8 Pharmacology Treatment Controversies in Bipolar Disorder Addressed

Nassir Ghaemi, MD, MPH; Stephen M. Strakowski, MD

MedScape | Disclosures | June 30, 2016 http://www.medscape.com/viewarticle/865254?src=WNL_infoc_160724_MSCPEDIT_v2&uac=230835EY&impID=1163609&faf=1

Editor’s Note: Medscape recently asked Stephen M. Strakowski, MD, inaugural chair of psychiatry at Dell Medical School, University of Texas, Austin, and Nassir Ghaemi, MD, MPH, a professor in the Department of Psychiatry at Tufts Medical Center in Boston, Massachusetts, to identify and address clinical controversies in the diagnosis and care of bipolar disorder (BD). What follows are their comments.

Controversy 1: Use of Antidepressants in BD

Should antidepressants be used in BD? If so, at what doses and in which patients?

Nassir Ghaemi, MD, MPH: My view is that antidepressants shouldn’t be used in the vast majority of patients with BD, for the simple reason that they’ve been proven ineffective.

Experts like to argue the ins and outs of the various randomized clinical trials, and they will point out all the possible ways in which they can be interpreted to eke out a tiny bit of support for using antidepressants. But in fact, the majority of trials consistently show no benefit, or very little benefit, of antidepressants in treating the acute depressive episodes in BD. The same has been shown in prevention.

Again, I emphasize randomized trials, because in my experience, many clinicians who support the use of antidepressants in BD often cite a nonrandomized cohort here and there, as if the more valid randomized literature didn’t exist. Besides the basic scientific point that our most valid studies find that the drugs don’t work better than placebo, other randomized trials have found that they can worsen the illness, both by causing acute mania and by causing rapid cycling.

The acute mania issue is again debated by experts, because many studies don’t differentiate from placebo—but others do. There are differences based on the agent used and dosing, but the fact that some agents can cause acute mania is reasonably proven.

The more important issue, in my view, is that replicated randomized trials have found that these agents can cause or worsen rapid-cycling. Thus, in some people, they are mood destabilizers that worsen the illness and counteract any potential benefits from mood stabilizers.

In sum, antidepressants in BD are ineffective at best, and harmful at worst, and thus best avoided in general.

Dr Strakowski: In general, I am in agreement with Dr Ghaemi. Like him, I do not believe there is strong evidence for the value of antidepressants in treating bipolar I disorder in particular, and probably in bipolar II disorder as well (although some studies suggest that selective serotonin reuptake inhibitors [SSRIs] might be useful in the latter). The STEP-BD study,[1] coupled with other recent work, was fairly convincing that modern antidepressants are neither particularly effective, but nor do they commonly precipitate mania.

There is also no strong literature supporting the efficacy of older antidepressants in this diagnosis; moreover, much of the literature suggesting that antidepressants induce mania arose primarily with tricyclic antidepressants (TCAs). However, whether TCAs and monoamine oxidase inhibitors (MAOIs) truly precipitate mania remains unclear; some studies, such as the NIMH Collaborative Depression Study,[2] found that depression in and of itself increases the risk for mania in BD, which virtually completely confounds antidepressant effects.

SSRIs may play a role in helping to manage co-occurring anxiety disorders in patients with BD, but the literature here remains modest. Consequently, in my own practice and most guidelines, there is still enough uncertainty that antidepressants are not completely removed from treatment pathways, but are perhaps third- or fourth-line therapy. In my own practice, instead I tend to lean on maximizing mood stabilizers, considering atypical antipsychotics, and incorporating cognitive-behavioral and other evidence-based therapies before considering antidepressants.

Dr Ghaemi: In terms of which agents are of the most concern regarding mania, clearly the older TCAs and MAOIs are associated with mania more so than the newer SRIs. The rates in observational trials tend to be about 25%-50% for the older agents, and about 10%-30% for SRIs. Among the latter, paroxetine has been studied the most and shown to be low risk in terms of acute mania. The same has been shown for bupropion, mainly at lower doses. Risk for acute mania with antidepressants also is inherently lower in type II than type I illness, with the above rates being cut in half or lower.

