Advances in the pharmacologic treatment of bipolar depression.

The pharmacologic treatment of bipolar depression has not been well studied in randomized, controlled trials. Thus important clinical questions regarding the efficacy in bipolar depression of mood stabilizers, antidepressants, and new antiepileptic and atypical antipsychotic agents have been relatively unaddressed. Until recently there were few data regarding the degree to which mood stabilizers reduce the risk of switching associated with antidepressant treatment. Likewise, although treatment guidelines have often recommended limiting antidepressant exposure in the maintenance treatment of bipolar depression, the potential risks of depressive relapse after antidepressant discontinuation were largely unknown. We review here data from new randomized, controlled trials published or presented during the past 5 years regarding the efficacy of antidepressants, mood stabilizers, lamotrigine, and olanzapine in the acute and maintenance treatment of bipolar depression. We also review new studies clarifying the protective effect of coadministration of mood stabilizers from antidepressant-associated switching and the risk of depressive relapse when antidepressants are discontinued during maintenance treatment.     

New approaches in managing bipolar depression

Historically, the pharmacologic treatment of bipolar depression has not been well studied. New data are beginning to emerge regarding the efficacy of new medications and the use of combinations of mood stabilizers and antidepressants in acute and long-term treatment of bipolar depression. We reviewed data from recent randomized, controlled trials of mood stabilizers and antidepressants in the treatment of bipolar depression and naturalistic studies examining the risk of switching and depressive relapse with ongoing antidepressant treatment.     

Impact of antidepressant discontinuation after acute bipolar depression remission on rates of depressive relapse at 1-year follow-up

OBJECTIVE: While guidelines for treating patients with bipolar depression recommend discontinuing antidepressants within 6 months after remission, few studies have assessed the implications of this strategy on the risk for depressive relapse. This study examined the effect of antidepressant discontinuation or continuation on depressive relapse risk among bipolar subjects successfully treated for an acute depressive episode. METHOD: Eighty-four subjects with bipolar disorder who achieved remission from a depressive episode with the addition of an antidepressant to an ongoing mood stabilizer regimen were followed prospectively for 1 year. The risk of depressive relapse among 43 subjects who stopped antidepressant treatment within 6 months after remission ("discontinuation group") was compared with the risk among 41 subjects who continued taking antidepressants beyond 6 months ("continuation group"). RESULTS: A Cox proportional hazards regression analysis indicated that shorter antidepressant exposure time following successful treatment was associated with a significantly shorter time to depressive relapse. Furthermore, patients who discontinued antidepressant treatment within the first 6 months after remission experienced a significantly shorter period of euthymia before depressive relapse over the length of 1-year follow-up. One year after successful antidepressant response, 70% of the antidepressant discontinuation group experienced a depressive relapse compared with 36% of the continuation group. By the 1-year follow-up evaluation, 15 (18%) of the 84 subjects had experienced a manic relapse; only six of these subjects were taking an antidepressant at the time of manic relapse. CONCLUSIONS: The risk of depressive relapse in patients with bipolar illness was significantly associated with discontinuing antidepressants soon after remission. The risk of manic relapse was not significantly associated with continuing use of antidepressant medication and, overall, was substantially less than the risk of depressive relapse. Maintenance of antidepressant treatment in combination with a mood stabilizer may be warranted in some patients with bipolar disorder.     

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.     

The impact of antidepressant discontinuation versus antidepressant continuation on 1-year risk for relapse of bipolar depression: a retrospective chart review

BACKGROUND: Current treatment guidelines recommend discontinuation of an antidepressant within 3 to 6 months after remission of depression in patients with bipolar illness. Yet few studies directly compare the impact of antidepressant discontinuation versus antidepressant continuation on the risk for depressive relapse in patients with bipolar disorder who have been successfully treated for a depressive episode. METHOD: In a retrospective chart review, patients with DSM-IV bipolar disorder who were treated for an index episode of depression by adding antidepressant medication to ongoing mood stabilizer medications were identified. The risk of depressive relapse in 25 subjects who stopped antidepressant medications after improvement was compared with the risk of depressive relapse in 19 subjects who continued antidepressants after improvement. RESULTS: Termination of antidepressant medication significantly increased the risk of a depressive relapse. Antidepressant continuation was not significantly associated with an increased risk of mania. CONCLUSION: While this study may have been limited by the retrospective nature of the chart review, nonrandomized assignment of treatment, and reliance on unstructured progress notes, it suggests that antidepressant discontinuation may increase the risk of depressive relapse in some patients with bipolar disorder. Further research is needed to clarify whether maintenance antidepressant treatment may be warranted in some patients with bipolar disorder, especially in those with frequent recurrent depressive episodes.     

