; Tel: 206-230-0330; Fax: 206-230-0336; E-mail:


Although remission has been the universally accepted goal of antidepressant therapy for several years, recent data have shown that >70% of patients do not achieve remission. Treatment-resistant depression (TRD) is characterized by a lack of or partial response to therapy in which there is an improvement in depressive symptoms but remission is not achieved and residual symptoms still remain. Inadequate treatment is at least partially to blame for the prevalence of TRD, with many patients switching medications continuously within the same class while never achieving full remission. Various strategies are used in clinical practice to address treatment of unresolved symptoms of depression, but few have been tested extensively in the context of well-designed clinical studies. Venlafaxine is a serotonin norepinephrine reuptake inhibitor that is often used following failure of selective serotonin reuptake inhibitors. This article reviews research on the efficacy of switching patients whose symptoms of depression persist, despite receiving treatment with antidepressant medication, to venlafaxine as an alternative therapy. A Medline search of published studies was conducted and additional unpublished studies were identified via a review of abstracts from psychiatric congresses and those provided by the sponsor of venlafaxine. A total of 14 clinical studies including >5,000 patients were identified, which collectively represent one of the largest evidence bases of studies in patients with TRD. Taken as a whole, the data are consistent with and support the use of venlafaxine in clinical practice as a common switch agent following initial antidepressant failure. 



Depression is a common but serious condition associated with substantial morbidity. As dictated by the American Psychiatric Association guidelines,1 the ultimate goal for treatment in patients suffering from a depressive disorder is complete remission of symptoms.


A three-phase model of treatment for depression, introduced by Kupfer2 more than a decade ago, recommended a thorough and continuous course of pharmacotherapy. Treatment begins with the acute phase and the primary goal is to achieve a response through medication or psychotherapy, eventually culminating in remission.2 A response is generally identified as significant improvement in depressive symptoms, ie, a ≥50% reduction in baseline symptom severity, although residual symptoms may still be present.1 It is estimated that approximately 50% of outpatients with nonpsychotic major depressive disorder (MDD) in efficacy trials respond to treatment with one antidepressant.3-7


Remission is clinically characterized by full restoration of normal capacity for psychosocial and occupational function.1 The commonly employed depression screening measures quantify remission in similar manners and include a 17-item Hamilton Rating Scale for Depression (HAM-D17) score of ≤7; a 9-item Patient Health Questionnaire (PHQ-9) score of ≤5; a Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR) score ≤5; and a Montgomery-Asberg Depression Rating Scale (MADRS) score ≤12.8-11 Remission rates for different antidepressant classes were recently examined in a meta-analysis of 15 head-to-head randomized control trials. Remission rates, as assessed by a HAM-D17 score ≤7 or MADRS score ≤12, were 49% for serotonin norepinephrine reuptake inhibitors (SNRIs), 44.1% for tricyclic antidepressants (TCAs), and 37.7% for selective serotonin reuptake inhibitors (SSRIs), based on intent-to-treat data of 2,458 patients with MDD treated for ≥6 weeks.12 However, it is important to note that not all studies in the meta-analysis included a placebo control. Remission rates in placebo-controlled studies may be lower.


The acute phase of treatment generally lasts 6–12 weeks.13 If a patient’s symptoms improve during this phase but do not return to normal functional levels, the course of therapy should be reevaluated and modified.1 The continuation phase of treatment begins after remission has been achieved and physical and emotional functions have been restored. The main goal is to prevent relapse, defined as a return of depressive symptoms.2 The minimum recommended duration of treatment in the continuation phase is 4–5 months.2,13 The maintenance phase of treatment is the long-term management of the depressive disorder. The goal of this phase is to prevent a recurrence,1 which is characterized by a return of depressive symptoms after recovery.2 The maintenance phase of treatment may be carried out indefinitely, depending on an individual’s risk of recurrence.1


Remission as Protection Against Relapse/Recurrence


Considering the chronic and progressive nature of depression, achieving remission is crucial for predicting future outcomes in the severity of the disease or in the emergence of new depressive episodes. Current data predict a >50% probability that an individual who has suffered one episode of depression will suffer from a second episode.14 Those with unresolved symptoms following the first episode are particularly at risk for a recurrence.14 With each successive episode, the risk for recurrence progressively increases such that an individual with a history of ≥3 episodes has a likelihood of recurrence within 5 years of approximately 80%.2 Specifically, the risks of not achieving and sustaining remission include a greater risk of relapse or recurrence, more chronic depressive episodes, and a shorter duration between depressive episodes.14-16 These increasingly frequent and severe episodes of depression translate into continued impairment at work16,17 and in relationships.18 In addition, patients failing to achieve remission may be at continued risk for increased morbidity and mortality with many other general medical conditions, such as cardiovascular disease.19 Residual symptoms of depression are also associated with a greater risk of suicide.20

Treatment-Resistant Depression

Treatment-resistant depression (TRD) is a chronic and progressive disease state that presents a significant problem for patients and clinicians. TRD is characterized by a nonresponse to therapy or a partial response to therapy in which depressive symptoms lessen in severity but still remain. In other words, TRD is characterized by the absence of remission despite treatment for depressive symptoms.21 The clinical course of TRD can be staged according to prior treatment history, as proposed by Thase and Rush.22 The 5-stage system is ordered sequentially as follows. Stage 1 includes failure of at least one adequate trial (ie, based on therapeutic dose and treatment duration) of one major class of antidepressants. Stage 2 involves failure of at least two adequate trials of at least two distinctly different classes of antidepressant. Stage 3 includes Stage-2 resistance plus failure of an adequate trial of a TCA or monoamine oxidase inhibitor (MAOI). Stage 4 involves Stage-3 resistance plus failure of an adequate trial of an MAOI and a TCA. In Stage 5, there is Stage-4 resistance plus failure of a course of bilateral electroconvulsive therapy (ECT).


As TRD is directly related to the absence of achieved remission, similar outcomes are observed in trials with TRD patients as are seen in those with residual symptoms after treatment. For example, in an analysis by Greenberg and colleagues,23 employees diagnosed with likely TRD used more than twice as many medical services as non-TRD employees. Dunner and colleagues24 also found high healthcare utilization, persistence of symptoms, and poor psychosocial outcomes in a group of severely treatment-resistant patients who were followed for 2 years.


Treatment Considerations


Although the implications of TRD are significant and apparent, the phenomenon remains common in both clinical research and clinical practice. In fact, in the recently published Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, >66% of patients did not achieve remission following first-line treatment with an SSRI with an adequate dose for an adequate duration of therapy (Figure).25


If a patient does not demonstrate adequate response with a particular antidepressant after 12 weeks of therapy at the initial dose or after 3–4 additional weeks at the maximum dose, therapy should be adjusted by either treatment substitution using another antidepressant, adding another antidepressant to the current therapy (ie, combination therapy), or adding another compound to the therapy for augmentation.1,26 When considering treatment substitution using another antidepressant, it is important to note that the data are inconclusive as to whether an in-class alternative (eg, from one SSRI to another SSRI) is as effective as choosing an agent from another antidepressant class. Intuitively, one would assume that choosing an antidepressant with a mechanism of action different from that of the failed therapy is likely to be the most successful option (eg, from an SSRI to an SNRI). Supporting this point, Thase and colleagues27 conducted a double-blind switch study in patients with chronic MDD who failed to respond to 12 weeks of either sertraline or imipramine therapy. The patients were given the alternative agent (ie, either sertraline or imipramine) and >50% of the nonresponders benefited from the switch, despite the chronicity of their conditions.


Unfortunately, relatively few rigorously designed studies have been conducted of either within-class or across-class switching. Furthermore, in the current literature there is considerable variability in the criteria used to define treatment response and remission, and particularly in the criteria used to define TRD. Thus, definitive conclusions and comparisons across studies are limited. There is no single or standard definition of TRD that is uniformly used in the literature. Some investigators have defined TRD according to stringent criteria, such as the failure to respond to at least three adequate trials of antidepressants from at least two different classes or ECT, plus at least one attempt at augmentation.28 Less restrictive criteria has also been proposed by Fava and colleagues29 who defined treatment resistance as the absence of sustained remission, according to depressive symptom severity or daily function, to one or more previous antidepressant treatments of adequate dose and duration. The current literature review focuses specifically on the efficacy of venlafaxine, an agent with arguably one of the largest evidence bases of studies in patients with unresolved symptoms of depression following initial antidepressant treatment.


Literature Review


A MEDLINE search was performed to include all studies in which patients with a diagnosis of depression with unresolved symptoms following antidepressant therapy were switched to venlafaxine therapy. The studies included in the review encompassed data in patients with prior partial response, nonresponse, or poor tolerance to antidepressant treatment. Also included were unpublished studies identified via a review of abstracts from psychiatric congresses. Remaining unpublished studies were made available via a request to Wyeth Research. In all, 14 studies were reviewed, including >5,000 patients (Tables 1 and 2).28,30-42 The studies that are reviewed are subsequently ordered according to official evidence-based medicine categories, with studies featuring the most robust data appearing first.




Randomized Comparative Studies


STAR*D: Treatment of Depression in SSRI Nonresponders


STAR*D is the largest prospective study to evaluate a series of sequential treatment strategies for various degrees of TRD.29 This landmark trial evaluated “real-world” patients and outcomes relevant to clinical practice. In contrast to a traditional clinical trial, STAR*D enrolled a broad spectrum of self-declared depressed patients representative of clinical practice, compared active treatments rather than active treatment against placebo, and focused on real-world outcomes such as measures of functioning. In addition, the design included open treatment with a novel randomization process that allowed patients to refuse certain treatment strategies, but required randomization to an individual treatment option within a chosen strategy. During Level 1, all patients received the SSRI citalopram. Patients who did not remit were eligible to enter Level 2, in which they agreed to either an augmentation or switch strategy and were then randomized to a specific treatment option. Patients not in remission by the end of Level 2 were eligible to proceed to subsequent levels. Results of the Level 2 switch and augmentation studies are reported by Rush and colleagues30 and Trivedi and colleagues,43 respectively.


STAR*D: Switching to Bupropion SR, Sertraline, or Venlafaxine ER After Failure of SSRIs for Depression


In the STAR*D Level 2 switch study by Rush and colleagues,30 patients with nonpsychotic MDD (n=727) who failed on citalopram due to intolerability or lack of efficacy were randomized to bupropion sustained-release (SR), sertraline, or venlafaxine extended release (ER) for up to 12 weeks. The primary outcome was symptom remission, as defined by a total score of ≤7 on the HAM-D17. Secondary outcomes included remission and response as determined by the QIDS-SR16 (as determined by a score of ≤5 at exit and a reduction of ≥50% on baseline scores, respectively). Remission rates as measured by the HAM-D17 and QIDS-SR16, respectively, were 24.8% and 25.0% for venlafaxine ER, 21.3% and 25.5% for bupropion SR, and 17.6% and 26.6% for sertraline. No statistically significant differences were observed among treatment groups. This investigation found that approximately one in four patients achieved remission after switching to another antidepressant following treatment failure with an SSRI. Although the study is limited by the lack of placebo control and by the unblinded delivery of treatment, the results have important practical implications. The remission rates were clinically meaningful and the findings suggest overall that both within-class and out-of-class medication switches are reasonable second-step options for the treatment of depression.


STAR*D: Augmentation with Bupropion SR or Buspirone After Failure of SSRIs for Depression


In the STAR*D Level 2 augmentation study by Trivedi and colleagues,43 patients with nonpsychotic MDD (n=565) who failed on citalopram due to intolerability or lack of efficacy were randomized to receive augmentation with either bupropion SR or buspirone for up to 12 weeks.30 The primary outcome was symptom remission, as defined by a total score of ≤7 on the HAM-D17. Secondary outcomes included remission and response as determined by the QIDS-SR16 (as determined by a score of ≤5 at exit and a reduction of ≥50% on baseline scores, respectively). Remission rates as measured by the HAM-D17 and QIDS-SR16, respectively, were 29.7% and 39.0% for bupropion SR and 30.1% and 32.9% for buspirone. Compared with buspirone, bupropion SR was associated with a greater reduction in QIDS-SR16 scores (P<.04), a lower QIDS-SR16 score at endpoint (P<.02), and fewer withdrawals due to intolerance (P<.009).30 The results suggest that augmentation of SSRIs with either bupropion SR or buspirone produces similar rates of symptom remission in patients who do not adequately benefit from SSRI monotherapy. There is evidence that augmentation of citalopram with bupropion SR had some significant therapeutic advantages over buspirone augmentation. Similar to the STAR*D switch study, this trial is limited by the lack of placebo control and unblinded treatment. However, the results have important practical implications because of the “real-world” design.


