Comparative Efficacy and Tolerability of Antipsychotics for Juvenile Psychotic Disorders: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Psychotic disorders produce important morbidity and disability in children and adolescents. There have been few relevant treatment trials, encouraging assessment of research aimed at testing efficacy and safety of antipsychotics for juveniles. We aimed to compare the short- and long-term efficacy and safety of antipsychotics to treat psychotic disorders among children and adolescents. METHODS: Four major bibliographic databases (PubMed, MEDLINE, PsycINFO, and EMBASE) were searched for clinical trials of antipsychotics in children or adolescents, from database inception to May 2021. We searched for clinical trials comparing antipsychotics with control conditions for juvenile psychosis based on blinded review by 2 independent investigators (C.S.Y. and M.L.). We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses and applied the Cochrane risk-of-bias tool to appraise study quality. One reviewer (A.B.) performed data abstraction which was confirmed by 2 independent, blinded reviewers (C.S.Y. and M.L.). Primary outcomes were scores rating psychosis symptoms and dichotomized retention in treatment protocols versus dropouts because of adverse events. Effect sizes were pooled using frequentist random-effects network meta-analysis modeling to generate summary rate ratios (RRs) and Cohen d standardized mean differences. RESULTS: Systematic searching generated 1330 unique records. Of these, short-term (n = 15, for 6 [3-12] weeks) and long-term (n = 10, for 12 [6-60] months) treatment trials involved 2208 (39.2% females; median age, 15.3 years), and 1366 subjects (35.0% females; median age, 15.6 years), respectively. Short-term reduction of psychosis scores ranked clozapine (d = -1.35; 95% confidence interval [CI], -1.97 to -0.73]), molindone (-1.22; 95% CI, -1.68 to -0.75), olanzapine (-1.12; 95% CI, -1.44 to -0.81), and risperidone (-0.93; 95% CI, -1.22 to -0.63) as the most effective agents. In longer-term treatment, only lurasidone was effective. Clozapine (RR, 12.8) and haloperidol (RR, 5.15) led to more all-cause and adverse event-related dropouts. There were few trials/drug (1 each for aripiprazole, asenapine, lurasidone, molindone, paliperidone, and ziprasidone, short term; aripiprazole, clozapine, haloperidol, lurasidone, and molindone, long-term). Heterogeneity and inconsistency were high, especially in long-term trials, without evidence of publication bias. CONCLUSIONS: Some antipsychotics were effective and tolerated short term, but longer-term evidence was very limited. The overall paucity of trials and of adequate controls indicates that more well-designed randomized controlled trials are required for adequate assessment of antipsychotic drug treatment for juveniles. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021232937.

Risk factors for early recurrence after discontinuing lithium in bipolar disorder.

BACKGROUND: Time to a new episode of bipolar disorder (BD) is shorter after discontinuing lithium rapidly. We now address this and other factors associated with the risk of early illness after discontinuing lithium. METHODS: We compared factors for association with recurrences of BD within 12 months of discontinuing long-term lithium treatment, using bivariate and multivariable analyses, as well as survival analysis to evaluate latency to new episodes versus rate of lithium-discontinuation and prior treatment duration. RESULTS: Among 227 BD subjects who received lithium for 4.47 [CI: 3.89-5.04] years and then discontinued, rapid treatment-discontinuation, and stopping for medical reasons were strongly associated with new illness-episodes within 12 months, as were diagnosis (BD-I > BD-II), greater morbidity during lithium-treatment, and less education, but neither longer treatment nor serum lithium concentrations. Discontinuation rate was strongly associated with shorter median latency to a new episode (rapid: 3.50; gradual [≥2 weeks]: 10.6 months), even with very early recurrences excluded to avoid potential contributions of emerging illness to treatment-discontinuation. Early recurrence was not associated with treatment-duration of ≥2 or ≥5 years or less. In multivariable logistic regression, rapid discontinuation, stopping for medical reasons, and BD-I diagnosis remained significantly, independently associated with early illness after lithium-discontinuation, with no effect of treatment duration. CONCLUSIONS: Early recurrence risk was again much greater after rapid discontinuation of lithium and discontinuing for medical reasons, somewhat greater with BD-I than BD-II, and following greater morbidity during lithium-treatment, but not related to dose or duration of preceding treatment exposure.

Ketamine for Bipolar Depression: A Systematic Review.