Have some guidelines for the treatment of acute bipolar depression gone too far in the restriction of antidepressants?

This paper gives a critical review of recommendations concerning the drug treatment of acute bipolar depression. The suggestions of different guidelines and consensus papers, especially in US-American and Canadian psychiatry, have a strong tendency against antidepressants in bipolar depression; they prefer mono-therapy with mood stabilizers and, in the case of co-medication with mood stabilizers and antidepressants in severe depression, to withdraw the antidepressant as early as possible. The intention of this restrictive use is to avoid the risk of mania and the risk of rapid cycling induced by antidepressants. However, apparently the risk of suicidal acts, which is as prominent in bipolar depression as in unipolar depression, has been totally neglected. Furthermore, the fact that none of the mood stabilizers have proven their antidepressive efficacy leads not only to the risk of depression-related suicidal behavior but also to the risk of chronicity of depressive symptoms due to undertreatment. Altogether the view expressed in some guidelines and consensus papers appears not well balanced. Furthermore, the fact that apparently the selective serotonin re-uptake inhibitors and possibly some other modern antidepressants have only a low risk of inducing a switch to mania should stimulate a rewriting of the guidelines on drug treatment in acute bipolar depression in a less restrictive way concerning the use of antidepressants. Received: 3 January 2000 / Accepted: 2 February 2000     

Evidence of treatment for depressive episodes of bipolar disorder

In recent years, many papers on the treatment of the depressive phase of bipolar disorder (bipolar depression), especially bipolar I disorder, with high-level evidence, have been reported. The results of meta-analyses have also been reported for some medications. In the pharmacotherapy for bipolar depression, quetiapine (300 mg/day), lithium (more than 0.8 mEq/L), olanzapine (5-20 mg/day) and lamotrigine (200 mg/day) are effective, with high-level evidence. The combination of lithium and lamotrigine is also effective for bipolar depression. There is no evidence for effectiveness of the combination of mood stabilizers and antidepressants for bipolar depression. This paper presents the evidence data of quetiapine, lithium, olanzapine, lamotrigine, carbamazepine, valproate, aripiprazole, antidepressants, a combination of medications, and electroconvulsive therapy for bipolar depression, based on large-size randomized controlled studies and meta-analyses. The first-line medications for bipolar depression in the practice guidelines published for the last three years are also included.     

Do antidepressants influence mood patterns? A naturalistic study in bipolar disorder

This prospective, longitudinal study compared the frequency and pattern of mood changes between outpatients receiving usual care for bipolar disorder who were either taking or not taking antidepressants. One hundred and eighty-two patients with bipolar disorder self-reported mood and psychiatric medications for 4 months using a computerized system (ChronoRecord) and returned 22,626 days of data. One hundred and four patients took antidepressants, 78 did not. Of the antidepressants taken, 95% were selective serotonin or norepinephrine reuptake inhibitors, or second-generation antidepressants. Of the patients taking an antidepressant, 91.3% were concurrently taking a mood stabilizer. The use of antidepressants did not influence the daily rate of switching from depression to mania or the rate of rapid cycling, independent of diagnosis of bipolar I or II. The primary difference in mood pattern was the time spent normal or depressed. Patients taking antidepressants frequently remained in a subsyndromal depression. In this naturalistic study using self-reported data, patients with bipolar disorder who were taking antidepressants--overwhelmingly not tricyclics and with a concurrent mood stabilizer--did not experience an increase in the rate of switches to mania or rapid cycling compared to those not taking antidepressants. Antidepressants had little impact on the mood patterns of bipolar patients taking mood stabilizers.     