A Double-Blind Trial of Venlafaxine ER Versus Citalopram in Patients with Severe Depression


Lenox-Smith and colleagues31 conducted a 12-week, randomized, double-blind, controlled study comparing venlafaxine ER (75–300 mg/day) and citalopram (20–60 mg/day) in 404 patients who did not respond to 8 weeks of monotherapy with an SSRI (other than citalopram). In patients with baseline HAM-D total scores >30, venlafaxine ER demonstrated significant improvement over citalopram in HAM-D total score and Clinical Global Impression–Severity (CGI-S) scale at week 12 (P<.05). The study suggests that flexible doses of venlafaxine ER or citalopram were effective and well tolerated in patients with TRD. Venlafaxine ER demonstrated some evidence of improved efficacy when compared with citalopram for treating patients who were still severely depressed following an adequate treatment course with an SSRI. Additional studies are warranted, particularly long-term, placebo-controlled, comparative trials in patients with prospectively defined TRD.


Venlafaxine and Paroxetine in TRD:
Double-Blind, Randomized Comparison


Poirier and Boyer32 conducted a 4-week, randomized, double-blind, controlled study comparing venlafaxine ER (75–300 mg/day) with paroxetine (20–40 mg/day) in 122 antidepressant nonresponders. Patients had a history of resistance to two previous successive antidepressant treatments for the current depressive episode. The first treatment was for ≥4 weeks at an effective dose and the second treatment was prescribed by the investigators at an effective dose for ≥4 weeks prior to baseline of the current study. The researchers observed a significant difference in favor of venlafaxine ER for HAM-D17 remission (score ≤10) (37% versus 18%; P=.02) and HAM-D17 response (≥50% reduction from baseline) (45% vs. 36%; P=.07), but no differences in response rates on the Clinical Global Impression–Improvement (CGI-I) or CGI-S scales with last observation carried forward analysis. The authors concluded that venlafaxine showed some evidence of superior efficacy when compared with paroxetine in this difficult-to-treat population. However, it is possible that the drug dosages used in the study may have accounted for the results since patients received venlafaxine at the upper end of the recommended dosage range (a mean dose of approximately 270 mg/day), while paroxetine patients received a maximum dose of 40 mg/day. The maximum recommend dose of paroxetine in some countries is 50 mg/day, an increase which could potentially result in improved response and remission rates. Additional studies are needed to investigate these findings.


Treatment of SSRI Nonresponders with Venlafaxine ER: A Randomized Comparison of Standard and Higher Dosing Strategies


Outpatients (n=232) who had previously failed SSRI treatment were randomized to 8 weeks of either “standard” (n=119; mean dose=148 mg/day) or “higher” (n=113; mean dose=309 mg/day) dose therapies of venlafaxine ER.33 Nonresponse to previous SSRI therapy was defined as having no clinically significant improvement in depression after ≥6-week treatment with a minimum dose of fluoxetine 20 mg, paroxetine 20 mg, sertraline 100 mg, or citalopram 40 mg. Between weeks 8 and 12, nonresponders in the standard group received higher dose therapy. At week 8, the higher dose group achieved significantly greater response rates on the CGI-I scale (68% versus 52%; P<.001) and the Patient Global Impressions (PGI) scale (intent-to-treat; 68% versus 50%; P<.001); however, there were no significant differences at week 12. HAM-D21 total scores and HAM-D17 response and remission rates did not differ significantly between dosing strategies at either weeks 8 or 12. The data indicate that depressed patients who had previously failed SSRI treatment for the current episode had relatively high rates of response to 12-week, open-label venlafaxine ER treatment. However, it is important to note that the study was limited by the unblinded treatment conditions and lack of placebo-control group. In addition, the investigators did not prospectively confirm the adequacy and tolerability of the index SSRI trial. Rigorously designed double-blind studies are needed to confirm these findings.


Venlafaxine ER Versus Conventional Antidepressants in the Remission of Depressive Disorders After Previous Antidepressant Failure: ARGOS Study


ARGOS was a 24-week, randomized, open-label, multicenter study of venlafaxine ER versus conventional antidepressants in 3,097 depressed patients (HAM-D17 ≥17) failing to tolerate or respond to at least 4 weeks of treatment with a different conventional antidepressant in a primary care setting.34 The most frequently prescribed conventional antidepressants during prior treatment were fluoxetine, paroxetine, sertraline, and citalopram. During the ARGOS study, the most frequently used conventional antidepressants were paroxetine (21.3% of patients), citalopram (20.1%), sertraline (19.1%), fluoxetine (17.0%), and mirtazapine (7.9%). Per usual standards, remission was defined as a score of ≤7 on the HAM-D17. After 24 weeks of treatment, the venlafaxine ER group demonstrated a significantly higher remission rate than the conventional antidepressant group (59.3% versus 51.5%, respectively; P<.0001; OR 1.37; 95% CI, 1.19–1.58; P<.01). The findings suggest that venlafaxine ER may be more effective than the conventional antidepressants used in this study for treating depression in patients who did not tolerate or respond adequately to prior treatment with a different conventional antidepressant. Limitations to consider when interpreting the results of this study include the open-label design and the greater baseline depression severity present in the venlafaxine ER group, despite initial random assignment. Double-blind trials comparing venlafaxine ER and conventional antidepressants are needed.


Non-Randomized, Non-Comparative Studies


Efficacy of Venlafaxine in Depressed Patients After Failure with Prior Antidepressant Treatment


Reynaert-Dupuis and colleagues35 conducted a 6-week, open-label, non-comparative, naturalistic study of 1,020 patients treated with venlafaxine (66% of patients switching from another antidepressant, 33% treatment-naïve) in a psychiatry practice. The mean duration of prior antidepressant treatment was measured in approximately 70% of the switch patients, of whom 92% had received >4 weeks of prior antidepressant treatment. For the patients switched to venlafaxine therapy, an increasing percentage of responders was reported over the course of the study (>50% by week 6) as determined by HAM-D21 and MADRS scores. The percentage of patients switched to venlafaxine who achieved remission also increased over the course of the study, with 20% of patients achieving remission by week 6. Patients who had switched due to lack of efficacy with their prior antidepressant were significantly more likely to be considered responders than those who switched for other reasons.35 Response rates were related to the type of antidepressant taken before venlafaxine; patients who switched from SSRIs were most likely to respond and patients who switched from TCAs were least likely to respond. Treatment-naïve patients who received venlafaxine as first-line therapy demonstrated a superior response (61.4% responders by week 6) to therapy than those who were switched from a prior antidepressant (52.7% responders by week 6). This study was the first large-scale trial to examine the effects of directly switching previously unresponsive patients to venlafaxine in a real-world setting, in which patients immediately switched medications without a wash-out period. The authors noted that it is possible that the lack of a wash-out period may have impacted the venlafaxine efficacy observed in the study by producing a withdrawal effect. However, the investigators believe a carry-over effect was unlikely. Controlled studies are warranted to support these data which indicate venlafaxine is an effective therapy in patients switched from previous antidepressant treatment.


Efficacy of Venlafaxine and Predictors of Response in a Prospective Open-Label Study of Patients with Treatment-Resistant MDD


In an 8-week, open-label, prospective switch (after TCA failure) study of 312 patients, Mitchell and colleagues36 found a 53% response rate in venlafaxine-treated patients (50% decrease in MADRS). There was a significantly higher response in patients with an absence (58%) versus the presence (31%; P<.001) of comorbid psychiatric disorder. This response varied depending on whether the comorbid disorder was “marked” (60%), “mild or moderate” (52%), or “severe” (43%) in baseline ratings on the CGI scale (P<.05). Likewise, response varied based on “relative” (61%) versus “absolute” resistance (49%; P=.06). A 20% or 30% improvement in scores at weeks 1 or 2 was associated with higher rates of final response on the MADRS (P<.0005). This trial provides evidence of the effectiveness of venlafaxine in a well-defined sample of patients with TRD. Of note, the trial is among the first to indicate that early improvement may be a robust predictor of final response in treatment-resistant patients. However, it is important to consider that some of the patients in this sample may have been less severely depressed than those in other studies because this trial required failure of at least one adequate course of antidepressants. However, the large sample size was likely representative of treatment-resistant patients typically encountered in clinical practice. The findings from this uncontrolled study require confirmation from more rigorously designed trials.


Venlafaxine in Treatment-Resistant MDD:
A Canadian Multicenter, Open-Label Trial


In an 8-week, open-label switch (after ≥8 weeks’ treatment with an adequate dose of an antidepressant) study in 152 inpatients and outpatients, de Montigny and colleagues37 observed that switching to venlafaxine therapy decreased HAM-D21 scores by 52% and MADRS scores by 50% from baseline. Venlafaxine therapy was also associated with a 58% HAM-D21 response (50% decrease) and a 28% HAM-D21 remission (≥75% decrease) rate. By week 8, 88% of patients had improved (minimally, much, or very much) from baseline on the CGI-I. The findings suggest that venlafaxine is effective for TRD because of the robust response associated with therapy, regardless of the number or type of previous antidepressant treatments. While the study is limited by its open-label design, well-defined criteria were used to characterize response to venlafaxine and to select patients with a documented history of treatment failure to an adequate antidepressant trial. Of note, the criteria used in this study to define treatment resistance may be less stringent than criteria used in other investigations.


Sustained Response to Open-Label Venlafaxine in Drug-Resistant MDD


Schweitzer and colleagues38 evaluated the response to venlafaxine in a 10-month extension phase of an open-label 8-week switch study in 149 treatment-resistant patients who had failed at least one adequate course of antidepressants. The researchers reported a 69% response (50% reduction in MADRS) after 8 weeks in the initial study phase; 73% were responders at the final extension-phase visit. Mean MADRS scores decreased from 33 to 13 by week 8, and to 11 by the final extension visit (decrease from entry into extension to end of extension phase was significant). Remission (MADRS <12) increased 37% to 49% from the initial to the final extension visit. Although the study design was open-label and there was likely variation in the degree of treatment resistance among patients, the results of this extension study indicate that treatment-resistant patients who received venlafaxine sustained their response for up to 12 months and demonstrated some evidence of additional improvement.


Venlafaxine for Treatment-Resistant Unipolar Depression


Consecutive patients (n=84) with triple-resistant depression were given venlafaxine in a 12-week study by Nierenberg and colleagues.28 Patients were chronically depressed (mean duration of the current episode was 4 years) and had failed to respond to at least three adequate trials of antidepressants from at least two different antidepressant classes or ECT, plus at least one attempt at augmentation. Full response was defined as a HAM-D21 score ≤8, a MADRS score ≤12, and a CGI-I score of 1; partial response was defined as a 50% decrease in HAM-D21 and MADRS, with final scores >8 and >12, respectively, and a CGI-I score of 2. Approximately 33% of patients were considered to be either full or partial responders (32.9% by HAM-D21, 30.0% by MADRS, and 40.0% by CGI-I) after 12 weeks of venlafaxine treatment. Response was sustained for at least 3 months in approximately 46% of responders after the acute response. Overall, the data suggest venlafaxine may be an effective antidepressant for patients with chronic, severe TRD. Additional controlled studies are needed to corroborate the findings from this study.


Efficacy of Venlafaxine in Patients with MDD Who Have Unsustained or No Response to SSRIs: An Open-Label, Uncontrolled Study


Kaplan39 conducted an 8-week open-label switch study after SSRI failure (inadequate or unsustained response [HAM-D25 score ≥16] to ≥6 weeks of treatment with ≥1 SSRI) in 73 outpatients treated in a psychiatric setting. The researchers observed a 91% response (HAM-D25 ≤10 + PGI21 ≥5), an 87% HAM-D remission (HAM-D25 ≤8), and an 86% PGI remission (PGI21 ≥7) associated with venlafaxine treatment. The results of this observational study suggest venlafaxine may be effective for the treatment of MDD in outpatients who do not respond or have an unsustained response to therapeutic doses of SSRIs. The authors note that it is possible that spontaneous remission or carry-over effects from prior antidepressant therapy could potentially account for the findings, thus, controlled trials of venlafaxine in a comparable study sample are needed.


Efficacy of Venlafaxine in MDD Resistant to SSRIs


In a 6-month switch (after lack of response to a therapeutic dose of an SSRI for ≥4 weeks) study of 69 patients in a multicenter, naturalistic setting, Saiz-Ruiz and colleagues40 found that venlafaxine therapy at a mean dose of 175 mg/day resulted in an 81% HAM-D17 response (50% decrease) and a 74% CGI-I response (score of 1 or 2). This observational investigation provides additional evidence of venlafaxine efficacy under clinical conditions for TRD, although double-blind, controlled studies are needed to generalize the conclusions.