BACKGROUND: Ketamine appears to have a therapeutic role in certain mental disorders, most notably unipolar major depressive disorder. However, its efficacy in bipolar depression is less clear. This study aimed to assess the efficacy and tolerability of ketamine for bipolar depression. METHODS: We conducted a systematic review of experimental studies using ketamine for the treatment of bipolar depression. We searched PubMed, MEDLINE, Embase, PsycINFO, and the Cochrane Central Register for relevant studies published since each database's inception. We synthesized evidence regarding efficacy (improvement in depression rating scores) and tolerability (adverse events, dissociation, dropouts) across studies. RESULTS: We identified 6 studies, with 135 participants (53% female; 44.7 years; standard deviation, 11.7 years). All studies used 0.5 mg/kg of add-on intravenous racemic ketamine, with the number of doses ranging from 1 to 6; all participants continued a mood-stabilizing agent. The overall proportion achieving a response (defined as those having a reduction in their baseline depression severity of at least 50%) was 61% for those receiving ketamine and 5% for those receiving a placebo. The overall response rates varied from 52% to 80% across studies. Ketamine was reasonably well tolerated; however, 2 participants (1 receiving ketamine and 1 receiving placebo) developed manic symptoms. Some participants developed significant dissociative symptoms at the 40-minute mark following ketamine infusion in 2 trials. CONCLUSIONS: There is some preliminary evidence supporting use of intravenous racemic ketamine to treat adults with bipolar depression. There is a need for additional studies exploring longer-term outcomes and alterative formulations of ketamine.

Prevention of suicidal behavior in bipolar disorder.

BACKGROUND: Excess mortality is a critical hallmark of bipolar disorder (BD) due to co-occurring general medical disorders and especially from suicide. It is timely to review of the status of suicide in BD and to consider the possibility of limiting suicidal risk. METHODS: We carried out a semi-systematic review of recent research reports pertaining to suicide in BD. FINDINGS: Suicide risk in BD is greater than with most other psychiatric disorders. Suicide rates (per 100,000/year) are approximately 11 and 4 in the adult and juvenile general populations, but over 200 in adults, and 100 among juveniles diagnosed with BD. Suicide attempt rates with BD are at least 20 times higher than in the adult general population, and over 50 times higher among juveniles. Notable suicidal risk factors in BD include: previous suicidal acts, depression, mixed-agitated-dysphoric moods, rapid mood-shifts, impulsivity, and co-occurring substance abuse. Suicide-preventing therapeutics for BD remain severely underdeveloped. Evidence favoring lithium treatment is stronger than for other measures, although encouraging findings are emerging for other treatments. CONCLUSIONS: Suicide is a leading clinical challenge for those caring for BD patients. Improved understanding of risk and protective factors combined with knowledge and close follow-up of BD patients should limit suicidal risk. Ethically appropriate and scientifically sound studies of plausible medicinal, physical, and psychosocial treatments aimed at suicide prevention specifically for BD patients are urgently needed.

Pharmacological treatment of adult bipolar disorder.

We summarize evidence supporting contemporary pharmacological treatment of phases of BD, including: mania, depression, and long-term recurrences, emphasizing findings from randomized, controlled trials (RCTs). Effective treatment of acute or dysphoric mania is provided by modern antipsychotics, some anticonvulsants (divalproex and carbamazepine), and lithium salts. Treatment of BD-depression remains unsatisfactory but includes some modern antipsychotics (particularly lurasidone, olanzapine + fluoxetine, and quetiapine) and the anticonvulsant lamotrigine; value and safety of antidepressants remain controversial. Long-term prophylactic treatment relies on lithium, off-label use of valproate, and growing use of modern antipsychotics. Lithium has unique evidence of antisuicide effects. Methods of evaluating treatments for BD rely heavily on meta-analysis, which is convenient but with important limitations. Underdeveloped treatment for BD-depression may reflect an assumption that effects of antidepressants are similar in BD as in unipolar major depressive disorder. Effective prophylaxis of BD is limited by the efficacy of available treatments and incomplete adherence owing to adverse effects, costs, and lack of ongoing symptoms. Long-term treatment of BD also is limited by access to, and support of expert, comprehensive clinical programs. Pursuit of improved, rationally designed pharmacological treatments for BD, as for most psychiatric disorders, is fundamentally limited by lack of coherent pathophysiology or etiology.

A randomized, crossover comparison of ketamine and electroconvulsive therapy for treatment of major depressive episodes: a Canadian biomarker integration network in depression (CAN-BIND) study protocol.