Diagnosing bipolar disorder and the effect of antidepressants: a naturalistic study

OBJECTIVES: To determine if bipolar disorder is accurately diagnosed in clinical practice and to assess the effects of antidepressants on the course of bipolar illness. METHOD: Charts of outpatients with affective disorder diagnoses seen in an outpatient clinic during 1 year (N = 85 with bipolar or unipolar disorders) were reviewed. Past diagnostic and treatment information was obtained by patient report and systematic psychiatric history. Bipolar diagnosis was based on DSM-IV criteria using a SCID-based interview. RESULTS: Bipolar disorder was found to be misdiagnosed as unipolar depression in 37% of patients who first see a mental health professional after their first manic/hypomanic episode. Antidepressants were used earlier and more frequently than mood stabilizers, and 23% of this unselected sample experienced a new or worsening rapid-cycling course attributable to antidepressant use. CONCLUSION: These results suggest that bipolar disorder tends be misdiagnosed as unipolar major depressive disorder and that antidepressants seem to be associated with a worsened course of bipolar illness. However, this naturalistic trial was uncontrolled, and more controlled research is required to confirm or refute these findings.     

When do antidepressants worsen the course of bipolar disorder?

Bipolar disorder may be more prevalent than previously believed. Because a substantial number of patients with bipolar disorder present with an index depressive episode, it is likely that many are misdiagnosed with unipolar major depression. Even if a correct diagnosis is made, depressive symptoms in bipolar disorder are notoriously difficult to treat. Patients are often treated with antidepressants, which, if used improperly, are known to induce mania and provoke rapid cycling. This article explores diagnostic conundrums in bipolar depression and their possible solutions, based on current research evidence. It also elucidates current evidence regarding the risks and benefits associated with antidepressant use and evaluates alternative treatment regimens for the depressed bipolar population, including the use of traditional mood stabilizers such as lithium, novel anticonvulsants such as lamotrigine, and atypical antipsychotics.     

Antidepressants for bipolar disorder——A meta-analysis of randomized,double-blind,controlled trials

OBJECTIVE： To examine the efficacy and safety of short-term and long-term use of antidepres- sants in the treatment of bipolar disorder. DATA SOURCES： A literature search of randomized, double-blind, controlled trials published until December 2012 was performed using the PubMed, ISI Web of Science, Medline and Cochrane Central Register of Controlled Trials databases. The keywords ＂bipolar disorder, bipolar I disorder, bipolar II disorder, bipolar mania, bipolar depression, cyclothymia, mixed mania and depression, rapid cycling and bipolar disorder＂, AND ＂antidepressant agent, antidepressive agents second- generation, antidepressive agents tricyclic, monoamine oxidase inhibitor, noradrenaline uptake in- hibitor, serotonin uptake inhibitor, and tricyclic antidepressant agent＂ were used. The studies that were listed in the reference list of the published papers but were not retrieved in the above-mentioned databases were supplemented. STUDY SELECTION： Studies selected were double-blind randomized controlled trials assessing the efficacy and safety of antidepressants in patients with bipolar disorder. All participants were aged 18 years or older, and were diagnosed as having primary bipolar disorder. Antidepressants or antidepressants combined with mood stabilizers were used in experimental interventions. Placebos, mood stabilizers, antipsychotics and other antide pressants were used in the control interventions. Studies that were quasi-randomized studies, or used antidepressants in combination with antipsy- chotics in the experimental group were excluded. All analyses were conducted using Review Man- ager 5.1 provided by the Cochrane Collaboration.     