Geriatric Depression Treatment in Nonresponders to SSRIs


Whyte and colleagues41 conducted a post-hoc analysis of two open-label extension studies of 53 patients from the National Institute of Mental Health Late-Life Depression Study who did not respond to paroxetine plus interpersonal psychotherapy. Comparisons were made between outcomes of patients in an “augmentation group” who were treated sequentially with 1–3 augmentation options (bupropion SR, nortriptyline, or lithium) and those in a “switch group” who were treated with venlafaxine ER. The researchers reported a 42% HAM-D17 response rate (three consecutive weekly scores of <10) for the venlafaxine ER switch group, compared with 45%, 31%, and 43% for the first, second, and third augmentation trials, respectively (overall response rate of 60% for all three augmentation trials). Response rates in the venlafaxine ER group were higher for patients with fewer previous treatment failures and for those who had experienced a relapse on paroxetine. Overall, similar rates of response were observed for the augmentation strategy and the strategy of switching to venlafaxine ER in elderly patients with prospectively defined TRD. Venlafaxine ER was generally better tolerated than the augmentation strategies. Strengths of the study include the use of a reliable, valid method of diagnosing depression and a prospective assessment of TRD. Definitive comparisons between the treatment strategies are difficult to make because of the lack of control groups, small sample sizes, and the varying degree of treatment resistance among patients, particularly since switch patients may have been more severely treatment resistant. Controlled studies of comparable, large populations are needed to investigate the study findings which suggest modest efficacy for both strategies, and a potential advantage for the venlafaxine ER switch strategy in geriatric TRD.


Safety and Efficacy of High-Dose Venlafaxine ER in Treatment-Resistant MDD


In a study by Mbaya,42 five patients with severe TRD were treated for up to 24 weeks with high-dose venlafaxine ER, up to 600 mg/day. Patients had previously failed to respond to adequate doses of a minimum of three antidepressants or two antidepressants and ECT and at least one attempt at augmentation. Efficacy was evaluated using the MADRS, HAM-D21, and CGI-I scales, and a >50% decrease in MADRS scores was observed in three of five patients. Likewise, a >50% decrease in HAM-D21 scores was observed in four of five patients receiving venlafaxine therapy. This small open case series is one of the first published studies to examine the effects of venlafaxine in doses up to 600 mg/day for severe TRD. A randomized, double-blind, comparative trial is needed to substantiate the findings which indicate that patients with severe MDD show some evidence of improvement with high-dose venlafaxine ER.


Failure to achieve an adequate response or remission following initial antidepressant therapy is common, with considerable consequences. After failure on an initial antidepressant, clinicians are faced with three potential options. Namely, switching, augmenting, or combination therapy. As was documented previously, the risks of not achieving and sustaining remission include a greater risk of relapse or recurrence, more chronic depressive episodes, and a shorter duration between depressive episodes. In addition, the probability of response or remission diminishes with the number of previous treatment trials. Rush and colleagues44 recently reported that patients who required more treatment steps (ie, were more treatment resistant) in the STAR*D trial had worse outcomes. Progressively lower rates of remission were associated with each of the four successive acute treatment steps in the trial. The QIDS-SR16 remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment levels, respectively. The overall cumulative remission rate was 67%. The rates of relapse were higher overall among patients who needed more acute treatments. Although the STAR*D trial employed an open design without placebo control, the results represent real-world clinical outcomes and highlight the importance of early intervention to both achieve and sustain remission. These findings, taken together with the studies reviewed in this article, demonstrate that an effective antidepressant agent should be selected as early as possible during the course of therapy to prevent a pattern of repeated unsuccessful attempts with multiple agents.


While there are little data supporting the efficacy of a within-class switch, switching to an antidepressant with a different mechanism of action, such as the SNRI venlafaxine, may reduce the likelihood of relapse or recurrence in patients with TRD. As shown in this literature review, venlafaxine is a widely studied agent in clinical research of TRD. The studies reviewed, particularly the randomized comparison trials, show venlafaxine is associated with modest rates of response and remission in patients who have failed previous SSRI treatment. However, it is important to note that the findings from the comparative studies do not uniformly find venlafaxine to be superior and the open-label non-randomized studies may overestimate treatment efficacy. Comparisons between augmentation and switch strategies are limited because of certain design features of the studies.


Overall, venlafaxine is an effective alternative for patients with TRD, and switching to an SNRI, such as venlafaxine, is a logical next step for patients who are failing to respond to an SSRI. While most studies suggest moderate doses of venlafaxine, higher dose venlafaxine (up to 300 mg/day) for continuation treatment up to 6 months has also been shown to be effective for achieving and sustaining remission in patients with recurrent MDD.45 Venlafaxine is also the first agent to have documented efficacy for ≥2 years in the prevention of recurrence during maintenance treatment.46 A timely assessment of treatment success and a vigorous approach to management of unresolved symptoms may help clinicians and patients overcome the chronic and progressive disease course so often seen following initial failures on agents such as SSRIs. Future clinical research to identify treatment alternatives for SSRI nonresponders may evaluate sequential treatment strategies similar to the approaches used in the STAR*D trial. In addition, exploration of the biochemical and genetic mechanisms underlying drug response is an evolving area of research and may provide novel insights into the treatment of TRD. PP


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27. Thase ME, Rush AJ, Howland RH, et al. Double-blind switch study of imipramine or sertraline treatment of antidepressant-resistaznt chronic depression. Arch Gen Psychiatry. 2002;59(3):233-239.


28. Nierenberg AA, Feighner JP, Rudolph R, Cole JO, Sullivan J. Venlafaxine for treatment-resistant unipolar depression. J Clin Psychopharmacol. 1994;14(6):419-423.


29. Fava M, Rush AJ, Trivedi MH, et al. Background and rationale for the sequenced treatment alternatives to relieve depression (STAR*D) study. Psychiatr Clin North Am. 2003;26(2):457-494.


30. Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354(12):1231-1242.


31. Lenox-Smith A, Schaeffer P, Reynolds A, Willard L. A double-blind trial of venlafaxine XR vs citalopram in patients with severe depression [abstract]. J Psychopharmacol. 2001;A11.


32. Poirier MF, Boyer P. Venlafaxine and paroxetine in treatment-resistant depression. Double-blind, randomised comparison. Br J Psychiatry. 1999;175:12-16. Erratum in: Br J Psychiatry. 1999;175:394.


33. Thase ME, Shelton RC, Khan A. Treatment with venlafaxine extended release after SSRI nonresponse or intolerance: a randomized comparison of standard- and higher-dosing strategies. J Clin Psychopharmacol. 2006;26(3):250-258.


34. Baldomero EB, Ubago JG, Cercos CL, Ruiloba JV, Calvo CG, Lopez RP. Venlafaxine extended release versus conventional antidepressants in the remission of depressive disorders after previous antidepressant failure: ARGOS study. Depress Anxiety. 2005;22(2):68-76.


35. Reynaert-Dupuis C, Zdanowicz N, Leyman S, Mignon A. Efficacy and tolerance of venlafaxine in depressed patients switched from prior antidepressant treatment. Primary Care Psychiatry. 2002;8(2):63-68.


36. Mitchell PB, Schweitzer I, Burrows G, Johnson G, Polonowita A. Efficacy of venlafaxine and predictors of response in a prospective open-label study of patients with treatment-resistant major depression. J Clin Psychopharmacol. 2000;20(4):483-487.


37. de Montigny C, Silverstone PH, Debonnel G, Blier P, Bakish D. Venlafaxine in treatment-resistant major depression: a Canadian multicenter, open-label trial. J Clin Psychopharmacol. 1999;19(5):401-406.


38. Schweitzer I, Burrows G, Tuckwell V, et al. Sustained response to open-label venlafaxine in drug-resistant major depression. J Clin Psychopharmacol. 2001;21(2):185-189.


39. Kaplan EM. Efficacy of venlafaxine in patients with major depressive disorder who have unsustained or no response to selective serotonin reuptake inhibitors: an open-label, uncontrolled study. Clin Ther. 2002;24(7):1194-1200.


40. Saiz-Ruiz J, Ibanez A, Diaz-Marsa M, et al. Efficacy of venlafaxine in major depression resistant to selective serotonin reuptake inhibitors. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26(6):1129-1134.


41. Whyte EM, Basinski J, Farhi P, et al. Geriatric depression treatment in nonresponders to selective serotonin reuptake inhibitors. J Clin Psychiatry. 2004;65(12):1634-1641.


42. Mbaya P. Safety and efficacy of high dose of venlafaxine XL in treatment resistant major depression. Hum Psychopharmacol. 2002;17(7):335-339.


43. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243-1252.


44. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.


45. Keller M, Kocsis JH, Kornstein S, et al. Comparing the efficacy of venlafaxine XR and fluoxetine for acute, continuation, and maintenance therapy in recurrent unipolar major depression. Poster presented at: 43rd Annual Meeting of the American College of Neuropsychopharmacology; December 12-16, 2004; San Juan, Puerto Rico.


46. Keller M, Yan B, Dunner D. Recurrence prevention: Efficacy of two years of maintenance treatment with venlafaxine XR in patients with recurrent unipolar depression. Poster presented at: 159th Annual Meeting of the American Psychiatric Association; May 20-25, 2006; Toronto, Canada.



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Antidepressant Drugs:
Early Onset of Therapeutic Effect

Donald S. Robinson, MD
Primary Psychiatry. 2007;14(3):23-24

Dr. Robinson is a consultant with Worldwide Drug Development in Burlington, Vermont.

Disclosure: Dr. Robinson has served as a consultant to Bristol-Myers Squibb, CeNeRx, Epix, Genaissance, Medicinova, Ono Pharmaceuticals, Predix, and Somerset.

It is widely accepted that antidepressants have a delayed therapeutic effect1-3 despite having immediate neurochemical actions. However, there is growing evidence that antidepressants at effective doses produce discernible clinical improvement in responding patients within 1–2 weeks.4,5 This alleged delay in therapeutic benefit, which has been attributed to all antidepressants, is assumed to result from an indirect effect on “downstream” neuronal pathways, despite drugs having differences in pharmacologic mechanisms of action.

The often-cited time lag in onset of therapeutic effect of antidepressants is now being questioned based on findings of several recent studies. Investigations have included both efficacy trials of adequate sample size specifically designed to assess early onset of antidepressant effect and meta-analyses of published placebo-controlled trials to look at the time course of the drug-placebo treatment difference.6-8 According to one placebo-controlled study assessing the behavioral effects of two prototypical antidepressants, measurable clinical improvement of depressive symptomatology occurs within a few days of initiating treatment.5

Meta-Analysis of Depression Trials

Brown University investigators conducted a comprehensive meta-analysis of all placebo-controlled efficacy trials in depression with weekly symptom ratings published between 1981 and 2001.8 The patient population involved >5,100 depressed patients treated with an approved antidepressant compared with 3,400 control subjects randomly assigned to placebo treatment. Data from 47 double-blind, placebo-controlled trials were included in the analysis, with comparison of mean change from baseline in weekly 17-item Hamilton Rating Scale for Depression (HAM-D)17 ratings for drug and placebo treatment. Mean pretreatment HAM-D17 scores were 25.6 and 25.3 for the medication and placebo groups, respectively. These ratings are consistent with depressive disorder of at least moderate severity.

Over the course of 6 weeks, mean reductions in HAM-D17 scores were 13.5 for active medication and 9.0 for placebo, representing 51.1% and 35.4% decreases in symptom severity, respectively. With both drug and placebo treatment, it was found that the largest decrease in HAM-D17 mean severity score occurred during the first week of treatment, with continuing but lesser reductions each week thereafter. Fifty-seven percent of the end-of-treatment drug-placebo difference (indicative of antidepressant effect) occurred within the first 2 weeks of treatment. Rather than a delayed response pattern, the antidepressant versus placebo separation exhibited early onset, with additional benefits of ongoing treatment gradually diminishing. A meta-analysis of Clinical Global Impression ratings as measure of clinical response yielded similar findings. For both outcome analyses, approximately two-thirds of the ultimate therapeutic benefit of active medication (drug versus placebo difference) occurred during the first 2 weeks of the 6-week course of treatment.

Individual Studies of Early Therapeutic Benefit

Because meta-analyses of published studies of placebo-controlled efficacy trials involve trials of varying and often limited sample size,8 the argument for early onset would be strengthened by data from individual trials of adequate sample size with more frequent ratings of clinical response. Two such studies involving larger samples of depressed patients have been conducted and have yielded findings similar to the Brown University study. A group of investigators in Zurich, Switzerland studied nearly 1,300 patients using daily depression self-ratings and found measurable antidepressant effects as early as day 5 of treatment. Furthermore, it was found that 90% of those patients who experienced any improvement by week 3 went on to become full responders.6 Another study of 370 depressed patients using self-reported symptoms every 3 days found a significant improvement in depression (and anxiety) symptoms for drug versus placebo within the first 3 days of treatment. As for the previous study, early improvement at 1 week was a strong predictor of ultimate treatment response.7

Early Onset of Behavioral Effects of Antidepressants

For definitive evidence of a drug’s clinical action as an antidepressant, a study should include both a comparator drug (active control) and a placebo control. Using a placebo-controlled study design with two active comparators, the behavioral effects of both the prototypical serotonin reuptake inhibitor paroxetine and the norepinephrine reuptake inhibitor desipramine were compared with placebo treatment of depressed inpatients.5,9 Behavioral changes were assessed twice weekly during the first 3 weeks of treatment, beginning at day 3. Time of onset and the temporal profile of behavioral changes were compared across treatment groups at each assessment point, using a mixed-model analysis of variance. Overall change over time was assessed using slope analysis as well as rate of change of HAM-D ratings during the first 3 weeks, adjusting for baseline severity. Analyses of symptom change using a survival analysis procedure10 was also carried out, yielding similar results.

