A randomized controlled trial of cognitive therapy for bipolar disorder: focus on long-term change

BACKGROUND: This study reports the outcome of a randomized controlled trial of cognitive therapy (CT) for bipolar disorder. The treatment protocol differed from other published forms of CT for bipolar disorder through the addition of emotive techniques. METHOD: Fifty-two patients with DSM-IV bipolar I or II disorder were randomly allocated to a 6-month trial of either CT or treatment as usual, with both treatment groups also receiving mood stabilizers. Outcome measures included relapse rates, dysfunctional attitudes, psychosocial functioning, hopelessness, self-control, and medication adherence. Patients were assessed during treatment by independent raters blind to the patients' group status. RESULTS: At posttreatment, patients allocated to CT had experienced less severe depression scores (Beck Depression Inventory and Montgomery-Asberg Depression Rating Scale) and less dysfunctional attitudes. After controlling for the presence of major depressive episode at baseline, there was a statistical trend toward a greater time to depressive relapse (p=.06) for the CT group. At 12-month follow-up, the CT group showed a trend toward lower Young Mania Rating Scale scores and improved behavioral self-control. The Clinical Global Impressions-Improvement scale, comparing the 18 months prior to treatment to the severity of illness status at follow-up, showed a substantial difference between groups in favor of CT. CONCLUSION: Our findings corroborate previous bipolar disorder research in demonstrating the value of CT, particularly immediately post-treatment, and indicate some continuation (albeit diminishing) of benefits in the succeeding 12 months. These findings suggest that psychological booster sessions may be crucial for maintaining the beneficial effects of cognitive therapy.     

A randomized trial of integrated group therapy versus group drug counseling for patients with bipolar disorder and substance dependence

OBJECTIVE: Although bipolar disorder and substance use disorder frequently co-occur, there is little information on the effectiveness of behavioral treatment for this population. Integrated group therapy, which addresses the two disorders simultaneously, was compared with group drug counseling, which focuses on substance use. The authors hypothesized that patients receiving integrated group therapy would have fewer days of substance use and fewer weeks ill with bipolar disorder. METHOD: A randomized controlled trial compared 20 weeks of integrated group therapy or group drug counseling with 3 months of posttreatment follow-up. Sixty-two patients with bipolar disorder and current substance dependence, treated with mood stabilizers for >or=2 weeks, were randomly assigned to integrated group therapy (N=31) or group drug counseling (N=31). The primary outcome measure was the number of days of substance use. The primary mood outcome was the number of weeks ill with a mood episode. RESULTS: Intention-to-treat analysis revealed significantly fewer days of substance use for integrated group therapy patients during treatment and follow-up. Groups were similar in the number of weeks ill with bipolar disorder during treatment and follow-up, although integrated group therapy patients had more depressive and manic symptoms. CONCLUSIONS: Integrated group therapy, a new treatment developed specifically for patients with bipolar disorder and substance dependence, appears to be a promising approach to reduce substance use in this population.     

Psychosocial therapies in bipolar disorder

The course of bipolar disorder is characterized by frequent recurrences, high levels of intermorbid symptoms, and poor psychosocial functioning even when patients take mood stabilizers. Psychosocial interventions have been developed as adjuncts to medication to prevent recurrences, enhance medication adherence, and enhance skills for coping with environmental stressors. This review of recent randomized clinical trials concludes that cognitive-behavioral therapy, family-focused therapy, interpersonal therapy, and group psychoeducation each have supportive evidence as adjuncts to pharmacotherapy in the outpatient maintenance of bipolar disorder.     

Relapse prevention in patients with bipolar disorder: cognitive therapy outcome after 2 years

OBJECTIVE: In a previous randomized controlled study, the authors reported significant beneficial effects of cognitive therapy for relapse prevention in bipolar disorder patients up to 1 year. This study reports additional 18-month follow-up data and presents an overview of the effect of therapy over 30 months. METHOD: Patients with DSM-IV bipolar I disorder (N=103) suffering from frequent relapses were randomly assigned into a cognitive therapy plus medication group or a control condition of medication only. Independent raters, who were blind to patient group status, assessed patients at 6-month intervals. RESULTS: Over 30 months, the cognitive therapy group had significantly better outcome in terms of time to relapse. However, the effect of relapse prevention was mainly in the first year. The cognitive therapy group also spent 110 fewer days (95% CI=32 to 189) in bipolar episodes out of a total of 900 for the whole 30 months and 54 fewer days (95% CI=3 to 105) in bipolar episodes out of a total of 450 for the last 18 months. Multivariate analyses of variance showed that over the last 18 months, the cognitive therapy group exhibited significantly better mood ratings, social functioning, coping with bipolar prodromes, and dysfunctional goal attainment cognition. CONCLUSIONS: Patients in the cognitive therapy group had significantly fewer days in bipolar episodes after the effect of medication compliance was controlled. However, the results showed that cognitive therapy had no significant effect in relapse reduction over the last 18 months of the study period. Further studies should explore the effect of booster sessions or maintenance therapy.     