Treatment of bipolar depression, a review of the literature and a suggestion for an algorithm

A review of the methodology and results of 9 controlled studies on the acute treatment of bipolar depression and the risk of switches into (hypo)mania is presented. There are indications but no proof for efficacy of mood stabilizers such as lithium, carbamazepine and valproate. Only lamotrigine has been shown to be effective, with a relative low risk of switching. Several antidepressants appear effective as well, but again there is no (placebo-controlled) proof of their efficacy. The only exception is tranylcypromine which has been found to be more effective than imipramine. The switch ratio into (hypo)mania by tricyclic antidepressants seems to be higher than by several other antidepressants, especially the selective serotonin reuptake inhibitors. In the acute treatment of bipolar depression, it is recommended to start with a mood stabilizer, and to add an antidepressant after 4-6 weeks in case of nonresponse. In severer cases, one might consider to start earlier with the combination of a mood stabilizer and an antidepressant, and in refractory patients, there is a place for tranylcypromine. In the maintenance treatment, there are indications that the combined treatment of a mood stabilizer (mostly lithium) and an antidepressant (TCA) is associated with an increased risk of switches into (hypo)mania, when compared to a mood stabilizer alone. Therefore, it is recommended to try whether a monotherapy with a mood stabilizer is effective, before combining it with an antidepressant.     

Treatment-resistant bipolar disorder

Despite the remarkable increase in medications validated as effective in bipolar disorder, treatment is still plagued by inadequate response in acute manic or depressive episodes or in long-term preventive maintenance treatment. Established first-line treatments include lithium, valproate and second-generation antipsychotics (SGAs) in acute mania, and lithium and valproate as maintenance treatments. Recently validated treatments include extended release carbamazapine for acute mania and lamotrigine, olanzapine and aripiprazole as maintenance treatments. For treatment-resistant mania and as maintenance treatments, a number of newer anticonvulsants, and one older one, phenytoin, have shown some promise as effective. However, not all anticonvulsants are effective and each agent needs to be evaluated individually. Combining multiple agents is the most commonly used clinical strategy for treatment resistant bipolar patients despite a relative lack of data supporting its use, except for acute mania (for which lithium or valproate plus an SGA is optimal treatment). Other approaches that may be effective for treatment-resistant patients include high-dose thyroid augmentation, clozapine, calcium channel blockers and electroconvulsive therapy (ECT). Adjunctive psychotherapies show convincing efficacy using a variety of different techniques, most of which include substantial attention to education and enhancing coping strategies. Only recently, bipolar depression has become a topic of serious inquiry with the dominant controversy focusing on the place of antidepressants in the treatment of bipolar depression. Other than mood stabilizers alone or the combination of mood stabilizers and antidepressants, most of the approaches for treatment-resistant bipolar depression are relatively similar to those used in unipolar depression, with the possible exception of a more prominent place for SGAs, prescribed either alone or in combination with antidepressants. Future work in the area needs to explore the treatments commonly used by clinicians with inadequate research support, such as combination therapy and the use of antidepressants as both acute and adjunctive maintenance treatments for bipolar disorder.     

Management of psychiatric comorbidity in fibromyalgia

Fibromyalgia is a chronic musculoskeletal pain condition of unknown etiology that predominantly affects women. Lifetime mood and anxiety disorders are common in patients with fibromyalgia and affect the course and severity of fibromyalgia. Recent fibromyalgia clinical trials have included clinical assessments to identify comorbid psychiatric disorders and determine the impact of comorbidity on treatment response. Options for the treatment of fibromyalgia patients with comorbid major depressive disorder or anxiety disorders include antidepressants with dual effects on serotonin and norepinephrine (eg, venlafaxine, duloxetine), which reduce pain in patients with fibromyalgia and have antidepressant and anxiolytic activity. Other possible treatments for anxiety or sleep disturbances associated with fibromyalgia include the alpha-2-delta ligands (eg, pregabalin, gabapentin) that reduce pain in fibromyalgia patients, have anxiolytic effects, and enhance slow-wave sleep. Antidepressants or alpha-2-delta ligands should be combined with established mood stabilizers in patients with comorbid fibromyalgia and bipolar disorder. There is also evidence to support exercise and cognitive-behavioral therapy in the treatment of fibromyalgia and mood or anxiety disorders. Many patients would likely benefit from combinations of pharmacologic and nonpharmacologic treatments.     