Dr Strakowski: Again, newer antidepressants, particularly in the presence of adequate mood stabilizers, appear to induce mania at rates no greater than placebo. The potential risks of TCAs and MAOIs, although not completely defined, coupled with their distasteful and risky side-effect profiles, suggest a truly limited role of these drugs in the treatment of individuals with BD.

Controversy 2: Antidepressants and Rapid Cycling

Can antidepressants cause rapid cycling?

Dr Ghaemi: As noted above, three replicated randomized trials have shown that this is the case: by Wehr and colleagues[3] and Wehr and Goodwin at the National Institute of Mental Health (NIMH)[4] in the 1970s with TCAs, and the STEP-BD study[1] using SRIs and newer agents, which is from our group. There are no randomized trials showing the reverse. Experts often cite observational data to the contrary, but randomized data are more valid than observational reports. Thus, the association is supported by the available evidence, although more studies are always helpful.

We have a third randomized trial, as yet unpublished, that again replicates this association: If persons with BD who have a rapid-cycling course are randomly assigned to receive antidepressants for 1 year, they have more depressive episodes than if they are randomly assigned to not receive antidepressants for 1 year. The clinical implication, as noted, is that in a substantial number of patients with BD—probably about one quarter—antidepressants worsen the illness, causing more and more mood episodes over time.

In these patients, antidepressants are mood destabilizers and are harmful, and probably counteract any potential benefit that might accrue from using mood stabilizers. My clinical experience for over two decades is that such patients will not improve until antidepressants are stopped and consistently avoided while mood-stabilizing agents are used. Often, by stopping and prohibiting any future antidepressant use, those same mood stabilizers that “failed” in the past (when given with antidepressants) will prove effective.

Dr Strakowski: Dr Ghaemi emphasizes a critical point that I often raise when discussing rapid cycling—namely, that this course of illness is typically time-limited and related to a precipitant or “irritant.” Possible precipitants include drug and alcohol use/abuse, thyroid disease, stressful life events, and antidepressants—although unfortunately, as Dr Ghaemi points out, the research evidence for most of these remains somewhat limited.

The presence of rapid cycling warrants a careful search for these possible precipitants, nonetheless, and then every attempt should be made to remedy or remove the precipitant. In these types of individuals, I will almost always work to simplify the treatment regimen and maximize mood-stabilizer coverage as suggested. Antidepressants do not play a role in the treatment of patients with rapid cycling.

As a caveat, mood lability is a common feature of mania; consequently, clinically I have found that patients diagnosed with so-called ultra-rapid cycling are often actually in a manic or mixed state. Again, use of antidepressants in patients with a manic or mixed state has no research support and may worsen illness, further supporting Dr Ghaemi’s point to eliminate antidepressants in patients who are experiencing rapid cycling.

Controversy 3: Neuroleptics Long-term?

Should neuroleptics be used on a long-term basis as “mood stabilizers”?

Dr Ghaemi: My view is that these agents are mistakenly viewed as effective by themselves for long-term prophylaxis of BD. Some have US Food and Drug Administration indications to this effect, but those studies are “enriched”—meaning that patients are preselected to respond to the neuroleptic for an acute mood episode before the prophylaxis study begins. In the 1 year or so of the prophylaxis study, most relapses occur in the first 6 months or less; in my view, this indicates relapse into the same acute mood episode that was present before the study began, not prevention of a totally new mood episode.

So if you treat a patient for acute mania with a neuroleptic, and then you stop the neuroleptic after the patient improves a few months later, and then the patient gets manic again a few months later—is that a totally new episode, or is that the same manic episode that the patient just experienced? It would be more convincing if episodes of the opposite polarity were prevented: that is, if a depressive episode occurred in the placebo arm after stopping treatment for an acute manic episode. But available data find that such enriched studies don’t prevent episodes of the opposite polarity.

In short, if you are known to like chocolate cake and are preselected to enter a study because you like chocolate cake, and no one else is allowed in the study, then if you are randomly assigned to eat chocolate vs vanilla cake, you’ll still like chocolate cake. This doesn’t prove that chocolate cake is inherently better than vanilla cake.