Mood state at study entry as predictor of the polarity of relapse in bipolar disorder.

Of the placebo-controlled maintenance studies conducted in bipolar disorder, few have enrolled patients who present depressed. In fact, only lithium and lamotrigine have been studied over the long term with placebo-controlled designs in recently manic and recently depressed bipolar patients. Given the magnitude of the unmet medical need and the data suggesting that symptomatic patients with bipolar disorder spend the majority of their time depressed, this is unfortunate. Our review of the pre-lithium literature and more recent publications suggests that mood state at study entry predicts the polarity of relapse and the response to treatment. Accordingly, a need exists to enroll recently depressed patients in maintenance studies to elucidate the complete spectrum of efficacy of putative mood stabilizers and improve the long-term treatment of bipolar depression. Patients presenting depressed for a maintenance study tend to relapse into depression; those presenting manic, into hypomania/mania/mixed states. This is particularly true during the first several months of the randomized treatment. The polarity of the index episode tends to predict the polarity of relapse into a subsequent episode in a ratio of about 2:1 to 3:1. We conclude that putative mood stabilizers must be tested in recently manic and recently depressed patients to determine their spectrum of prophylactic efficacy.     

Preliminary results of a fine‐grain analysis of mood swings and treatment modalities of bipolar I and II patients using the daily prospective life‐chart‐methodology

Objective: The study aimed to increase the knowledge about the detailed course differences between different forms of bipolar disorder. Method: Using the prospective life‐chart‐clinician version, we compared the fine‐grain analysis of mood swings and treatment modalities of 18 bipolar II with 31 bipolar I patients. Results: During an observational period of a mean of 26 months we observed an increase of euthymic days, and a decrease of (sub)depressive and (hypo)manic days. Days in a (sub)depressed state were more frequent than days of (hypo)mania as well as days of subdepression or hypomania in comparison to days of full‐blown depression or mania. Bipolar II patients showed an increase in hypomanic days receiving more frequently antidepressants. Bipolar I patients, with a decrease of manic days, were significantly taking more often mood stabilizers. Conclusion: Treatment in a specialized bipolar clinic improves the overall outcome, but bipolar II disorder seems to be still treated sub‐optimally with a possible iatrogenic increase of hypomanic days.     

Recurrent cases of corticosteroid-induced mood disorder: clinical characteristics and treatment

BACKGROUND: Corticosteroids often induce steroid psychosis, a collection of heterogeneous syndromes with different pathophysiologic mechanisms. To date, no study has focused specifically on recurrent corticosteroid-induced mood disorders and considered their long-term outcome and treatment strategies. METHOD: Nine patients whose initial clinical presentation met DSM-IV criteria for a substance-induced mood disorder were identified by a review of medical records. Their clinical characteristics and treatments were examined. RESULTS: All 9 corticosteroid-treated patients had a clinical course of bipolar disorder. Seven patients initially developed a manic or hypomanic state with subacute onset ranging from 1 to 3 months. Six patients had manic episodes accompanied by psychotic features. The proportion of manic episodes relative to total mood episodes of the 9 patients was 65.6%, suggesting manic predominance. Seven patients showed mood episodes that had no direct relationship to corticosteroid therapy and were preceded by various psychosocial stressors. Four of 5 patients who received steroid pulse therapy rapidly became manic or hypomanic. Antidepressants as well as mood stabilizers were useful for treatment of the present 9 patients. CONCLUSION: Recurrent cases of corticosteroid-induced mood disorder have interesting clinical features, such as subacute onset, manic predominance, frequent accompanying psychotic features, and similar recurrent episodes in association with psychosocial stressors and corticosteroid use. Management, including psychopharmacologic intervention, should be indicated by a consideration of the underlying illnesses and psychosocial stressors.     