Patterns of psychotropic drug prescription for U.S. patients with diagnoses of bipolar disorders

OBJECTIVE: Bipolar disorders are prevalent major illnesses with high rates of morbidity, comorbidity, disability, and mortality. A growing number of psychotropic drugs are used to treat bipolar disorder, often off-label and in untested, complex combinations. METHODS: To quantify utilization rates for psychotropic drug classes, this study used the 2002-2003 U.S. national MarketScan research databases to identify 7,760 persons with ICD-9 bipolar disorder subtypes. Survival analysis was used to estimate times until initial monotherapies were augmented, changed, or discontinued. RESULTS: The most commonly prescribed first drug class was antidepressants (50% of patients), followed by mood stabilizers (25%: anticonvulsants, 17%, and lithium, 8%), sedatives (15%), and antipsychotics (11%). At study midpoint only 44% of patients were receiving monotherapy. Those receiving monotherapy were ranked by initial drug prescribed and percentage of patients (bipolar I and bipolar II): antidepressants (55% and 65%), lithium (51% and 41%), antipsychotics (32% and 31%), anticonvulsants (28% and 29%), and sedatives (28%, 25%). Median time to adding another psychotropic was 2.5-times less than median time to changing the initial treatment (16.4 compared with 40.9 weeks), and stopping was rare. Median weeks until therapy was changed in any way for 25% of patients was as follows: lithium, 29 weeks; antidepressants, 13; anticonvulsants, 13; antipsychotics, 13; and sedatives, 9. CONCLUSIONS: Antidepressants were the first-choice agent twice as often as mood stabilizers. Lithium was sustained longer than monotherapy with other mood stabilizers. Time to augmentation was much shorter than time to change or discontinuation.     

The bipolar spectrum and the antidepressant view of the world

Whereas much progress has been made in the diagnosis and treatment of schizophrenia and depression in recent years, bipolar disorder continues to be frequently misunderstood, leading to its inconsistent diagnosis and treatment. In this article, we seek to identify the causes of this problem and suggest possible solutions, based on a critical review of studies concerning the nosology of bipolar disorder and the effects of antidepressant agents. Bipolar disorder appears to be underdiagnosed as well as frequently misdiagnosed as unipolar major depressive disorder. Underdiagnosis can stem from patients' impaired insight into mania and failure to involve family members in the diagnostic process and also from clinicians' inadequate understanding of manic symptoms. Underdiagnosis may also reflect disagreement about the breadth of the bipolar spectrum. We therefore propose a heuristic definition of "bipolar spectrum disorder," a diagnosis that gives greater weight to family history and antidepressant-induced manic symptoms. This diagnosis would include all forms of bipolar illness that are not type I or II . The evidence also suggests that antidepressants are probably overused and mood stabilizers underused. We consequently recommend aggressive use of mood stabilizers and less emphasis on antidepressants. In summary, the state of diagnosis and treatment in bipolar disorder is suboptimal. More diagnostic attention to the criteria for mania is necessary. In addition, the current pattern of antidepressant use in bipolar disorder does not appear to be evidence-based.     

Olanzapine: a second generation antipsychotic drug and an "atypical" mood stabilizer?

The term "mood stabilizer" has been widely used since the early 1990's but it still does not have a uniform and generally accepted definition. Usually, agents that are effective in ameliorating acute manic or depressive episodes and have some prophylactic efficacy against the recurrence of new phases are considered as mood stabilizers. Lithium is unquestionably the prototype drug of this class; others, like some anticonvulsants, have been subsequently added to the list. Recent clinical research indicates that some of the newer second-generation antipsychotics may have very similar properties. In controlled clinical studies of acute manic and mixed episodes, olanzapine has proved to be at least as effective as lithium, divalproex, or haloperidol - often with additional benefits, such as faster onset of action, or wider spectrum of target symptoms. Added to mood stabilizers, olanzapine significantly enhances their antimanic efficacy. It also has intrinsic antidepressant properties; and in combination with fluoxetine, this has resulted in convincing efficacy in bipolar depressive episodes. Long-term maintenance treatment with olanzapine has extended the periods of remission and shown prophylactic efficacy against the recurrence of both manic and depressive episodes that is comparable or, in the case of preventing manic relapses, even superior to lithium. While none of the current agents meet the most stringent criteria for an "ideal" mood stabilizer, there is strong evidence that olanzapine, just like lithium, is effective across all phases of bipolar disorder without provoking either manic or depressive symptomatology. Regardless of formal definition criteria, this is exactly what clinicians expect of a dependable mood stabilizer.     