BACKGROUND: Recent evidence underscores the utility of rapid-acting antidepressant interventions, such as ketamine, in alleviating symptoms of major depressive episodes (MDE). However, to date, there have been limited head-to-head comparisons of intravenous (IV) ketamine infusions with other antidepressant treatment strategies in large randomized trials. This study protocol describes an ongoing multi-centre, prospective, randomized, crossover, non-inferiority trial comparing acute treatment of individuals meeting diagnostic criteria for a major depressive episode (MDE) with ketamine and electroconvulsive therapy (ECT) on efficacy, speed of therapeutic effects, side effects, and health care resource utilization. A secondary aim is to compare a 6-month maintenance strategy for ketamine responders to standard of care ECT maintenance. Finally, through the measurement of clinical, cognitive, neuroimaging, and molecular markers we aim to establish predictors and moderators of treatment response as well as treatment-elicited effects on these outcomes. METHODS: Across four participating Canadian institutions, 240 patients with major depressive disorder or bipolar disorder experiencing a MDE are randomized (1:1) to a course of ECT or racemic IV ketamine (0.5 mg/kg) administered 3 times/week for 3 or 4 weeks. Non-responders (< 50% improvement in Montgomery-Åsberg Depression Rating Scale [MADRS] scores) crossover to receive the alternate treatment. Responders during the randomization or crossover phases then enter the 6-month maintenance phase during which time they receive clinical assessments at identical intervals regardless of treatment arm. ECT maintenance follows standard of care while ketamine maintenance involves: weekly infusions for 1 month, then bi-weekly infusions for 2 months, and finally monthly infusions for 3 months (returning to bi-weekly in case of relapse). The primary outcome measure is change in MADRS scores after randomized treatment as assessed by raters blind to treatment modality. DISCUSSION: This multi-centre study will help identify molecular, imaging, and clinical characteristics of patients with treatment-resistant and/or severe MDEs who would benefit most from either type of therapeutic strategy. In addition to informing clinical practice and influencing health care delivery, this trial will add to the robust platform and database of CAN-BIND studies for future research and biomarker discovery. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03674671. Registered September 17, 2018.

Melancholia: does this ancient concept have contemporary utility?

Many efforts have been made to develop coherent and clinically useful categories of depressive illness, especially to facilitate prediction of morbidity and guide treatment-response. They include proposals to resurrect the ancient concept of melancholia, as a form of severe depression with particular symptomatic and proposed psychobiological characteristics. However, modern research is inconsistent in supporting differences between melancholic and nonmelancholic depression. In our recent study of over 3200 patient-subjects with DSM-5 major depressive episodes with/without melancholic characteristics, and matched for illness severity, prevalence of melancholic features was 35.2% with remarkably few clinical and demographic differences between melancholic and nonmelancholic subjects. Also, our systematic review of trials comparing melancholic and nonmelancholic subjects found little difference in responses to antidepressant treatments. These findings indicate that the concept of melancholia may have limited value for clinical prediction and treatment-selection. Overlap of symptoms in melancholic and nonmelancholic depression, based on DSM criteria, may limit distinction of melancholia; alternative definitions can be sought, and psychomotor retardation is a particularly strong differentiating feature. For now, however, melancholia seems best considered a state-dependent depression-type strongly associated with greater symptomatic severity, rather than a distinct syndrome. Its DSM-5 current status as a depression-type specifier seems appropriate, and it may be a logical target for genetic and other biomedical studies.

Maintenance Pharmacological Treatment of Juvenile Bipolar Disorder: Review and Meta-Analyses.

BACKGROUND: Guidelines for maintenance treatment of juvenile bipolar disorder rely heavily on evidence from adult studies and relatively brief trials in juveniles, leaving uncertainties about optimal long-term treatment. We aimed to systematically review long-term treatment trials for juvenile bipolar disorder. METHODS: We analyzed data recovered by a systematic literature search using the PRISMA guidelines statement, through 2018, for peer-reviewed reports on pharmacological treatments for juvenile bipolar disorder lasting ≥24 weeks. RESULTS: Of 13 reports with 16 trials of 9 treatments (18.8% were randomized and controlled), with 1773 subjects (94.4% BD-I; ages 6.9-15.1 years), lasting 11.7 (6-22) months. Pooled clinical response rates were 66.8% (CI: 64.4-69.1) with drugs vs 60.6% (53.0-66.7) in 3 placebo-control arms. Random-effects meta-analysis of 4 controlled trials yielded pooled odds ratio (OR) = 2.88 ([0.87-9.60], P = .08) for clinical response, and OR = 7.14 ([1.12-45.6], P = .04) for nonrecurrence. Apparent efficacy ranked: combined agents >anticonvulsants ≥lithium ≥antipsychotics. Factors favoring response ranked: more attention deficit/hyperactivity disorder, polytherapy, randomized controlled trial design, nonrecurrence vs response. Adverse events (incidence, 5.50%-28.5%) notably included cognitive dulling, weight-gain, and gastrointestinal symptoms; early dropout rates averaged 49.8%. CONCLUSIONS: Pharmacological treatments, including anticonvulsants, lithium, and second-generation antipsychotics, may reduce long-term morbidity in juvenile bipolar disorder. However, study number, quality, and effect magnitude were limited, leaving the status of scientific support for maintenance treatment for juvenile bipolar disorder inconclusive.