The study showed that early clinical effects of these two antidepressants were apparent by at least 7 days for desipramine and 10 days for paroxetine treatment.5 The initial behavioral actions of the two drugs proved to be somewhat different. With desipramine treatment, significant initial improvement compared with placebo was apparent for motor retardation and depressed mood, while anxiety and hostility symptoms improved early with paroxetine. Treatment with both drugs was associated with significantly more rapid reduction in hostility during the first 2 weeks compared with placebo treatment. For both of these antidepressants, HAM-D total severity score and the depressed mood/motor retardation factor showed significant clinical improvement compared with placebo treatment at week 1.


Meta-analysis of published placebo-controlled efficacy studies, as well as individual trials in depression designed to assess onset of antidepressant effect, have examined the issue of the purported time lag in therapeutic benefit. Contrary to common belief that there is delayed onset of antidepressant benefit, these studies provide compelling evidence that antidepressants at effective doses have nearly immediate effects and demonstrate significant improvement within the first weeks of treatment. In addition to a consistent finding of early onset of therapeutic benefit of antidepressants, behavioral differences have been reported in the clinical actions of desipramine and paroxetine during initial treatment. Desipramine treatment was associated with early improvement in motor retardation and depressed mood, while anxiety and hostility symptoms showed early response to paroxetine. The fact that significant clinical effects occur close in time to the almost immediate neuropharmacologic actions of antidepressants suggests that antidepressant efficacy results from direct enhancement of neuronal transmission at monoaminergic synapses, rather than a purported indirect and delayed “downstream” effect on neuronal pathways. PP


1. Quitkin FM, Rabkin JG, Ross D, Stewart JW. Identification of true drug response to antidepressants. Use of pattern analysis. Arch Gen Psychiatry. 1984;41(8):782-786.

2. Anderson IM, Nutt DJ, Deakin JF. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 1993 British Association of Psychopharmacology guidelines. J Psychopharmacol. 2000;14(1):3-20.

3. Schatzberg AF, Cole JO, DeBattista C, et al. Antidepressants: Manual of Clinical Psychopharmacology. 4th ed. Washington, DC: American Psychiatric Publishing; 2003:137-157.

4. Mitchell AJ. Two-week delay in onset of action of antidepressants: new evidence. Br J Psychiatry. 2006;188:105-106.

5. Katz MM, Bowden CL, Berman N, Frazer A. Resolving the onset of antidepressants’ clinical actions: critical for clinical practice and new drug development. J Clin Psychopharmacol. 2006;26(6):549-553.

6. Stassen HH, Angst J, Delini-Stula A. Delayed onset of action of antidepressant drugs? Survey of results of Zurich meta-analyses. Pharmacopsychiatry. 1996;29(3):87-96.

7. Parker G, Roy K, Menkes DB, et al. How long does it take for antidepressant therapies to act? Aust N Z J Psychiatry. 2000;34(1):65-70.

8. Posternak MA, Zimmerman M. Is there a delay in the antidepressant effect? A meta-analysis. J Clin Psychiatry. 2005;66(2):148-148.

9. Katz MM, Tekell JL, Bowden CL, et al. Onset and early behavioral effects of pharmacologically different antidepressants and placebo in depression. Neuropsychopharmacology. 2004;29(3):566-579.

10. Stassen HH, Delini-Stula, Angst J. Time course of improvement under antidepressant treatment: a survival-analytical approach. Eur Neuropsychopharmacol. 1993;3(2):127-135.

Journal CMEs

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Ruth E. Geller, MD, and Joseph F. Goldberg, MD

Needs Assessment: Bipolar disorder is a chronic and episodic condition that has social, economic, and emotional consequences. Over the past decade, researchers have identified psychosocial determinants of illness, and therapies aimed at addressing these causal components have been developed. Utilizing evidence-based psychotherapies for bipolar disorder can have a positive impact on patient care.

Learning Objectives:

• Recognize the components of morbidity associated with bipolar disorder.

Describe key components of four evidence-based psychotherapies for bipolar disorder. 

• Evaluate augmenting pharmacotherapy with psychotherapy in bipolar disorder.


Identify patients most likely to benefit from specific psychotherapeutic interventions.


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 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: February 13, 2007.


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

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

Primary Psychiatry. 2007:14(3):59-69

Dr. Geller is resident psychiatrist in the Department of Psychiatry at Mount Sinai Hospital in New York City. Dr. Goldberg is associate professor of clinical psychiatry at the Mount Sinai School of Medicine in New York City and director of the Affective Disorders Program at Silver Hill Hospital in New Cananan, Connecticut.


Disclosures: Dr. Geller reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Goldberg is on the advisory boards and/or speaker’s bureaus of Abbott, AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, GlaxoSmithKline, and Pfizer; and receives grant support from Eli Lilly and GlaxoSmithKline.


Please direct all correspondence to: Joseph F. Goldberg, MD, Silver Hill Hospital, 208 Valley Rd, New Canaan, CT 06840; Tel: 203-801-2363; Fax: 203-966-9336; E-mail:



Until recently, clinicians believed that pharmacotherapy alone was the mainstay of care for patients with bipolar disorder, and psychotherapeutic intervention held little or no benefit. However, over the past several decades, evidence has shown that several validated, disease-specific forms of psychotherapy demonstrate unique value as adjuncts to pharmacotherapy management. Based on the stress-vulnerability model of mental illness, which highlights the interplay of biopsychosocial factors in disease risk and relapse, psychotherapies have been recognized as providing unique therapeutic benefits based on cognitive, interpersonal, and other psychosocial dimensions of illness. In addition, clinicians have realized that patients and people in their lives can learn techniques to more effectively manage bipolar disorder. This article describes evidence-based psychotherapeutic approaches for the treatment of bipolar disorder. Four psychotherapeutic modalities have been validated through randomized, controlled clinical trials and have shown efficacy in combination with standard pharmacologic treatment. Evidence-based psychotherapies for bipolar disorder include cognitive-behavioral therapy, family-focused treatment, interpersonal and social rhythm therapy, and psychoeducation. This article reviews each of these modalities and identifies evidence behind each approach. 



Despite pharmacotherapy advances across manic, depressed, mixed, and maintenance phases of bipolar disorder, symptomatic recurrence continues to be evident in a majority of patients.1 Residual2 and subsyndromal3 symptoms frequently persist between distinct episodes and can trigger relapses,1-4 impair functioning, and disrupt quality of life.5 Since functional recovery often lags behind symptomatic or syndromic recovery, patients must negotiate occupational and social ramifications of affective episodes on a daily basis.2,6,7 Poor quality of life may be evident even during periods of euthymia.5,8 Chronic illness may lead to persistent demoralization, which can impact illness outcome.5 Despite the efficacy of psychotropic agents under optimal circumstances, 50% of bipolar disorder patients deviate from adequate adherence.9,10 Thus, pharmacotherapy alone seldom represents optimal management of bipolar disorder.


Given the great psychosocial consequences of bipolar disorder, psychotherapy represents a critical treatment component. Research in the past 2 decades has led to several modalities of psychotherapy based on bipolar disorder disease models. As an adjunct to pharmacotherapy, clinical trials indicate that appropriate psychotherapies can reduce relapse rates by up to 40%.11 Moreover, effective psychotherapies can provide patients with skills that enable them to negotiate the cognitive challenges and psychosocial stresses that directly result from manic and depressive episodes. This article examines specific forms of psychotherapy relevant to the management of bipolar disorder and highlights methods for clinicians to incorporate the basic elements of each form to improve treatment outcomes.


Origins, Rationales, and Goals of Psychotherapy


Although the etiology of bipolar disorder remains unknown, theoretical foundations behind effective psychotherapy have evolved in the past 2 decades. Psychotherapy efforts grew from early 20th century psychodynamic formulations by Winnicott12 and Klein,13 among other researchers. “Manic defense” was understood as an intrapsychic phenomenon in which depression represented anger turned inward and mania represented an unconscious defense against depression. While there has been little empirical study of this hypothesis, there is some evidence to suggest the presence of low self-esteem in patients with mania.14 Psychoanalytic orientations maintain that insight into the nature of presumed conflicts represent a directly curative process. Diminished awareness of illness is recognized among individuals with bipolar disorder15—and poor insight could drive illness denial and treatment nonadherence—but there have been few studies of possible psychodynamic contributors to bipolar disorder or the potential efficacy of psychoanalytic treatment as a means to ameliorate affective symptoms.


Modern bipolar disorder psychotherapy began with the empiric studies of Beck16 and Kovacs and Beck17 in the 1960s and 1970s, which identified links between cognitive distortions and depression. In unipolar depression, cognitive-behavioral therapy (CBT) came to represent an intervention designed to reduce depressive symptoms, with comparable efficacy to antidepressants.18 Adaptations to bipolar disorder began in the 1990s, initially as an amalgam of psychoeducation with tenets from CBT for unipolar depression19 and as an adjunct to pharmacotherapy. A second innovative effort to develop skills-based psychotherapy came from the work of Klerman and colleagues,20 which focused on the interpersonal correlates of depression leading to the development of interpersonal psychotherapy (IPT). Subsequently, adaptations of IPT by Frank and colleagues21 and Malkoff-Schwartz and colleagues22 incorporated recognition of the impact of disruptions to daily rhythms (eg, chronobiologic or circadian influences such as sleep-wake cycle perturbations) and led to the development of interpersonal/social rhythm therapy (IP/SRT) specific to bipolar disorder. Family-focused therapy (FFT) represents a third skills-based psychotherapy, developed by Miklowitz and colleagues,23-25 which was designed to address the impact of interpersonal, emotional, and communication styles within families of bipolar disorder patients. Psychoeducation represents a fourth type of psychotherapy approach relevant to bipolar disorder,26,27 which focused on improving disease management skills, including the recognition of prodromes and the barriers to medication adherence.


Each type of psychotherapy has been validated through empirical studies on their effect on symptomatic and functional recovery in bipolar disorder. In addition, structured group-based psychotherapies have been developed that draw on cognitive-behavioral and psychoeducational principles and have been adapted for specific subgroups (eg, inpatients or those with comorbid substance use disorders). Most formalized individual- and group-based psychotherapies have been manualized and are typically administered in time-limited, structured sessions in modular fashion over several months. Further, psychoeducational principles have formed the basis of institutional team approaches for increasing self-management in bipolar disorder patients, as seen in the collaborative care model developed by the United States Department of Veterans Affairs.28,29


When Should Formal Psychotherapy Be Administered?


Few studies have clarified when psychotherapy yields optimal efficacy in the course of bipolar illness. Most clinicians agree that during acute mania or in the presence of florid psychosis, impaired attention and behavioral disinhibition likely preclude meaningful work in focused individual psychotherapies. Regarding depressive symptom severity, it is plausible that impaired attention, ability to shift sets, and capacity for flexible thinking (eg, melancholia) could render psychotherapies less effective in severe than in mild-to-moderate depression. However, randomized studies have not yet demonstrated whether or not structured psychotherapies improve quality of life or functional outcome when treatment occurs during euthymic versus non-euthymic mood states.


In nonrandomized data from the National Institute of Mental Health Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), Miklowitz and colleagues30 observed that among severely depressed bipolar patients, symptomatic and functional improvement occurred more often during high-frequency, intensive psychotherapy of any type. Patients with less severe depression at baseline showed clinical improvements with less frequent and intensive psychotherapy. Strategies based on accurate patient symptom self-reporting may be more beneficial when patients, motivated by a distressing affective state, report affective complaints, which has been suggested to occur more during depression than mania.26,27


The “kindling” model of affective relapse posits that stressful life events may be especially likely to precipitate affective episodes early in the lifetime course of illness.31 While studies have found that life stresses contribute to relapse throughout the life course of bipolar disorder,32,33 it is possible that the psychosocial stigmata of bipolar disorder may be particularly susceptible to modification by psychotherapeutic interventions before the elapse of multiple affective episodes.


Clinicians who are knowledgeable in the basic principles of bipolar-specific psychotherapies are able to utilize them to enhance pharmacotherapy outcomes across phases of treatment. For example, Miklowitz and colleagues34 found that despite the presence of optimized serum lithium levels, high-expressed emotion in the immediate families of bipolar disorder patients are associated with increased symptoms and poorer functioning.


A related and unstudied construct examines methods for clinicians to determine patient candidacy or appropriate fit for a specific psychotherapy modality. Methods are analogous to how psychoanalytic treatment appropriateness is gauged based on factors such as psychological mindedness and capacity for introspection. There are no explicit criteria that can determine which psychotherapy is best suited to a bipolar disorder patient. In practical terms, clinicians may draw upon techniques from each existing psychotherapy by recognizing relevant phenomena, such as visible tendencies toward cognitive distortions or the marked presence of family interpersonal factors (eg, emotional over-involvement).