Dr Strakowski: Although I actually prefer vanilla cake (and lemon meringue pie even more), one could argue that the only truly established “mood stabilizer” is lithium, given the breadth of trials and its long history of use in European and other lithium clinics. In fact, in my own practice, lithium is my first drug of choice for all patients with BD.

That said, unfortunately, many patients cannot tolerate effective serum levels—and among those who do, a sizeable minority simply will not respond, so that alternatives are needed. Among these alternatives are anticonvulsants and antipsychotics, none of which has overwhelming evidence for long-term mood stabilization. Consequently, for individual patients, careful symptom monitoring during systematic trial and error to find which alternative is best tolerated and reduces the occurrence of affective episodes over longer periods is critical. I cannot overemphasize the importance of mood-charting over months, and even years, when making these decisions.

Among the antipsychotics, there is probably no role for long-term use of conventional (neuroleptic) antipsychotics, because studies suggest that at best they fail to prevent depression and at worse may precipitate depression (although studies are admittedly limited). Second-generation and later antipsychotics appear to be better choices but, to Dr Ghaemi’s point, remain incompletely tested

Controversy 4: Treating Type I vs Type II

Should the treatment of bipolar II disorder differ from that of bipolar I disorder?

Dr Ghaemi: Some experts make a big deal about the difference between bipolar I and bipolar II disorder, accepting that antidepressants are ineffective in the former but asserting that they are effective and safe in the latter. Some randomized trials report benefit and safety in bipolar II disorder, but there are others that report inefficacy.

I’m open to the notion that some patients with bipolar II disorder may benefit from low-dose antidepressants, in the short term especially, but I’m doubtful they are helpful in most patients—even those with type II illness. However, if someone has very mild bipolar II disorder, with rare and infrequent hypomanic episodes, they may have some benefit with some low-dose antidepressants.

Dr Strakowski: The diagnosis of bipolar II disorder is one of the least reliable in psychiatric practice because hypomania is infrequently witnessed, so that clinicians end up almost exclusively relying on reporting; here, individuals with chronic depression that waxes and wanes will often be mistakenly told they have “mood swings” and receive an erroneous diagnosis of bipolar II disorder. These patients are almost certainly manageable with antidepressants.

On the other hand, Amsterdam and Brunswick[5] and others have completed work in more carefully defined bipolar II disorder suggesting that SSRI monotherapy may be effective in some of these patients; this research also suggests that bipolar II disorder, at least in some individuals, may be more similar to recurrent major depression than bipolar I disorder.

Because the jury is still out on these issues, my recommendation in patients with bipolar II disorder is to first very carefully review evidence for the diagnosis—and then, when convinced that the diagnosis is probably correct, try to gain improvement through optimizing mood stabilizers before considering antidepressants.

Controversy 5: BD or Borderline?

How can BD be distinguished from borderline personality disorder?

Dr Ghaemi: Not by using the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), in my view. Most people focus on mood lability, which is a useless criterion because it is shared by both conditions. So too is the case with sexual impulsivity and unstable relationships. To differentiate conditions, one should focus on what is different between them, not what is the same.

The problem with the DSM is that it mostly lists only symptom criteria, but it doesn’t use other diagnostic validators in its criteria. Other validators of importance are course of illness and genetics.

BD is highly genetic (about 80%-90% heritability in meta-analyzed data); borderline personality, according to meta-analyzed data, is more mildly so (about 50% heritability in meta-analyzed data). They have different courses: Borderline personality was conceived as occurring in persons with childhood trauma that was often sexual, usually repetitive, and associated with repeated parasuicidal self-harm. BD has none of the above features but begins on average at age 19 years, and in about one half of persons, there is normal functioning between episodes. Thus, I would focus on the course of illness and genetic criteria to differentiate these conditions.

Dr Strakowski: Dr Ghaemi hits on the two key points that I use when making this distinction. The first is that BD is highly heritable, so a lack of any family history of psychiatric illness makes the diagnosis suspect (and a borderline personality disorder perhaps more likely).