Diagnosis and management of patients with bipolar II disorder

Bipolar II disorder is frequently misdiagnosed as major depressive disorder. In particular, correct diagnosis of bipolar II disorder may be delayed by years due to the predominance of depressive symptoms and the relative subtlety of hypomania, which may manifest only briefly and without elevated mood. The prevalence of bipolar II disorder varies from 0.5% to about 5% depending on the criteria used. Diagnosis can be improved by using mood disorder questionnaires, systematic probing, and prospective mood diary charting. There is a dearth of research into treatment of bipolar disorder. The limited available evidence suggests that lithium and lamotrigine may have efficacy in preventing relapse of mood episodes. Acute bipolar II depression could be treated with a combination of a mood stabilizer plus an antidepressant or pramipexole and in rare cases with antidepressant monotherapy. Hypomania will likely respond to monotherapy with antimanic agents. Adjunctive psychosocial treatments may provide additional benefit in patients with bipolar II disorder.     

Bipolar depression: trial-based insights to guide patient care

For the majority of patients with bipolar disorder, major depressive episodes represent the most debilitating and difficult-to-treat illness dimension. Patients spend significantly more time depressed than manic or hypomanic, and attempt suicide more frequently during this illness phase, yet the availability of treatments remains limited. The discovery of more effective therapeutics for managing depressive episodes is arguably the greatest unmet need in bipolar disorder. This article provides an evidence-based summary of pharmacological treatments for the acute and longitudinal management of bipolar depression. Clinical trial results are reviewed for a diverse array of compounds, inclusive of traditional mood stabilizers (eg, lithium and divalproex), atypical antipsychotics, unimodal antidepressants, and modafinil. Where applicable, differences in efficacy across compounds are examined through discussion of number needed to treat and effect size determinations. A pragmatic clinical approach is presented for management of the depressed phase of bipolar disorder.     

Quetiapine monotherapy for bipolar depression

Bipolar depression is more common, disabling, and difficult-to-treat than the manic and hypomanic phases that define bipolar disorder. Unlike the treatment of so-called "unipolar" depressions, antidepressants generally are not indicated as monotherapies for bipolar depressions and recent studies suggest that -even when used in combination with traditional mood stabilizers - antidepressants may have questionable value for bipolar depression. The current practice is that mood stabilizers are initiated first as monotherapies; however, the antidepressant efficacy of lithium and valproate is modest at best. Within this context the role of atypical antipsychotics is being evaluated. The combination of olanzapine and the antidepressant fluoxetine was the first treatment to receive regulatory approval in the US specifically for bipolar I depression. Quetiapine was the second medication to be approved for this indication, largely as the result of two pivotal trials known by the acronyms of BOLDER (BipOLar DEpRession) I and II. Both studies demonstrated that two doses of quetiapine (300 mg and 600 mg given once daily at bedtime) were significantly more effective than placebo, with no increased risk of patients switching into mania. Pooling the two studies, quetiapine was effective for both bipolar I and bipolar II depressions and for patients with (and without) a history of rapid cycling. The two doses were comparably effective in both studies. Although the efficacy of quetiapine monotherapy has been established, much additional research is necessary. Further studies are needed to more fully investigate dose-response relationships and comparing quetiapine monotherapy to other mood stabilizers (lithium, valproate, and lamotrigine) in bipolar depression, both singly and in combination. Head-to-head studies are needed comparing quetiapine to the olanzapine-fluoxetine combination. Longer-term studies are needed to confirm the persistence of response and to better gauge effects on metabolic profiles across months of therapy. A prospective study of patients specifically seeking treatment for rapid cycling and those with a history of treatment-emergent affective shifts also is needed. Despite the caveats, as treatment guidelines are revised to incorporate new data, the efficacy and tolerability of quetiapine monotherapy must be given serious consideration.