Nonspecific factors in psychotherapy, such as therapeutic alliance, also can obscure one modality’s method of action over another. Furthermore, there has been suggestion that any form of structured psychotherapy may yield a substantial benefit over pharmacotherapy management alone, regardless of the specific modality employed. Controlled trials have not been conducted with sufficient statistical power to draw such comparative conclusions across the differential effects of specific psychotherapies.


Each structured psychotherapy finds that affective states can be triggered and perpetuated by psychological factors such as individual cognitive style, and social factors such as negative life events, disruption in sleep-wake cycle, and family communication styles high in expressed emotion. Though the specific therapeutic approaches differ in theoretical underpinnings and emphasis, all target medication non-adherence, family or other interpersonal conflict, stressful life events, alcohol or drug abuse, and social and circadian rhythm disruption. These therapies also share common goals that include increasing knowledge and awareness of the illness, decreasing relapse rates, and improving overall functioning and quality of life. Basic tenets associated with each modality are summarized in Table 1.


Cognitive-Behavioral Approaches


CBT is based on a theoretical model that states chronic mood symptoms lead to negative distortions in thoughts, attitudes, and assumptions about the world and oneself in relation to it. Consequently, negative cognitions serve to perpetuate depression. Patients with depression show biases in their tendencies to selectively perceive or recall negative information about themselves and process depressive material more efficiently than material of neutral or positive content.35-38 Bipolar disorder patients have been shown to demonstrate dysfunctional attitudes that bear on goal attainment, dependency, and achievement.39 Dysfunctional attitudes appear more pervasive in hypomanic patients than in remitted or euthymic bipolar patients, but are less extensive than attitudes found in unipolar depressed patients.40 The cognitive model stresses the interplay between thoughts, feelings, and behaviors. Treatment employs an active therapeutic stance and typically involves structured sessions with agenda-setting, review of prior learning and homework, completion of the current agenda and skills practice, assignment of new homework, and eliciting patient feedback about the session.


Psychotherapy mechanics involve examining and challenging the basis of automatic thoughts as they become identified or the distortion of preconscious information processing that shapes attitudes, assumptions, and beliefs due to faulty evidence or reasoning processes. Patients record examples of dysfunctional thought patterns based on daily life experiences in a logbook and scrutinize evidence to support the basis of their beliefs by generating rational responses to each thought. Unhappiness concerning a job promotion that was given to a colleague instead of the patient could trigger overgeneralized thoughts and feelings of failure, predictions about future inability to achieve success, and assumptions of low self-worth. Feelings of envy or unlovability could be stimulated. Psychotherapy would generate alternative explanations and interpretations for the event (eg, the colleague had greater seniority or was better qualified for the promotion) and rational responses to cognitive distortions (eg, “The other person may have been better qualified than I was,” or “I could be happier with a different job”).


Automatic thoughts of patients with depression are notable for themes of loss and failure, as contrasted with a greater focus on themes concerning threat, danger, and unpredictability among patients with primary anxiety disorders. This “cognitive content-specificity hypothesis” postulates that differences in information processing and attention lead to differences in symptomatology.41 Researchers have utilized this hypothesis to design assessment instruments useful for bipolar disorder. Reilly-Harrington42 suggested that attributional styles and dysfunctional attitudes interacted with negative life events to increase manic and depressive symptoms over time. Similarly, bipolar manic patients have been shown to endorse maladaptive cognitions and beliefs associated with mania more so than unipolar depressed patients or healthy subjects. This finding supports the association between biased information processing systems and maladaptive cognitive schemas relative to affective episodes.43 Principles of CBT maintain that restructuring of cognitive patterns and beliefs may influence the course of bipolar disorder. As cognitive aberrations may precede behavioral aberrations, identifying prodromal cognitions associated with depression, mania, and hypomania could prove useful in predicting and preventing destructive behavioral sequelae.


A recently developed self-report rating scale that assesses cognitive schemas in patients with bipolar disorder, the Cognitive Checklist for Mania, has been used to characterize the extent to which bipolar disorder patients endorse thought patterns consistent with either depression or mania.43,44 In a pilot study of 35 inpatients with major depressive disorder, 20 with schizoaffective disorder, and 45 with bipolar I disorder, mean scores for manic patients exceeded scores for depressed-phase or mixed-episode patients. The finding showed that patients with mania can be reliably distinguished from others based upon endorsement of particular cognitions on a standardized questionnaire. Other ratings of cognitive distortions measured in clinical trials have focused on dysfunctional attitudes, which appear to persist in patients with bipolar disorder despite improvements in subjective mood.45


In addition to reducing depressive symptoms, CBT targets medication adherence, early detection of prodromes and appropriate intervention, stress and lifestyle management, and alleviation of comorbid conditions such as anxiety or substance use disorders. CBT therapists work with patients to identify thought distortion and to respond rationally to biased cognitions in order to provide symptomatic relief. CBT therapists frequently use stories and metaphors to convey key concepts and utilize in-session rehearsal and role-play to prepare patients for real-life challenges. In addition, therapists may employ motivational interviewing as described by Rollnick and Miller.46 This technique encourages patients to draw conclusions about the importance of medication and treatment adherence by reviewing their personal illness history and consequences of adherence or non-adherence to prescribed regimens.

Cognitive-Behavioral Therapy Outcome Studies

As summarized in Table 2,47-54 there are several short- and long-term randomized trials involving CBT for bipolar disorder. Evidence indicates that CBT added to pharmacotherapy reduces short-term relapse rates, decreases hospitalization, and improves medication adherence.47-51 Gains achieved through CBT appear to be most robust during active treatment and soon thereafter52 but may attenuate during longer-term (eg, >12 month) follow-up.49,52,53 A randomized trial of CBT versus treatment-as-usual found no difference in recurrence rates except for an advantage of CBT among patients with £12 lifetime episodes.54 The aggregate of studies suggest that CBT does not reduce overall episode recurrence in bipolar disorder,55 but may be helpful to diminish associated features such as depression severity or medication non-adherence. 



Brief CBT appears helpful for patients with few prior affective episodes.11 Data are mixed on whether CBT is more effective for depression or mania. Lam and colleagues52 found a reduction in depressive episodes but not manic/hypomanic episodes. Perry and colleagues48 found the opposite, with fewer manic relapses but no difference on depressive relapse rates.


Cochran47 conducted a randomized outcome study examining the effect of CBT on medication adherence. Patients who received 6 weeks of CBT demonstrated improved lithium compliance compared with those who received usual care. Additionally, these patients were less likely to discontinue care against medical advice than were control patients. The CBT-treated group also had fewer total hospitalizations.


Perry and colleagues48 conducted a controlled trial to assess the efficacy of teaching bipolar disorder patients how to recognize initial symptoms and seek treatment. Sixty-nine patients with recent relapse (within the past 12 months) were randomized to usual care versus 7–12 CBT sessions. The CBT intervention achieved a 30% reduction in manic relapses, shorter and less frequent hospitalizations for mania, but no difference in rates of depression or time to first depressive relapse. The CBT intervention significantly improved overall social functioning and employment.


Lam and colleagues50-52 conducted a 30-month CBT trial involving 6 months of active treatment and 2 years of follow-up aimed at relapse prevention. The beneficial effect of CBT was strongest during the 6 months of active treatment and during the initial 6 months following treatment. During these 12 months of the study period, CBT reduced total bipolar episodes, days spent in bipolar episode, and number of bipolar admissions. Improvement in mood symptoms and social functioning were observed. During the last 18 months, CBT continued to yield fewer days in bipolar episode but failed to reduce relapse rate.


Family-Focused Therapy and the Role of Expressed Emotion


FFT has attracted attention as a useful approach for mobilizing the support system of a patient to improve care in bipolar disorder.23-25,56 Derived originally from studies of negative expressed emotion and particular family communication styles as contributors to relapse in schizophrenia,57-60 FFT focuses on efforts to reduce family stress (eg, emotional overinvolvement) and negative communication styles (eg, hostility and criticism) that may directly foster relapse. Miklowitz and colleagues34 studied 23 bipolar patients and found a five-fold increase in relapse rates among those patients from families with communication styles high in expressed emotion. However, randomized trials have found that family-expressed emotion status is associated with levels of depression during treatment but not time until affective relapse.61


Given the high degree of family stress and caregiver burden in bipolar disorder,62,63 family-based treatments may be particularly valuable when interpersonal tensions in the home environment are evident. Family members are engaged in treatment by learning how to recognize early relapse symptoms, while patients are encouraged to write contracts on how families should respond when signs are present. In addition, FFT may decrease affective morbidity to the extent that negative expressed emotion can exacerbate symptoms in bipolar disorder patients.34

Family-Focused Therapy Outcome Studies

Findings from randomized trials of FFT for bipolar disorder are summarized in Table 3.23-25,56,61,64,65 In a series of studies comparing FFT to crisis management in 101 bipolar outpatients, Miklowitz and colleagues23-25 found that 21 sessions of FFT decreased depressive and manic symptoms significantly and also offered protection against depressive recurrences.


Prior expressed emotion studies60 have demonstrated a clear relationship between high expressed emotion and relapse in schizophrenia. Thus, family-expressed emotion has been posited as a key substrate for FFT. However, Kim and colleagues61 found that baseline expressed emotion status was not a significant predictor of outcome during randomized treatment either with family intervention or crisis management, the latter representing a treatment-as-usual condition. Family intervention consisted of either FFT or integrated family and individual treatment. During 2-year follow-up, patients from families with higher levels of expressed emotion reported higher levels of depression regardless of treatment condition, although across treatments, expressed emotion status made no difference in time to disease relapse. When expressed emotion components were dissected, higher levels of criticism predicted higher levels of depression and mania. In mania, the association was stronger in the family treatment group than in the crisis management group. High levels of emotional over-involvement did not predict higher levels of mania or depression.


Rea and colleagues56 conducted a randomized, controlled trial that showed an outpatient, family-based treatment for bipolar disorder decreased the risk of hospitalization and relapse compared with individual treatment. These investigators followed 53 recently hospitalized, bipolar, manic patients for 1 year of active treatment and a 1-year follow-up. While the family-treated group did not differ from the individual-treatment group during the active treatment phase, a dramatic difference was noted between the groups in the year following treatment. Compared to individually-treated patients, family-therapy patients experienced lower rates of relapse (28% versus 60%) and hospitalization (12% versus 60%).


Interpersonal/Social Rhythm Therapy


Frank and colleagues66,67 have adapted IPT theories to the treatment of bipolar disorder. IP/SRT combines interpersonal psychotherapy with behavioral modification and regularization of daily routines. IP/SRT emphasizes that negative life events can impede recovery in bipolar disorder, especially through disruption of social and circadian rhythms. Given that disruptions in sleep-wake cycle have been shown to precipitate affective episodes, instituting good sleep hygiene has been posited as a protective factor in preventing negative life events from destabilizing vulnerable people.68 Therapists help patients normalize daily routines, particularly in the hours of sleeping, eating, and exercising. The concept of social “zeitgebers” [time-givers]69 summarizes this model and postulates that unstable or disrupted daily routines lead to circadian rhythm disruption, which spurs affective episodes in at-risk individuals.


Interpersonal components of IP/SRT, which are derived from IPT, include attention to interpersonal problems and disputes, role transitions, and interpersonal deficits. Grief work is also a focus of this therapy; for many patients newly adjusting to a diagnosis of bipolar disorder, this includes grief for loss of the formerly healthy self.

Interpersonal/Social Rhythm Therapy Outcome Studies

IP/SRT appears to be more efficacious in depressive as opposed to manic symptoms. This finding parallels results of CBT reported by Lam and colleagues51,52 that showed greater effectiveness for CBT in depression than mania. Findings are also consistent with those reported for FFT by Miklowitz and colleagues,23-25 yielding a reduction in depressive but not manic symptoms.


Frank and colleagues70 compared IP/SRT to an intensive clinical management (ICM) approach. When comparing these approaches in a two-phase (acute and maintenance) study, researchers found that bipolar type I patients who received IP/SRT in the acute treatment phase experienced longer survival time without new affective episodes and were more likely to remain well for 2 years of follow-up preventive maintenance. The outcome was favorable for participants who received IP/SRT during the acute phase regardless of what they received during the maintenance phase, which suggested that a critical period for providing IP/SRT may be immediately following an acute episode. Patients with many physical health problems or significant comorbid anxiety disorders did better with ICM. Further investigation is warranted into which patient subsets may benefit from standard IP/SRT. Interestingly, changing psychotherapy treatment arms (ie, IP/SRT to ICM or vice-versa) was also associated with higher recurrence rates and could reflect the adverse impact of disruptions to stable routines.64


The control condition in the study by Frank and colleagues70 was an active treatment as well. The ICM group received education on bipolar disorder, pharmacotherapy for the illness, sleep hygiene, and careful symptom monitoring, as well as medication effects, including adverse effects and non-specific support. Thus, therapeutic benefits provided by the ICM approach may have masked IP/SRT efficacy by comparison.