The second is that borderline personality disorder, as defined as a “personality disorder,” is not really established until the late teens/early 20s and then is essentially persistent over time. In contrast, BD is episodic, with improved function during euthymic periods; this distinction is the most useful from a diagnostic perspective.

The two conditions are not mutually exclusive, however, so both may occur. My general rule of thumb when uncertain is to err on the side of broader treatment options and better prognosis (ie, a diagnosis of BD) to make treatment decisions and while accumulating additional information.

Controversy 6: Underdiagnosed or Overdiagnosed?

Is BD underdiagnosed, overdiagnosed, both, or neither?

Dr Ghaemi: The usual reply is to say “both,” but one could say that about any condition, because all conditions involve some mistakes, some misdiagnoses. The real question is which is more predominant: Do misdiagnoses tend to go in the direction of missing BD when it is present, or mistakenly diagnosing BD when it is absent?

As a matter of percentages, the answer is that multiple studies have found that BD is predominantly missed when it is present, hence it is underdiagnosed. The rates tend to be about 30%-40%, even in studies by those who claim overdiagnosis. The rate at which BD is mistakenly diagnosed when it is not present has never been shown to be more than 13%, even in studies that claim overdiagnosis.

A common error is to mistake unreliability for overdiagnosis. The mistaken studies claiming overdiagnosis do so because they report that about 50% of patients diagnosed by clinicians with BD do not have it when reinterviewed by researchers. But this is not over- or underdiagnosis; this is simply unreliability. The same rates can be found with every psychiatric illness, and in fact with many other medical diagnoses. The kappa value for major depressive disorder (MDD) in the DSM-5 field trials was about 0.3—which means that more than 50% of the time, when clinicians would diagnose MDD, they were wrong. This isn’t systematic overdiagnosis of any single condition, but rather unreliability of all psychiatric diagnosis.

Dr Strakowski: My prediction is that there are small subgroups around the world in which BD is overdiagnosed for a variety of reasons, but as Dr Ghaemi points out, the preponderance of evidence continues to suggest that the condition is too often missed. Some data suggest that it still takes multiple physician visits and up to 7 years to finally land on a (correct) BD diagnosis.

Within certain ethnic groups, namely African Americans, people with BD are very commonly misdiagnosed, in this case with schizophrenia. In fact, it appears that if you are African American and have a mood disorder, you have a nine times greater risk of being misdiagnosed with schizophrenia than a similar white patient.

Our research suggests that in African American patients, mood symptoms are either not identified or minimized; it is critical to remember that schizophrenia is a diagnosis of exclusion in all patients, but especially in this population at risk for misdiagnosis.

Controversy 7: Interpreting the Mixed Modifier

How would you interpret or use the new DSM-5 mixed modifier?

Dr Ghaemi: I think this is a step forward, because it allows the concept of mixed states to apply to MDD, and not just BD. It harkens back to the original notion of mixed states—which had nothing to do with BD, but instead reflected the idea that most mood states of any kind, whether depressive or manic, are not purely one way or the other, but tend to have some mixture of mood symptoms of both kinds.

The problem with the DSM-5 definition is that it was abstract and speculative, rather than based on empirical data. The DSM-5 task force decided, on a priori speculative grounds, to disallow any “overlapping” mood symptoms when diagnosing mixed features. Thus, irritable mood and psychomotor agitation, which are the most common mixed symptoms, are not allowed as diagnostic of mixed features in DSM-5. This would be like saying that in the diagnosis of migraine, pain in the head is not allowed as a diagnostic symptom.

The empirical literature contradicts the DSM-5 opinion—but unfortunately, as with all things DSM-related, the profession is faced with a top-down mandate of a professional organization, even when the scientific literature supports other views. I appreciate the step made by DSM-5, but I support using the mixed concept on the basis of our best scientific data, not the theoretical views of DSM-5.

Dr Strakowski: The struggle with the constantly changing definitions of “mixed states” in DSM-5 and all of its predecessors is an ongoing failure to recognize the roles of diagnostic constructs. Namely, there are three major roles: 1) to guide treatment, because evidence has accumulated that a specific diagnostic construct responds to a specific treatment; 2) to guide prognosis on the basis of the same rationale, so that we can help patients know what to expect; and 3) to guide research, so that two investigators talking about something will define it similarly.