Mindfulness-based cognitive therapy for nonremitted patients with bipolar disorder

Introduction: Bipolar disorder is characterized by recurrent episodes of depression and/or mania along with interepisodic mood symptoms that interfere with psychosocial functioning. Despite periods of symptomatic recovery, many individuals with bipolar disorder continue to experience substantial residual mood symptoms that often lead to the recurrence of mood episodes. Aims: This study explored whether a new mindfulness‐based cognitive therapy (MBCT) for bipolar disorder would increase mindfulness, reduce residual mood symptoms, and increase emotion‐regulation abilities, psychological well‐being, positive affect, and psychosocial functioning. Following a baseline clinical assessment, 12 individuals with DSM‐IV bipolar disorder were treated with 12 group sessions of MBCT. Results: At the end of treatment, as well as at the 3 months follow‐up, participants showed increased mindfulness, lower residual depressive mood symptoms, less attentional difficulties, and increased emotion‐regulation abilities, psychological well‐being, positive affect, and psychosocial functioning. Conclusions: These findings suggest that treating residual mood symptoms with MBCT may be another avenue to improving mood, emotion regulation, well‐being, and functioning in individuals with bipolar disorder.     

Longitudinal outcome and medication noncompliance among manic patients with and without mood-incongruent psychotic features.

The prognostic utility of mood-incongruent psychotic features was examined in a sample of 23 hospitalized manic patients. Patients were initially subdivided according to whether they met Research Diagnostic Criteria (RDC) for schizoaffective, mainly affective (mood-incongruent) manic disorder (SAM; N = 11) or RDC primary manic (mood-congruent or nonpsychotic) manic disorder (PM; N = 12). Patients were then followed over a 9-month posthospitalization period and rated every 3 months for relapse status, symptom severity, social adjustment, and medication noncompliance. Patients with SAM and PM did not differ at follow-up on rates or timing of manic or depressive relapses or on cycling of symptoms of mood disorder. However, at follow-up, SAM patients had more severe positive and negative psychotic symptoms and poorer social adjustment, and were less medically compliant than PM patients. Results are consistent with the view that mania with mood-incongruent psychotic features is a poor-prognosis subtype of bipolar disorder.     

Psychotherapie bei bipolaren affektiven Störungen

Mood stabilisers show convincing evidence of relapse prevention in patients suffering from bipolar affective disorder. However, despite continuous medication the majority of patients suffer from relapses. It seems logical to apply principles of psychological intervention to bipolar patients. Elements of psychotherapy are: psychoeducation about symptoms, prodromal states, and course of illness; symptom monitoring; and influencing cognitive and behavioural strategies to improve symptomatology, social functioning, compliance, and relapse prevention. The goal of this review is to summarise the current status of controlled studies including psychological approaches to bipolar patients, to describe the efficacy of psychotherapy, and to address lack of knowledge and future trends in this clinical field. We located 461 reports about psychological interventions with bipolar patients but identified only 28 controlled and methodologically sound studies. In those studies 2294 patients were treated. Almost all (over 90%) fulfilled bipolar I criteria. All psychotherapies include psychoeducation and information about bipolar affective disorders and ask patients to self-monitor daily symptoms and other daily events. The majority of psychotherapies are cognitive-behaviorally oriented and treat patients in a one-to-one setting, but family oriented approaches and group settings were also prevalent. Studies show evidence that psychotherapy in combination with mood stabilizers improved depressive (to less extent manic) symptoms (d=0.39) and almost doubled the period of time between two episodes (d=0.71). Open questions are: indicators and predictors of successful outcome, length and intensity of treatment, essential elements of helpful intervention, long-term follow-up, and prevention of bipolar disorders in high-risk groups.     

Family-focused treatment of bipolar disorder: 1-year effects of a psychoeducational program in conjunction with pharmacotherapy.