Psychoeducational Approaches


The primary objective of psychoeducation is to increase awareness of bipolar disorder and its management among patients and family members to facilitate early detection of prodromal symptoms. A fundamental premise is that patients can be taught to recognize early or prodromal signs of illness relapse before full episodes recur, and that patients’ enhanced capacity to detect and report early signs of illness may result in better and more responsive care.48 Psychoeducation can also increase adherence, enhance ability to cope with psychosocial repercussions of the illness, augment interpersonal skills, and improve overall quality of life.


Psychoeducation can be offered in individual or didactic group settings and take the form of a series of structured classes or lessons. It can also be offered in brief, educational interventions as part of routine medication management visits. Patients are taught skills to manage stress and regulate their lifestyle, avoid substance abuse, and reduce suicidality.


The prototype of a psychoeducational intervention is the Life Goals Program developed by Bauer and McBride.71 The Life Goals Program is a tightly structured group therapy intervention aimed at helping bipolar disorder patients more actively participate in their treatment while addressing functional deficits resulting from the illness. Group intervention consists of two phases. In the first phase, participants are taught illness management skills intended to increase knowledge about the disorder, affective triggers, and adaptive coping strategies. In the second phase, the program utilizes CBT augmented with interpersonal and psychodynamic interventions to help patients achieve their goals and address individual life circumstances, which can impede mental health maintenance. The program encourages group leaders to actively moderate the interpersonal milieu of the group and to maintain low emotional intensity, protecting group members from becoming overwhelmed. The Life Goals Program has shown that psychoeducational treatment, as part of a multimodal program, significantly decreases both emergency room use and costs.

Psychoeducational Outcome Studies

Psychoeducation has repeatedly been shown to be superior to usual care when utilized as part of a multimodal approach in the treatment of bipolar disorder. For example, Otto and colleagues72 observed that psychoeducation strategies augmenting standard pharmacotherapy are associated with longer-term mood and affective stability as compared with pharmacotherapy alone. When used in an integrated treatment setting, Colom and colleagues65 found that a 21-week psychoeducational intervention reduced the number of relapsed cases, rehospitalizations, and recurrences per patient as well as prolonged the time until affective recurrences. Colom and colleagues65 found a 60% recurrence in the control group versus 38% in the treatment group during the active treatment phase. During the 2-year follow-up phase, the effect was robustly maintained. There was a 92% recurrence in the control group compared with 67% recurrence in the treatment group. The effect held for recurrence to any episode, depression, hypomania, and mixed episode, but significance was not reached for reduction in time to mania.


The benefits of psychoeducation to delay time to affective recurrences appear longer with adjunctive psychotherapy plus pharmacotherapy than with pharmacotherapy alone, regardless of the presence of comorbid personality disorders.73 In contrast to most other forms of structured psychotherapy, psychoeducation appears less effective for reducing acute affective symptoms than for helping to prevent relapses or recurrences during maintenance treatment phases.


Special Populations:
Substance Abuse Comorbidity


Drug and alcohol abuse or dependence arise in 50% of bipolar disorder patients and frequently contributes to poor treatment outcome.74-76 Patients and clinicians often assume bipolar disorder and substance misuse are linked as a reflection of patient efforts to self-medicate problems with mood as a driving force. Little evidence exists to support this hypothesis as an explanation for most instances of substance use comorbidity.77 Some clinicians find that patients who report that drug or alcohol use is self-medicating may have a different problem other than their addiction and may be rationalizing their substance abuse or avoiding confronting denial about having an addiction. Other patients may also misidentify the consequences of an addiction, such as a substance-induced depression. While there are few empirical studies on this issue, Weiss and colleagues78 observed that approximately 66% of patients with dual-diagnosis bipolar disorder and substance use disorders identified their substance use as an effort to self-regulate affective symptoms. It was that subgroup of patients who appeared to benefit most from a structured group psychotherapy (integrative group therapy), an adaptation of CBT with relapse prevention skills developed by Weiss and colleagues79,80 for the treatment of patients with bipolar disorder and comorbid substance abuse.


Suicide Prevention


Because suicide attempts and completions remain disproportionately elevated among bipolar disorder patients, special mention is warranted regarding the role of psychotherapy in its management. Although lithium has come to represent a cornerstone of pharmacotherapy to enhance suicide prevention in bipolar disorder,81 there exist psychological dimensions relevant to suicide that psychotherapeutic interventions may be uniquely suited to address. Clinical trials suggest up to a three-fold reduction in suicidal behavior in bipolar disorder patients when a structured psychotherapy is added to pharmacotherapy.82


The assessment and treatment of depression remains a fundamental aspect of suicide prevention, although specific psychological constructs appear related to suicide risk, including hopelessness,83 desperation,84 and loss of resiliency.85 Furthermore, suicide prevention in high-risk patients may be improved by addressing reasons for living,86 management of stress related to interpersonal loss,87 and techniques to reduce inclinations to act on impulse (eg, mindfulness training).88 Brief (10-session) CBT among recent suicide attempters, regardless of diagnosis, has been shown to significantly reduce the risk for reattempts, as compared to usual treatment for up to 18 months.89 Similarly, family-based interventions aimed at enhancing communication and problem-solving may offer further benefit to help reduce suicide risk in bipolar disorder.90 Many of the key elements from existing structured psychotherapies can offer potential unique value for judging suicide risk and introducing strategies to help reduce suicidal actions.


Remission in bipolar disorder can be difficult to achieve and maintain. Functional impairment in areas such as work, education, recreational activities, interpersonal relationships, and living situation has been shown to persist significantly beyond symptomatic remission. Thus, achieving satisfactory quality of life for bipolar disorder patients remains difficult despite appropriate pharmacotherapy. There is currently a database with randomized, controlled trials involving several structured psychotherapies as adjuncts to pharmacotherapy that can help to reduce affective symptom burden, help to anticipate prodromal signs of relapse, reduce medication nonadherence, diminish suicide risk, and potentially improve global functioning. Findings from clinical trials suggest that some psychotherapy forms may be more effective when implemented acutely (eg, during depressive episodes) but with lesser effects for relapse prevention (eg, CBT, FFT), while others (such as psychoeducation) may be more advantageous for relapse prevention than acute symptom remission.


There may also be biologic reasons why psychotherapy is most effective early in the illness course. As suggested by the kindling hypothesis, emergence of affective episodes over time takes on greater automaticity, episodes are less reflective of particular life events or stressors, and an illness variant may be less amenable to therapeutic intervention. In addition, patients with increased episode frequency may simply have a more severe form of the disease, whose natural history is less responsive to intervention of any type.


Future studies are needed to better elucidate which specific forms of psychotherapy may be best suited to individual patients, to clarify which phases of illness are most appropriate for psychotherapeutic intervention (ie, acute depression versus maintenance treatment; depressed phase versus euthymic phase), and to discern the effects of psychotherapy on common comorbidities (eg, CBT for comorbid anxiety disorders). Specific mechanisms by which unique psychosocial interventions exert their effect (eg, targeting of dysfunctional thoughts; reductions in negative expressed emotion) are still incompletely understood and warrant further investigation. Given both the therapeutic benefits and potential cost efficiency of psychotherapy to reduce hospitalization and other higher levels of service utilization, it would seem incumbent upon healthcare policy makers and third-party insurers to help assure adequate provider training and minimize obstacles for patients to access community-based structured psychotherapies. PP


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David L. Ginsberg, MD

Primary Psychiatry. 2007;14(3):31-33

Dr. Ginsberg is director of outpatient services in Tisch Hospital’s Department of Psychiatry at New York University Medical Center in New York City.


Disclosure: Dr. Ginsberg receives honoraria for lectures, papers, and/or teaching from AstraZeneca and GlaxoSmithKline; and receives research support from Cyberonics.



Atomoxetine-Induced Salivary Gland Stones


Atomoxetine is a norepinephrine reuptake inhibitor approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adults. In randomized controlled trials, approximately 70% of children and adolescents with ADHD without comorbidity responded as measured by reduced scores on a variety of ADHD scales.1,2 Prior to being studied in ADHD, atomoxetine was known as tomoxetine and studied as an antidepressant. In those trials,3 as well as in a recent case report,4 atomoxetine induced mania, a finding consistent with antidepressant activity. The following is the first published report of sialolithiasis in association with atomoxetine.5


A 36-year-old patient with adult ADHD was responding well to 16 weeks of treatment with dextroamphetamine spansules 20 mg/day. Due to wearing off of the effects too early in the day, atomoxetine 18 mg was added. The patient denied having any special diet or a personal or family history of gout or arthritis. Within 10 days of starting atomoxetine, he developed a painful pulsatile swelling below his jaw line, later confirmed by a computed tomography scan as a left submandibular sialolith in the salivary gland, which was extruded. A second sialolith developed after another 10 days of atomoxetine treatment. After atomoxetine was discontinued, the stone passed. Two weeks later, the patient restarted atomoxetine; within 4–5 days he experienced another recurrence. He again discontinued atomoxetine and repeated the cycle on three further occasions with shorter time intervals to stone recurrence upon each reexposure. Each time, he reexperienced pain and swelling of the gland. By massaging the gland digitally, he was able to pass the stones—numbering at least 10, described as off-white and bullet shaped—without assistance. At no time did the patient ever develop dry mouth with atomoxetine. Subsequently, he was advised by both his otolaryngologist and his psychiatrist to discontinue the atomoxetine altogether. Since then, he has had no further stones develop in 6 months of follow-up.


The temporal course of events described above is consistent with salivary gland stone formation due to exposure to atomoxetine. In general, sialolithiasis is a common cause of salivary dysfunction that typically involves the submandibular gland. The incidence of symptomatic stones is 27.5–59.0 cases per 1 million individuals. Factors which promote the formation of these calculi include increased salivary calcium, salivary stasis, calcification of organic material, and reduced dietary phytate, a crystallization inhibitor of calcium salts found in plant seeds.6,7 The only known systemic cause of salivary stones is gout.8 According to the authors of this report, a search of the literature and contact with the manufacturer of atomoxetine failed to reveal any other cases of sialolithiasis in association with atomoxetine. Searches of reports of sialolithiasis with sympathomimetic drugs or with norepinephrine reuptake inhibitors were also negative. Interestingly, there are a few reports of salivary gland swelling associated with the norepinephrine reuptake inhibitor mianserin9 and with the b2-adrenergic agonist ritodrine,10,11 so noradrenergic activation may play a role here. Regardless of the presumed mechanism of action, clinicians who prescribe atomoxetine ought to be aware of the possibility of precipitating salivary gland stone formation in susceptible patients. PP


1. Michelson D, Allen AJ, Busner J, et al. Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry. 2002;159(11):1896-1901.
2. Spencer T, Heiligenstein JH, Biederman J, et al. Results of 2 proof-of-concept, placebo-controlled studies of atomoxetine in children with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2002;63(12):1140-1147.
3. Steinberg S, Chouinard G. A case of mania associated with tomoxetine. Am J Psychiatry. 1985;142(12):1517-1518.
4. Henderson TA. Mania induction associated with atomoxetine. J Clin Psychopharmacol. 2004;24(5):567-568.
5. Jerome L, Gardner D, Kutcher SP. First case of sialolithiasis associated with atomoxetine. J Clin Psychopharmacol. 2007;27(1):111-112.
6. Escudier MP, McGurk M. Symptomatic sialoadenitis and sialolithiasis in the English population, an estimate of the cost of hospital treatment. Br Dent J. 1999;186(9):463-466.
7. Baurmash HD. Submandibular salivary stones: current management modalities. J Oral Maxillofac Surg. 2004;62(3):369-378.
8. Grases F, Santiago C, Simonet BM, Costa-Bauza A. Sialolithiasis: mechanism of calculi formation and etiologic factors. Clin Chim Acta. 2003;334(1-2):131-136.
9. Gundert-Remy. Can salivary gland swelling, edema, and “direct” hyperbilirubinemia develop as sequelae of chronic administration of mianserin? [German] Internist (Berl). 1996;37(5):518-519.
10. Minakami H, Takahashi T, Izumi A, Itoi H, Tamada T. Enlargement of the salivary gland after ritodrine treatment in pregnant women. BMJ. 1992;304(6843):1668.
11. Marioni G, Marchese-Ragona R, Ottaviano G, Campobasso C, Staffieri A. Parotitis due to ritodrine tocolytic treatment for preterm labor. Otolaryngol Head Neck Surg. 2005;132(4):665-666.