In the case of the DSMs, which are predominantly and widely used as clinical documents, changes in diagnostic constructs should occur rarely and only with evidence suggesting that a change is needed. Unfortunately, the mixed-state definitions in the DSM change so often, with so little evidence that a change is necessary or an improvement, that in the end I don’t think we have enough information to tell whether the most recent change improved how we care for people or not and certainly has not added to research. My hope is that the current iteration will stay in place long enough to be tested to see whether it meets any of the roles a diagnostic construct plays.

Controversy 8: BD or ADHD?

Can attention-deficit/hyperactivity disorder (ADHD) and BD be distinguished? What is the role of stimulants in comorbid BD/ADHD?

Dr Ghaemi: As with borderline personality disorder, I would focus not on symptoms shared in common (inattention), but differences in genetics and course. If BD genetics and repeated mood episodes are present, then in my view the diagnosis should be BD, not ADHD.

I believe that the concept of comorbidity is mistaken when we fail to take a hierarchical approach and avoid diagnosing ADHD in persons with active anxiety, mood, and psychotic symptoms, all of which can cause inattention. We don’t diagnose “fever disorder” in everyone with pneumonia; we should be diagnosing ADHD in persons with manic, depressive, or anxious symptoms. Thus, in general, I think we should also avoid using stimulants in such persons, in part because stimulants are also antidepressants and have all of the mood-destabilizing effects described above. Thus, they can worsen BD.

Instead, by avoiding stimulants, we find that attention will improve in many persons once mood is improved. In a minority of patients in whom this is not the case, we may be dealing with longer-term cognitive impairment, which is associated with long-standing BD. In the long run, lithium is neuroregenerative and may provide some eventual cognitive benefits.

Short-term improvement with amphetamine stimulants need to be weighed against the animal data indicating that those agents are neurotoxic, causing neuronal harm. This has never been disproven in humans, and we should not assume these agents are safe in humans but harmful in animals. My concern would be that long-term use of these agents could worsen the cognitive impairment that is part of active BD. Thus, in my view, stimulants are best avoided in general in BD.

Dr Strakowski: ADHD and affective episodes in BD share many similar symptoms that include inattention, distractibility, and impulsivity, which leads to diagnostic confusion across the age span. However, although mood symptoms can occur in individuals with ADHD, typically these will not rise to the level of affective and particularly manic syndromes.

Moreover, by definition ADHD starts before age 12 years (in DSM-5), whereas BD (ie, mania) is not expressed fully until the teenage years. ADHD is persistent; BD is episodic. Finally, per Dr Ghaemi’s point, BD is much more heritable—so that a strong family history of mood disorders, or the absence of such, also may distinguish the two.

All of this is to say that a careful assessment can often determine whether, in persons with BD, the symptoms truly meet criteria for a second ADHD diagnosis or instead are simply part of the mood episode or interepisode symptoms. In my clinical consulting experience, I have encountered a frequent tendency to overdiagnose ADHD in adults, primarily by not attending to the onset age requirement of ADHD. That said, in younger patients, this co-occurrence is commonly reported in clinical research studies.

Minimal controlled research is available to guide treatment decisions, but clinical expert opinion currently appears to commonly land on the view that stimulants are probably safe, at least in the short term, for truly comorbid ADHD in BD if the BD has been optimally stabilized.

Moreover, in the treatment of BD, whether or not stimulants are truly destabilizing is not really known, although this is generally assumed. The long-term safety and efficacy of stimulants used as treatments for any reason in patients with BD remain unknown; more controlled clinical trials are needed in both children and adults (obviously, stimulant abuse worsens the course). Stimulants, then, probably remain in treatment algorithms for BD, but are third- or fourth-line after other treatments have failed.