BACKGROUND: Few studies have examined the combined effects of psychosocial treatment and pharmacotherapy for bipolar disorder. This study used a randomized, controlled design to examine a 9-month, manual-based program of family-focused psychoeducational treatment (FFT). METHODS: Bipolar patients (N = 101) were recruited shortly after an illness episode and randomly assigned to 21 sessions of FFT (n = 31) or to a comparison treatment involving two family education sessions and follow-up crisis management (CM; n = 70). Both treatments were delivered over 9 months; patients were simultaneously maintained on mood stabilizing medications. Patients were evaluated every 3 months for 1 year as to relapse status, symptom severity, and medication compliance. RESULTS: Patients assigned to FFT had fewer relapses and longer delays before relapses during the study year than did patients in CM. Patients in FFT also showed greater improvements in depressive (but not manic) symptoms. The most dramatic improvements were among FFT patients whose families were high in expressed emotion. The efficacy of FFT could not be explained by differences among patients in medication regimes or compliance. CONCLUSIONS: Family-focused psychoeducational treatment appears to be an efficacious adjunct to pharmacotherapy for bipolar disorder. Future studies should evaluate family treatment against other forms of psychotherapy matched in amount of therapist-patient contact.     

A prospective, longitudinal study of percentage of time spent ill in patients with bipolar I or bipolar II disorders

Background:  There is a recent appreciation that patients with bipolar disorder spend a substantial period of time with minor or subsyndromal mood symptoms both manic and depressive. This study examined time spent in minor and subsyndromal mood states as well as with mania and depression in a cohort of well characterized bipolar I and II patients who were followed prospectively for an average of three years.
Method:  Detailed life-charting data were obtained from 138 patients with bipolar disorder. Mood states were characterized as euthymic, subsyndromal, minor or major affective episodes based on rigorously defined criteria. The amount of time spent in these mood states during follow-up was examined.
Results:  Patients in the total sample and within each bipolar subtype spent approximately half of their time euthymic. The remainder of the time was spent in varying severity of mood states. However, the majority of time was spent with minor and subsyndromal symptoms, both manic and depressive. Bipolar I patients differ from bipolar II in that significantly more time was spent with subsyndromal, minor and manic symptoms. There was no difference in time spent with depressive symptoms between the two groups.
Conclusions:  Patients with bipolar disorder spend a substantial proportion of time with depressive or manic symptoms with the preponderance being minor or subsyndromal. Awareness of subthreshold symptoms in bipolar disorders and treatment of such symptoms may be improved by establishing guidelines that specifically outline appropriate strategies for reducing the duration of subsyndromal symptoms in bipolar disorder.     

Treatment of seasonal affective disorder: Unipolar versus bipolar differences

Evidence-based treatments for seasonal affective disorder (SAD) include light therapy and pharmacotherapy. We briefly review the diagnosis and treatment of SAD, focusing on clinical and treatment differences between patients with unipolar and bipolar illness. Special considerations for the management of SAD in patients with bipolar disorder are discussed, including the need to monitor for emergence of manic and hypomanic mood switches, to use mood stabilizers in patients with bipolar I disorder, and to be aware of potential interactions between bright light and medications used in treating bipolar disorder. Chronobiological treatments such as bright light therapy may be combined with pharmacotherapy to enhance therapeutic effects, reduce adverse side effects, and optimize treatment in patients with seasonal and nonseasonal bipolar disorder.     

Lamotrigine and antiepileptic drugs as mood stabilizers in bipolar disorder

OBJECTIVE: To review the clinical trials literature on the use of antiepileptic drugs (AED) as mood stabilizers and to suggest an evidence-based approach when utilizing these agents in bipolar disorder. METHOD: The literature is reviewed and subdivided into the following sections: carbamazepine and oxcarbazepine, valproate, lamotrigine, gabapentin and other AED, and discussion. RESULTS: Data exist to support the use of carbamazepine and valproate - and to a lesser extent, oxcarbazepine - in the management of acute manic episodes associated with bipolar I disorder. Lamotrigine, gabapentin, and other AED have not demonstrated consistent anti-manic effects. Clinical trials data favor lamotrigine over all other AED in the treatment of acute bipolar I depression and in rapid cycling bipolar disorder (particularly type II), although the absence of an active comparator in these lamotrigine trials must be noted. Lamotrigine, carbamazepine, and valproate all have evidence supporting their roles as potential long-term mood stabilizers to prevent bipolar relapse, with lamotrigine having a stronger effect in the prevention of depression. CONCLUSION: The AED are a heterogeneous group of medications with differential spectrum of efficacy in the treatment of bipolar disorder.     