Quetiapine-Induced Erythema Multiforme Minor


Quetiapine is a second-generation antipsychotic (SGA) indicated for the treatment of schizophrenia; as monotherapy for the acute treatment of manic episodes, as well as an adjunct to treatment with lithium or divalproex for bipolar type I disorder; and for bipolar depression. Pharmacologically, it is an antagonist at serotonin (5-HT)1A and 5-HT2, dopamine (D)1 and D2, histamine-1, and adrenergic a1 and a2 receptors.1


Erythema multiforme is an acute, self-limiting, inflammatory skin eruption. The rash is made of spots that are red welts, sometimes with purple or blistered areas in the center. Often it also affects the mouth, eyes, and other moist surfaces. Erythema multiforme has been so named because of the “multiple forms” it appears in; there is a large degree of variety in its clinical presentation. This variation has led to erythema multiforme being divided into two overlapping subgroups: erythema multiforme minor and Stevens-Johnson syndrome. These are different faces of the same disease.2


Erythema multiforme is a relatively common problem. Half the cases are in young people (under 20 years of age). It is rare both at <3 years of age and at >50 years of age. Males are slightly more affected than females and there is no racial predilection. One-third of erythema multiforme sufferers will have a recurrence of the disease. Seasonal epidemics are common.2


As its name suggests, erythema multiforme minor is the less severe of the two types and accounts for 80% of erythema multiforme. The rash appears over a few days. However, in some patients several crops follow each other during one attack. There may be minor burning or itch. It is most intense over the backs of the hands and feet. There are usually round “bulls eye” target-shaped rings on the palms. In severe cases, some blisters may be present both on the skin and lips. The rash lasts for 1–2 weeks and then recedes, leaving residual brown pigmentation.2


Typically, the main cause of erythema multiforme minor is the herpes virus, either as a cold sore, genital herpes, or a hidden infection. Other cases are due to other bacterial or viral infections or reactions to medications. If the infection returns at a later date, or the medication is taken again, the rash will soon follow. Medications that are most commonly associated with erythema multiforme include anticonvulsants, nonsteroidal anti-inflammatory drugs, allopurinol, penicillin, and sulfa-contained drugs such as sulfonamides and captopril. What follows is the first published case of erythema multiforme minor in association with the SGA quetiapine.3


A 21-year-old woman presented with “school refusal” and home withdrawal for 1 year. After receiving intervention through her guidance system at school, she was referred for clinical treatment and subsequently admitted to a Taiwanese Psychiatric Center in Taipei. Drug-naïve prior to admission, she was diagnosed with undifferentiated-type schizophrenia and started on quetiapine 100 mg/day. On the eleventh day, quetiapine was titrated up to 400 mg/day when erythematous, edematous papules were noted over the face. While not painful, the patient complained of the cosmetic effect of the papules. Her doctors prescribed antihistamines for what appeared to be a mild, transient drug eruption. Unfortunately, within the next 24 hours, the condition progressed to one manifested by edematous and swelling chins, painful tongue ulceration, and the extensive spread of lesions from the trunk to the extremities. Later, the patient complained of bilateral shoulder joint soreness. The skin lesions showed signs of erythematous, edematous change. There was no sign of further progressive desquamation. A comprehensive work-up consisting of complete blood count, hepatic and renal tests, rheumatoid markers such as C3/C4, erythrocyte sedimentation rate, and chest x-ray were all negative. After ruling out various infectious diseases such as herpes simplex virus and internal organ malignancy, a dermatologist consultant diagnosed drug-induced erythema multiforme minor. Topical steroids and oral antihistamines were administered followed by the discontinuation of quetiapine. As she remained paranoid and the eruptions rapidly resolved, the patient refused to undergo a biopsy or to allow blood samples to be drawn from her. Drug-free for the next 2 weeks, the patient accepted a trial of risperidone, which, although another atypical antipsychotic, has a distinct chemical structure and different pharmacologic profile from quetiapine. She improved significantly both behaviorally and cognitively, which resulted in her being discharged from the hospital 3 weeks later. No further drug reactions were noted.


The case described above is consistent with quetiapine-induced erythema multiforme minor. Based on experience with other medications associated with erythema multiforme, it is likely that the risk increases with rapid dose escalation. Individual genetic factors, as yet unidentified for most patient populations and drugs, also likely play a role.4 Querying patients about a past personal or family history of drug-associated rash may be useful for identifying those most at risk, in whom perhaps more gradual dosage titration ought to be considered. PP


1. Seroquel [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals; October 2006.
2. American Osteopathic College of Dermatology. Erythema Multiforme. Available at: Accessed February 5, 2007.
3. Lin GL, Chiu CH, Lin SK. Quetiapine-induced erythema multiforme minor: a case report. J Clin Psychopharmacol. 2006;26(6):668-669.
4. Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004;428(6982):486.



Serotonin Syndrome Due to Duloxetine-Cyclobenzaprine Combination


Serotonin syndrome results from excessive serotonin stimulation and is characterized by the triad of mental status changes, neurologic abnormalities, and autonomic instability.1 Symptoms may include confusion, restlessness, diarrhea, tremor, diaphoresis, myoclonus, and hyperreflexia.2 Severe cases may result in seizures, coma, or death. Medications with serotonergic activity such as serotonin reuptake inhibitors (SRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), L-tryptophan, amphetamines, and lithium have the potential for causing this condition, especially when used in combination or taken as an overdose.3 Other medications associated with serotonin syndrome include opiates, antiemetics such as ondansetron and metoclopramide, antimicrobials including linezolid and ritonavir, triptans, and dextromethorphan.4


Cyclobenzaprine, marketed under the name Flexeril, is a tricyclic amine salt indicated for relief of muscle spasm associated with acute, painful musculoskeletal conditions. Its chemical structure resembles that of TCAs. Pharmacologically, cyclobenzaprine exhibits reserpine antagonism, norepinephrine potentiation, and strong central and peripheral anticholinergic effects.5 It also likely augments central serotonin transmission. Previous “Psychopharmacology Reviews” have reported on episodes of paranoid psychosis associated with cyclobenzaprine use.6,7 The following is a report of serotonin syndrome resulting from an interaction between cyclobenzaprine and the serotonin norepinephrine reuptake inhibitor duloxetine.8


A 53-year-old man with a history of multiple low-back surgeries was admitted for the removal of infected spinal hardware. He had a history of chronic pain and depression, for which he was receiving duloxetine 60 mg/day, pregabalin 75 mg BID, bupropion 300 mg/day, and oxycodone or hydromorphone as needed for pain. The patient underwent uneventful removal of his spinal hardware under general endotracheal anesthesia. Postoperative pain was managed with opiates; his infection was treated with vancomycin. Two days after the surgery, the patient developed worsening confusion with hallucinations. On the fifth postoperative day, over the course of a few hours, he became very diaphoretic, tachycardic, and markedly agitated. Pronounced tremors, spontaneous sustained clonus, and multifocal myoclonus were noted. Laboratory studies revealed hypernatremia (154 mEq/L) and lactic acidosis (arterial pH 7.27, anion gap 20, lactate level 10.1 mmol/L). There was only mild hyperthermia and no significant increase of his creatine kinase concentration (highest 265 U/L). Because of the extreme severity of his agitation, the patient’s trachea was intubated after administration of propofol and vecuronium. He was then sedated with a continuous infusion of propofol and scheduled intravenous lorazepam. To allow for serial neurologic examinations, sedation was withheld at prearranged intervals. The patient was rehydrated, with a b-blocker used to ameliorate the tachycardia.


In reviewing the case, the treating physicians recognized that the patient had been given cyclobenzaprine 10 mg TID very shortly before the onset of his confusion. His medication regimen also included duloxetine 60 mg/day, which the patient had been taking for the previous 4 months, and oxycodone 5 mg every 6 hours as needed for pain, which he had also been using for several weeks before the current hospital admission. Bupropion had not been administered for more than 60 hours. Cyclobenzaprine and duloxetine were stopped. The serotonin antagonist cyproheptadine 8 mg via nasogastric tube every 6 hours was administered for 72 hours. Over the next few days, the patient’s clinical status improved steadily. Two days later, he was tracheally extubated and recovered without sequelae.


The temporal sequence of events described above is consistent with serotonin syndrome resulting principally from an interaction between cyclobenzaprine and duloxetine. A contributing role in precipitating serotonin syndrome from the opiates oxycodone and hydromorphone, as well as from use of the norepinephrine dopamine reuptake inhibitor bupropion, cannot be excluded. The package insert for cyclobenzaprine warns against its use in conjunction with MAOIs but not with SRIs. Given the seriousness of serotonin syndrome, clinicians ought to be aware of the potential for duloxetine, as well as likely other SRIs, to result in this condition when used in combination with cyclobenzaprine. PP


1. Lavery S, Ravi H, McDaniel WW, Pushkin YR. Linezolid and serotonin syndrome. Psychosomatics. 2001;42(5):432-434.
2. Sternbach H. The serotonin syndrome. Am J Psychiatry. 1991;148(6):705-713.
3. Birmes P, Coppin D, Schmitt L, Lauque D. Serotonin syndrome: a brief review. CMAJ. 2003;168(11):1439-1442.
4. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120.
5. Flexeril [package insert]. Whitehouse Station, NJ: Merck & Co; 1998.
6. Beeber AR, Manring JM Jr. Psychosis following cyclobenzaprine use. J Clin Psychiatry. 1983;44(4):151-152.
7. O’Neil BA, Knudson GA, Bhaskara SM. First episode psychosis following cyclobenzaprine use. Can J Psychiatry. 2000;45(8):763-764.
8. Keegan MT, Brown DR, Rabinstein AA. Serotonin syndrome from the interaction of cyclobenzaprine with other serotonergic drugs. Anesth Analg. 2006;103(6):1466-1468.


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Allen Childs, MD, FAPA, and Larry Price, PhD
Primary Psychiatry. 2007;14(3):50-56

Dr. Childs is chief psychiatrist in the Multiple Disabilities Unit at North Texas State Hospital in Vernon, clinical associate professor of psychiatry at the University of Texas Southwestern Medical School in Dallas, and medical director at Electromedical Products International. Dr. Price is associate professor of psychometrics and statistics and associate dean for research and sponsored projects at the College of Education at Texas State University in San Marcos.


Disclosure: Drs. Childs and Price report no affiliation with or financial interest in any organization that may pose a conflict of interest.


Please direct all correspondence to: Allen Childs, MD, FAPA, Clinical Associate Professor of Psychiatry, c/o North Texas State Hospital, Vernon Campus, P.O. Box 2231, Vernon, TX 76384; Tel: 940-552-9901; Fax: 940-553-2514; E-mail: allen.childs@dshs.state.tx.


Focus Points

• Cranial electrotherapy stimulation (CES) has anti-aggressive effects in chronically ill neuropsychiatric patients.


• CES can be used safely with all psychoactive medications.


• Among 48 patients, 83% responded positively to CES.


• Aggressive episodes as well as use of restraints, seclusion, and as-needed emergency medications all declined following CES in a difficult-to-treat neuropsychiatric population.


• Sudden assault syndrome is characterized by repeated attacks without apparent motivation, medication resistance, and responsiveness to CES.


• CES has United States Food and Drug Administration approval for the treatment of anxiety, depression, and insomnia.


The study sought to determine if 3 months of daily cranial electrotherapy stimulation (CES) treatment reduced aggression in violent neuropsychiatric patients in a maximum security hospital.CES was used to treat 48 chronically aggressive neuropsychiatric patients in a maximum security psychiatric hospital. Retrospective chart review compared 3 months pre-treatment with 3 months of active therapy. Early patients had responded positively to CES with a 41% reduction in episodes of violence (P<.001), a 40% reduction in episodes requiring restraint (P<.001) and seclusion (P<.05), and 42% fewer as-needed emergency medications (P<.01). A subgroup of 10 treatment-resistant psychotic patients, who attacked without warning or apparent motivation and were designated as having sudden assault syndrome, were 48% less violent on CES (P<.001). CES has significant anti-aggressive effects in violent neuropsychiatric patients, who are often refractory to medication. This safe, easy-to-administer treatment can benefit long-term severely ill patients.


A report from Germany described a 60% improvement rate in medication-resistant schizophrenic patients who had been ill >5 years and who had undergone cranial electrotherapy stimulation (CES) treatment for >2 years.1 A preliminary report of the first nine cases of the 48 reported herein showed a decline of 58% in number of aggressive episodes, a decline of 72% in number of seclusions, 58% fewer incidences requiring restraints, and 53% fewer required PRN medications.2


CES has widespread effects on electrophysiology and neurochemistry. Quantitative electroencephalograms as well as pre- and post-CES have shown significant increases in alpha waves (8–12 Hz) accompanied by decreases in delta waves (1–3 Hz).3 A comprehensive, annotated bibliography of CES detailing 126 human and 29 animal studies4 refers to cerebral spinal fluid studies showing a 150% to 200% increase in serotonin following CES treatment.5 The enzyme monoamine oxidase (MAO)-B rises with CES, indicating increased metabolism of dopamine and tyramine.6 Meta-analysis of studies of CES in anxiety conducted by Klawansky and colleagues7 found an effect size of r=.53, meaning the average patient was 53% improved, a strong effect size. CES devices have been in use in the United States for >50 years, and the Food and Drug Administration has granted clearance for CES devices to be marketed for the treatment of anxiety, insomnia, and depression.