  1. Sachs GS, Thase ME, Otto MW, et al. Rationale, design, and methods of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Biol Psychiatry. 2003;53:1028-1042. Abstract
  2. Elkin I, Shea MT, Watkins JT, et al. National Institute of Mental Health Treatment of Depression Collaborative Research Program. General effectiveness of treatments. Arch Gen Psychiatry. 1989;46:971-982. Abstract
  3. Wehr TA, Sack DA, Rosenthal NE, Cowdry RW. Rapid cycling affective disorder: contributing factors and treatment responses in 51 patients. Am J Psychiatry. 1988;145:179-184. Abstract
  4. Wehr TA, Goodwin FK. Rapid cycling in manic-depressives induced by tricyclic antidepressants. Arch Gen Psychiatry. 1979;36:555-559. Abstract
  5. Amsterdam JD, Brunswick DJ. Antidepressant monotherapy for bipolar type II major depression. Bipolar Disord. 2003;5:388-395. Abstract
  6. Rationale, design, and methods of the systematic treatment enhancement program for bipolar disorder (STEP-BD).

Biol Psychiatry.  2003; 53(11):1028-42 (ISSN: 0006-3223)

Sachs GS; Thase ME; Otto MW; Bauer M; Miklowitz D; Wisniewski SR; Lavori P; Lebowitz B; Rudorfer M; Frank E; Nierenberg AA; Fava M; Bowden C; Ketter T; Marangell L; Calabrese J; Kupfer D; Rosenbaum JF Partners Bipolar Treatment Center, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was conceived in response to a National Institute of Mental Health initiative seeking a public health intervention model that could generate externally valid answers to treatment effectiveness questions related to bipolar disorder. STEP-BD, like all effectiveness research, faces many design challenges, including how to do the following: recruit a representative sample of patients for studies of readily available treatments; implement a common intervention strategy across diverse settings; determine outcomes for patients in multiple phases of illness; make provisions for testing as yet undetermined new treatments; integrate adjunctive psychosocial interventions; and avoid biases due to subject drop-out and last-observation-carried-forward data analyses. To meet these challenges, STEP-BD uses a hybrid design to collect longitudinal data as patients make transitions between naturalistic studies and randomized clinical trials. Bipolar patients of every subtype with age >/= 15 years are accessioned into a study registry. All patients receive a systematic assessment battery at entry and are treated by a psychiatrist (trained to deliver care and measure outcomes in patients with bipolar disorder) using a series of model practice procedures consistent with expert recommendations. At every follow-up visit, the treating psychiatrist completes a standardized assessment and assigns an operationalized clinical status based on DSM-IV criteria. Patients have independent evaluations at regular intervals throughout the study and remain under the care of the same treating psychiatrist while making transitions between randomized care studies and the standard care treatment pathways. This article reviews the methodology used for the selection and certification of the clinical treatment centers, training study personnel, the general approach to clinical management, and the sequential treatment strategies offered in the STEP-BD standard and randomized care pathways for bipolar depression and relapse prevention.

  1. National Institute of Mental Health Treatment of Depression Collaborative Research Program. General effectiveness of treatments.

Arch Gen Psychiatry.  1989; 46(11):971-82; discussion 983 (ISSN: 0003-990X)

Elkin I; Shea MT; Watkins JT; Imber SD; Sotsky SM; Collins JF; Glass DR; Pilkonis PA; Leber WR; Docherty JP Mood, Anxiety and Personality Disorders Research Branch, National Institute of Mental Health, Bethesda, MD.