Clozapine in adolescent inpatients with acute mania

Some bipolar patients with acute manic episodes can be refractory to conventional treatment with mood stabilizers. Clozapine, an atypical antipsychotic, has been reported to be effective in adults with treatment-resistant bipolar disorder. We describe the therapeutic effect of clozapine in 10 adolescent inpatients (12- to 17-year-olds) with severe acute manic or mixed episodes who did not improve after treatment with conventional drugs (mood stabilizers, antipsychotics). At hospital discharge, 15 to 28 days after clozapine treatment, all patients had responded positively according to the Clinical Global Impression-Improvement Scale scores. The mean changes in Mania Rating Scale, Brief Psychiatric Rating Scale, Children's Global Assessment Scale, and Clinical Global Impression-Severity Scale were significant (p < 0.001). Clozapine dosage was 142.5 +/- 73.6 mg/day (range 75-300 mg/day). Side effects (increased appetite, sedation, enuresis, sialorrhea) were frequent but not severe enough to require reduction of dosage. Mean weight gain after 6 months was 6.96 +/- 3.08 kg (10.7%). Neither decrease of white cells nor epileptic seizures were reported during follow-up (12-24 months). These preliminary findings suggest that clozapine may improve the clinical picture in adolescents with treatment-refractory manic or mixed episodes. Controlled studies on larger samples are warranted.     

A randomized study of family-focused psychoeducation and pharmacotherapy in the outpatient management of bipolar disorder

BACKGROUND: Bipolar patients are at risk for relapses of their illness even when undergoing optimal pharmacotherapy. This study was performed to determine whether combining family-focused therapy (FFT) with pharmacotherapy during a postepisode interval enhances patients' mood stability during maintenance treatment. METHODS: In a randomized controlled trial, 101 bipolar patients were assigned to FFT and pharmacotherapy or a less intensive crisis management (CM) intervention and pharmacotherapy. Outcome assessments were conducted every 3 to 6 months for 2 years. Participants (mean +/- SD age, 35.6 +/- 10.2 years) were referred from inpatient or outpatient clinics after onset of a manic, mixed, or depressed episode. FFT consisted of 21 sessions of psychoeducation, communication training, and problem-solving skills training. Crisis management consisted of 2 sessions of family education plus crisis intervention sessions as needed. Both protocols lasted 9 months. Patients received pharmacotherapy for 2 study years. Main outcome measures included time to relapse, depressive and manic symptoms, and medication adherence. RESULTS: Rates of study completion did not differ across the FFT (22/31, 71%) and CM groups (43/70, 61%). Patients undergoing FFT had fewer relapses (11/31, 35%) and longer survival intervals (mean +/- SD, 73.5 +/- 28.8 weeks) than patients undergoing CM (38/70, 54%; mean +/- SD, 53.2 +/- 39.6 weeks; hazard ratio, 0.38; 95% confidence interval, 0.20-0.75; P =.003; intent to treat). Patients undergoing FFT showed greater reductions in mood disorder symptoms and better medication adherence during the 2 years than patients undergoing CM. CONCLUSION: Combining family psychoeducation with pharmacotherapy enhances the postepisode symptomatic adjustment and drug adherence of bipolar patients.     

Morbidity in 258 bipolar outpatients followed for 1 year with daily prospective ratings on the NIMH life chart method

BACKGROUND: A number of recent longitudinal outcome studies have found substantial long-term morbidity in patients with bipolar disorder. The detailed course and pattern of illness emerging despite comprehensive treatment with mood stabilizers and adjunctive agents have previously not been well delineated. METHOD: 258 consecutive outpatients admitted from 1996 to 1999 to the Stanley Foundation Bipolar Network who had a full year of prospective daily clinician ratings on the National Institute of Mental Health-Life Chart Method were included in the analysis. Patients were diagnosed by the Structured Clinical Interview for DSM-IV, with the majority (76%) having bipolar I disorder. They completed a questionnaire on demographics and prior illness course, and variables associated with outcome were examined in a hierarchical multinomial logistic regression analysis. Patients were treated naturalistically with a mean of 4.1 psychotropic medications during the year. RESULTS: Despite comprehensive pharmacologic treatment, mean time depressed (33.2% of the year) was 3-fold higher than time manic (10.8%); 62.8% of patients had 4 or more mood episodes per year. Two thirds of the patients were substantially impacted by their illness; 26.4% were ill for more than three fourths of the year, and 40.7% were intermittently ill with major affective episodes. After logistic regression analysis, those who were ill most of the year, compared with the largely well group, had a significantly greater family history of substance abuse, 10 or more depressive episodes, and limited occupational functioning prior to Network entry. CONCLUSION: A majority of outpatients with bipolar illness, even with intense monitoring and treatment in specialty clinics, have a considerable degree of residual illness-related morbidity, including a 3-fold greater amount of time spent depressed versus time spent manic. A personal or family history of substance abuse, 10 or more prior depressions, and limited occupational functioning predicted the poorest outcomes. Additional interventions, particularly those targeted at treating depressive phases of bipolar illness, are greatly needed.     