Materials and Methods

Since 2001, North Texas State Hospital at Vernon (NTSH-V) has treated >120 aggressive neuropsychiatric patients with CES. A retrospective chart review was carried out on all patients receiving CES from 2001–2005, yielding 48 cases with adequate pre-treatment data (2–3 months) and 2–3 months of active treatment data. Outcomes that were tallied in the chart review included the following measures of aggressive behavior: the number of significant physical and verbal aggressive episodes, frequency of the use of restraints, frequency of the use of seclusion, and number of medications given on an as-needed or emergency basis (hereafter referred to as PRN medications). Diagnoses and other demographic data were also gathered.


All patients gave informed consent for CES and were typically treated for 20 minutes to 1 hour twice daily while they went about their activities on the unit. The prescriptive device used was the Alpha-Stim 100,8 which produces a modified square waveform at a frequency of either 0.5 Hz (cycles per second) or 100.0 Hz at a current of 100–600 microamperes. This treatment involves the transcranial application of extremely low-dose electrical current to the brain (≤600 microamperes) through moistened electrodes attached to the ear lobes from a pocket-sized device.


The patients remained on their usual (often multiple) antipsychotics and mood stabilizers during CES and continued participation in the hospital’s social learning, educational, and vocational rehabilitation programs.

Patient Characteristics

Every patient had multiple comorbidities. Forty-five patients (n=48) carried psychotic diagnoses, 31 patients had mental retardation (28 mild, 3 moderate), and 6 patients had central nervous system (CNS) trauma. Well-controlled seizure disorders were noted in 18 patients. Some form of personality disorder was diagnosed in almost all cases, but only 3 patients were diagnosed primarily with antisocial personality disorder. Two patients had Huntington’s chorea, and pervasive developmental disorder with psychosis was noted in two other cases, both of whom were also mentally retarded. One patient met criteria for intermittent explosive disorder. Psychotic diagnoses included 12 patients with schizoaffective disorder (manic type), eight patients with disorganized schizophrenia, seven patients with paranoid schizophrenia, five patients with undifferentiated schizophrenia, and two patients with bipolar disorder (manic type).


The patients, between 18–62 years of age, had been hospitalized from a few months to >20 years and included many of the most resistant people in the maximum security unit of NTSH-V. This 320-bed hospital receives patients whose aggression has exceeded the management capacity of the state’s 25 other psychiatric hospitals and state schools. Review boards at these facilities had declared 41 of these patients “manifestly dangerous,” who, according to the Texas Administrative Code, are patients whose aggression has not improved in spite of treatment focused on reducing their dangerousness. The remaining seven patients had been found incompetent to stand trial on felony charges involving bodily injury.

Sudden Assault Syndrome

A subgroup of 10 patients had sudden assault syndrome (SAS), exhibiting behavioral characteristics that differed from their other 38 equally aggressive peers. Rather than the more familiar patterns of aggression (eg, obvious anger at someone or something, command auditory hallucinations, fear of attack or humiliation by others), these 10 patients showed none of these traits before or after their repeated assaults. They seldom showed anger or distress, giving staff no warning of impending attacks. Afterward, they never expressed any rationale (psychotic or otherwise) that might be seen as a motivation for hitting others. They were not fearful or angry. Typical responses to staff inquiries were “I don’t know” or no response at all.9


Although all 10 of these patients were psychotic, staff were unable to identify explanatory surges or patterns of change in delusional thinking that might account for these patients’ frequent, unpredictable violence. Their aggression did not result from demands by staff or attacks by peers. Their psychoses were highly medication resistant, as was their assaultiveness, even after years of multiple medication trials. Four of the 10 patients never, or almost never, required restraint, seclusion, or PRN medicine after their assaults, as they did not continue to fight after striking the first blow. They never showed remorse. Curiously, they were not seen by staff as hostile in spite of their repeated attacks, which, when directed at staff, were regarded as “nothing personal.”

Case Report

A 57-year-old unmarried Caucasian woman was admitted to the maximum-security unit of NTSH-V, having been found to be “manifestly dangerous” at another state hospital where she had carried out 17 assaults on peers and staff over a 2-month period. In spite of numerous medication changes, 1:1 and even 2:1 staff coverage, and other specialized interventions, she continued to attack, throw furniture, kick walls and doors, and require frequent restraints. She would fall down up to eight times a day, accuse staff of shoving her, and make false reports to the Department of Regulatory Services. She was floridly paranoid, developed grudge lists, and would follow peers and staff around yelling at them to get away from her. At other times, she would target peers for assault when they were taking staff’s time and attention, which she was demanding. She sometimes expressed remorse over her actions, but did not change her behavior.


The patient’s history of psychiatric hospitalizations began nearly 40 years ago, having first been hospitalized at 15 years of age. Since 1991, she was in state hospitals in Texas 11 times and was in prison for 2 years for stealing a car with a baby in the back seat. For the past 13 years, she was homeless when not incarcerated. Throughout the years, antipsychotics, including clozapine, would produce a certain level of improvement in the schizoaffective disorder in that her hallucinations would become quiescent, but she was never able to be maintained in half-way houses or nursing homes because of her violent behavior. Her last such placement ended when she broke an attendant’s arm. She was thought to be of borderline intelligence, but had obtained a general equivalency diploma while in prison. The patient had grown up in a sexually and physically abusive home, had started using alcohol and street drugs at age 12, and described herself as an alcoholic like her father by 21 years of age.


In the first 3 months at NTSH-V, she was treated with maximum doses of quetiapine and ziprasidone along with a large dose of oxcarbazepine and escitalopram. She had 12 episodes of physical assault in this pre-CES period, requiring 12 restraints and 66 PRN medication administrations. In spite of the large doses of medicine, she was sleepless many nights, ate irregularly, and was deeply paranoid and withdrawn between aggressive outbursts.


CES was started at the .5 Hz setting, 1 hour twice daily and 15–45 minutes up to three times/day for her frequent agitated episodes. Compliance with CES improved after 2 weeks, and she began sleeping and eating better. Oxcarbazepine and ziprasidone were discontinued and a small dose of clozapine (200 mg/day) was added. Two weeks later the quetiapine dose was cut in half and she continued the escitalopram. In the first month of CES, she had only five aggressive episodes and required four restraints. PRNs dropped to 19.


After 6 weeks of CES, the patient’s personality changed dramatically. She became outgoing, was no longer accusatory, and her grooming and hygiene became exceptional. Her assaultive behavior stopped altogether, as did the necessity for PRNs and other interventions. At the end of 3 months of CES she passed the dangerousness review board and was returned to the referring hospital. There was no recurrence of her illness on discontinuation of the CES treatments. Observers familiar with the patient from her years at both hospitals commented on what a different person she had become.


Of the 48 cases included in this report, 40 responded positively to CES (an 83% response rate). Figure 1 and Table 1 provide the prevalence (frequency counts) of aggressive episodes, seclusions, restraints, and PRNs from pretest to posttest for the total sample. In the 3 months prior to CES, the 48-person group committed 1,301 acts of aggression, the severity of these episodes reflected in the necessity for restraint and/or seclusion in >50% of the incidents. During the 3 months of active CES treatment, this group committed 767 acts of aggression, a decline of 41%. Number of seclusions required declined from 199 to 120 (a decrease of approximately 40%), and number of times patients required restraint decreased from 446 to 268 (a decrease of approximately 40%). During the same time frame, frequency of PRN medication went from 648 times over 3 months of pre-treatment to 377 times during 3 months of active treatment (a decline of approximately 42%). Table 2 provides the statistical findings for the total sample.






















The 10 SAS cases, taken separately, revealed nine responders with the following changes in behavior: aggressive episodes were down from 325 to 170 (a decline of 48%), seclusions decreased by 44%, restraints dropped by 54%, and PRNs were used more than 80% less (Figure 2). Table 3 provides the statistical findings for the patients exhibiting incidence of SAS.












Overall, 32 patients were discharged from the hospital, and only one has been readmitted as of this writing. Five of the six CNS trauma cases improved. All of the 7 previously incompetent to stand trial cases, six of whom were CES responders, have been found competent and have been returned to the courts for judicial processing. None of these patients were diagnosed with antisocial personality disorder. Two other patients, one of whom was primarily antisocial, and the other with pronounced antisocial traits, were non-responders to CES.


There were no troublesome side effects of CES in this population, though early in the treatment a few patients destroyed devices by throwing them on the floor. Some patients noted mild drowsiness. A sensation of light-headedness may occur early in a treatment session and usually disappears if the current is decreased. Compliance was good for almost all cases, whether responsive or not. Often, patients requested and were given CES treatments on a PRN basis; at other times staff initiated extra CES sessions when patients became agitated. For most patients, the earlier in an outburst the CES treatment was started, the better the calming result. CES has been used up to 4 hours continuously in four highly agitated individuals. All patients who benefited were offered ongoing CES treatments, and some have been using it daily for 4 years.


These data confirm the previously reported anti-aggressive effect of CES. The favorable impact on these treatment-resistant cases has significantly lowered the level of violence on the wards of NTSH-V. Particularly notable are the relatively large effect sizes found in this study, indicating that not only did this treatment result in significant improvements across numerous outcomes, but that the amount of improvement in these areas was generally quite large.


The most striking improvements occurred in the sudden assault patients, eight of whom had been hospitalized from 10–25 years. There was no other change in their treatment, including medication, that might have otherwise accounted for the sustained improvement in their behavior. In each of the nine patients who responded to CES, relatedness (eg, social skills, interpersonal initiative), hygiene, and program participation improved. Certainly, every psychiatric hospital caring for chronically ill patients has cases like these, whose psychoses have minimally improved on adequate (or even multiple, high dose) psychotropic medications, but who remain unpredictably aggressive. In this group, it is meaningful that seven of the 10 have been declared no longer “manifestly dangerous” and have left the maximum-security hospital without having to return. None of these discharges were anticipated prior to the use of CES.


The reduction of PRN medicine was particularly striking, at 42%. The decrease of 271 PRN medication doses in 3 months resulted in a savings of >$12,000 for these medication expenses alone.


Benefits were cumulative with some of the most robust successes appearing 4–6 months after starting CES. It is likely that a longer course of CES is required in these severe illnesses (eg, disorganized schizophrenia). After the first few days, compliance with CES treatments was rarely a problem even in those patients who were otherwise barely approachable. A clinical trial of 3–6 months in these difficult patients can be confidently recommended.


Patients regularly reported feeling more relaxed. The mechanism of the anti-aggressive effects of CES may result from its ability to induce the brain to generate more alpha waves.3 CES seemed to augment or even work synergistically with the usually prescribed antipsychotics and mood stabilizers. This was especially apparent when CES was used in conjunction with modest (<300 mg/day) doses of clozapine in the most refractory cases (8 of the 48).












Other mechanisms of the reported improvement may relate to the finding that CES is known to increase the enzyme MAO-B in the CNS, meaning dopamine is being turned over at a faster rate.6 γ-aminobutyric acid, one of the major inhibitory neurotransmitters in the nervous system, also increases during CES treatment; this increase could contribute to its calming effect.6 Finally, the steep rise of 150% to 200% in cerebral spinal fluid levels of serotonin subsequent to CES treatment might also be central to its anti-aggressive effects.5


Regardless of the possible mechanisms, CES has shown itself to be effective in a broad range of significantly ill, highly aggressive, neuropsychiatric patients in this maximum-security psychiatric hospital. Experience suggests CES may be beneficial in violent prison populations, and studies in these institutions are underway. At a time when psychiatric hospitals are under increasing pressure to diminish the use of seclusion and restraint, CES could be a useful addition to the treatment regimen of patients with behavioral dyscontrol.


Interestingly, as the hospital gained more experience with CES, clinicians began to prescribe it earlier in hospital stays (sometimes within hours of admission) because of the urgent need to control medication-refractory aggression. Most of the 50 patients who were treated immediately upon their arrival were as aggressive as the 48 reported herein, and they will be the subject of a separate report.


Since this was an uncontrolled, longitudinal cohort study, it is possible, though highly unlikely, that some other outside influence (eg, season of the year, the passage of time, a new therapist) could have been responsible for the significant reductions in aggressive behavior that were reported. In particular, the passage of time was not a factor, as many of the patients included in this report had maintained highly aggressive behavior for many years prior to CES treatment. Nor did this study control for increased attention to each patient while undergoing CES treatment. Based on the literature regarding the impact of increased attention on aggression, it is not likely that the attention given each patient in connection with CES treatment could possibly have the type of significant effect found in these 48 patients. Late-occurring improvements due solely to medications were unlikely, as most of the patients had been on many medications for years. It is the conclusion of the authors of this article that the data strongly support that CES treatment resulted in the significant decreases in aggression in these 48 patients. As a safe, efficacious, and cost-effective intervention, CES should be considered for wider use in seriously ill patients. PP


1. Klimke A, Klieser E. Effectiveness of neuro-electric therapy in drug resistant endogenous psychoses [German]. Fortschr Neurol Psychiatry. 1991;59(2):53-59.


2. Childs A. Cranial electrotherapy stimulation reduces aggression in a violent retarded population: a preliminary report. J Neuropsychiatry Clin Neurosci. 2005;17(4):548-551.


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