We investigated the effectiveness of two brief psychotherapies, interpersonal psychotherapy and cognitive behavior therapy, for the treatment of outpatients with major depression disorder diagnosed by Research Diagnostic Criteria. Two hundred fifty patients were randomly assigned to one of four 16-week treatment conditions: interpersonal psychotherapy, cognitive behavior therapy, imipramine hydrochloride plus clinical management (as a standard reference treatment), and placebo plus clinical management. Patients in all treatments showed significant reduction in depressive symptoms and improvement in functioning over the course of treatment. There was a consistent ordering of treatments at termination, with imipramine plus clinical management generally doing best, placebo plus clinical management worst, and the two psychotherapies in between but generally closer to imipramine plus clinical management. In analyses carried out on the total samples without regard to initial severity of illness (the primary analyses), there was no evidence of greater effectiveness of one of the psychotherapies as compared with the other and no evidence that either of the psychotherapies was significantly less effective than the standard reference treatment, imipramine plus clinical management. Comparing each of the psychotherapies with the placebo plus clinical management condition, there was limited evidence of the specific effectiveness of interpersonal psychotherapy and none for cognitive behavior therapy. Superior recovery rates were found for both interpersonal psychotherapy and imipramine plus clinical management, as compared with placebo plus clinical management. On mean scores, however, there were few significant differences in effectiveness among the four treatments in the primary analyses. Secondary analyses, in which patients were dichotomized on initial level of severity of depressive symptoms and impairment of functioning, helped to explain the relative lack of significant findings in the primary analyses. Significant differences among treatments were present only for the subgroup of patients who were more severely depressed and functionally impaired; here, there was some evidence of the effectiveness of interpersonal psychotherapy with these patients and strong evidence of the effectiveness of imipramine plus clinical management. In contrast, there were no significant differences among treatments, including placebo plus clinical management, for the less severely depressed and functionally impaired patients.

  1. Rapid cycling affective disorder: contributing factors and treatment responses in 51 patients.

Am J Psychiatry.  1988; 145(2):179-84 (ISSN: 0002-953X)

Wehr TA; Sack DA; Rosenthal NE; Cowdry RW Clinical Psychobiology Branch, NIMH, Bethesda, MD 20892.

For 51 patients with rapid cycling affective disorder, clinical and family history data indicated that the illness was phenotypically and genetically related to more typical forms of affective disorder, was characterized by a bipolar course (100%), and was more common in women (92%). Manic-depressive cycles were separate from menstrual cycles. At the time of onset of rapid cycling, 73% of the patients were taking antidepressant drugs; the continuation of rapid cycling was associated with antidepressant drug therapy in 51% of the patients. Although most patients had been referred to a research ward because they were considered to be refractory to treatment, 37% attained essentially complete remissions, usually during treatment with lithium and/or monoamine oxidase inhibitors.


  1. Rapid cycling in manic-depressives induced by tricyclic antidepressants.

Arch Gen Psychiatry.  1979; 36(5):555-9 (ISSN: 0003-990X)

Wehr TA; Goodwin FK

Maintenance tricyclic antidepressants induced rapid cycling between mania and depression in five female bipolar (manic-depressive) patients. Lithium carbonate did not prevent the tricyclic-induced rapid cycling, although two patients subsequently responded well to lithium carbonate alone. In these patients, the action of tricyclics can be conceptualized as accelerating rather than counteracting the natural, cyclic course of the illness in all of its phases. In this respect, tricyclics are analogous to several other drugs that are capable of modulating the frequency of oscillatory biological processes.

  1. Antidepressant monotherapy for bipolar type II major depression.

Bipolar Disord.  2003; 5(6):388-95 (ISSN: 1398-5647)

Amsterdam JD; Brunswick DJ Department of Psychiatry, Depression Research Unit, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. jamsterd@mail.med.upenn.edu

OBJECTIVES: Bipolar type II (BP II) disorder is thought to be distinct from BP I disorder on genetic and biological grounds, and it is not merely a milder form of the illness. It affects 1.5-2.5% of the US adult population, and is characterized by highly recurrent depressive episodes with a substantial morbidity from alcoholism and non-affective psychopathology, and a higher suicide rate than either BP I or unipolar depression. Treatment recommendations for BP II depression are based upon concerns over drug-induced manic-switch episodes, and suggest using either a mood stabilizer alone or a combination of an SSRI plus a mood stabilizer. Recent evidence, however, indicates that the rate of manic switch episodes may be modest in BP II patients. Recent studies have provided evidence that antidepressant monotherapy may be an effective initial and long-term treatment for BP II major depression with a low manic-switch rate. METHODS: In this article, we review the recent literature on BP II disorder, with a focus on the treatment of BP II major depression. RESULTS: We present a summary of data from recent studies by our group and others indicating that antidepressant monotherapy for BP II depression may be safe and effective with a low manic-switch rate. CONCLUSION: Antidepressant monotherapy may be beneficial for some patients with BP II major depression.