Antidepressants and suicidal behavior in bipolar disorder

Patients with bipolar disorder are at very high risk for suicidal ideation, non-fatal suicidal behaviors and suicide and are frequently treated with antidepressants. However, no prospective, randomized, controlled study specifically evaluating an antidepressant on suicidality in bipolar disorder has yet been completed. Indeed, antidepressants have not yet been shown to reduce suicide attempts or suicide in depressive disorders and may increase suicidal behavior in pediatric, and possibly adult, major depressive disorder. Available data on the effects of antidepressants on suicidality in bipolar disorder are mixed. Considerable research indicates that mixed states are associated with suicidality and that antidepressants, especially when administered as monotherapy, are associated with both suicidality and manic conversion. In contrast, growing research suggests that antidepressants administered in combination with mood stabilizers may reduce depressive symptoms in patients with bipolar depression. Further, the only prospective, long-term study evaluating antidepressant treatment and mortality in bipolar disorder, although open-label, found antidepressants and/or antipsychotics in combination with lithium, but not lithium alone, reduced suicide in bipolar and unipolar patients (Angst F, et al. J Affect Disord 2002: 68: 167–181). We conclude that antidepressants may induce suicidality in a subset of persons with depressive (and probably anxious) presentations; that this induction may represent a form of manic conversion, and hence a bipolar phenotype, and that lithium's therapeutic properties may include the ability to prevent antidepressant-induced suicidality.     

Depression with versus without manic features in rapid-cycling bipolar disorder

Depression has been identified as a hallmark feature of rapid-cycling bipolar disorder, although less attention has been paid to the presence of manic features accompanying depression in rapid cyclers. To provide greater information about the extent to which depression arises with or without salient manic features in rapid cycling, we conducted a preliminary study of rapid cycling in outpatients seeking treatment at an academic specialty center for bipolar disorder. Forty DSM-IV affectively symptomatic bipolar outpatients with past year DSM-IV rapid cycling underwent systematic evaluation of symptoms and illness characteristics. Manic and depressive symptoms, treatments, and clinical features were rated by standardized scales. Major depression was present in most rapid cyclers (85%), but salient manic features were also evident in half of all depressed rapid cyclers. A lifetime history of suicide attempts was significantly more common in rapid cyclers who presented with major depression plus salient manic features than in those who presented with pure depression or pure mania (p = .033). Antidepressants were being prescribed for approximately one third of depressed rapid cycling patients regardless of the presence of concomitant manic features, whereas mood stabilizers tended to be used less often when manic features accompanied depression. Depression in conjunction with manic symptoms, rather than pure depression alone, may be more common among rapid-cycling bipolar patients who seek treatment. Lifetime suicide risk may be greater among rapid cycling patients whose depression occurs in tandem with manic symptoms. Prescribing habits in the community that favor antidepressants over mood stabilizers may promote further mood destabilization in this population. Further studies with larger sample sizes are needed to affirm these provisional findings.     

Pharmacotherapy of bipolar depression: An update

Bipolar affective disorder is a virulent illness with high rates of recurrence, disability, social impairment, and suicide. Although the manic or hypomanic episodes define the disorder, the depressions are more numerous and less responsive to treatment. As the initial depressive episodes are commonly misdiagnosed, initiation of therapy with mood stabilizers is often delayed, increasing the likelihood of treatment-emergent affective switches on antidepressant monotherapy. The empirical basis for selecting treatments for people with bipolar depression is weak, and only the combination of olanzapine and fluoxetine has received US Food and Drug Administration (FDA) approval. Conventional mood stabilizers are preferred for first-line therapies, although atypical antipsychotics are increasingly used, and FDA approval of quetiapine is pending. Antidepressants—particularly selective serotonin reuptake inhibitors and bupropion— are indicated when mood stabilizers are ineffective and for “breakthrough“ depressions.