Suicidal risk factors in major affective disorders.

BACKGROUND: Rates and risk factors for suicidal behaviour require updating and comparisons among mood disorders.AimsTo identify factors associated with suicidal risk in major mood disorders. METHOD: We considered risk factors before, during and after intake assessments of 3284 adults with/without suicidal acts, overall and with bipolar disorder (BD) versus major depressive disorder (MDD), using bivariate comparisons, multivariable regression modelling and receiver operating characteristic (ROC) analysis. RESULTS: Suicidal prevalence was greater in BD versus MDD: ideation, 29.2 versus 17.3%; attempts, 18.8 versus 4.78%; suicide, 1.73 versus 0.48%; attempts/suicide ratio indicated similar lethality, 10.9 versus 9.96. Suicidal acts were associated with familial BD or suicide, being divorced/unmarried, fewer children, early abuse/trauma, unemployment, younger onset, longer illness, more dysthymic or cyclothymic temperament, attention-deficit hyperactivity disorder (ADHD), substance misuse, mixed features, hospital admission, percentage time unwell, less antidepressants and more antipsychotics and mood stabilisers. Logistic regression found five independent factors: hospital admission, more depression at intake, BD diagnosis, onset age ≤25 years and mixed features. These factors were more associated with suicidal acts in BD than MDD: percentage time depressed/ill, alcohol misuse, >4 pre-intake depressions, more dysthymic/cyclothymic temperament and prior abuse/trauma. ADHD and total years ill were similar in BD and MDD; other factors were more associated with MDD. By ROC analysis, area under the curve was 71.3%, with optimal sensitivity (76%) and specificity (55%) with any two factors. CONCLUSIONS: Suicidal risks were high in mood disorders: ideation was highest with BD type II, attempts and suicides (especially violent) with BD type I. Several risk factors for suicidal acts differed between BD versus MDD patients.Declaration of interestNo author or immediate family member has financial relationships with commercial entities that might appear to represent potential conflicts of interest with the information presented.

An International Society of Bipolar Disorders task force report: Precursors and prodromes of bipolar disorder.

OBJECTIVES: To clarify the clinical features preceding the onset of bipolar disorder (BD) has become a public health priority for the prevention of high morbidity and mortality. BD remains frequently under- or misdiagnosed, and under- or mistreated, often for years. METHODS: We assessed the predictive value of precursors and prodromes of BD. We assessed precursors of first-lifetime manic or hypomanic episodes with/without mixed features in retrospective and prospective studies. The task force evaluated and summarized separately assessments of familial risk, premorbid personality traits, retrospective, and prospective studies. RESULTS: Cyclothymic features, a family history of BD, retrospectively reported attenuated manic symptoms, prospectively identified subthreshold symptoms of hypomania, recurrence of depression, panic anxiety and psychotic features, have been identified as clinical precursors of BD. The prodromal symptoms like [hypo]mania often appears to be long enough to encourage early identification and timely intervention. CONCLUSIONS: The predictive value of any risk factor identified remains largely unknown. Prospective controlled studies are urgently needed for prevention and effective treatment.

Correction to: Depressive residual symptoms are associated with illness course characteristics in a sample of outpatients with bipolar disorder.

Depressive residual symptoms are.

Depressive residual symptoms are associated with illness course characteristics in a sample of outpatients with bipolar disorder.

Rates of 50-70% of residual symptoms referring to subsyndromal manifestations between episodes that do not meet the required criteria for episode definition were reported in bipolar disorder (BD). However, the specific role of these symptoms on the course of BD patients is poorly understood; thus, we aimed to investigate factors associated with depressive residual symptoms. Overall, 255 currently euthymic BD outpatients on maintenance treatment, including 95 (37.2%) males and 160 (62.8%) females, were consecutively recruited at the Section of Psychiatry, Department of Neuroscience, University of Genoa (Italy) and underwent detailed structured interviews, comprehensive clinical interviews, and clinical record reviews for assessment/collection of relevant information concerning the course of illness and clinical status including cross-referral of all available information. After categorizing subjects according to the presence/absence of residual symptoms, groups were compared along clinical variables and variables associated with residual symptoms were analyzed using multivariate analyses. Subjects with residual symptoms were less likely to report substance abuse (χ2(2) = 11.937, p ≤ 0.005) and lifetime psychotic symptoms (χ2(2) = 10.577, p = 0.005), and more likely to report higher illness episodes, longer duration of illness (t253 = 67.282, p ≤ 0.001; t253 = 10.755, p ≤ 0.001), and longer duration of current illness episode (t253 = 7.707, p ≤ 0.001) than those without residual symptoms. After multivariate analyses, a significant positive contribution to residual symptoms was given only by duration of current illness episode (ß = 0.003; p ≤ 0.05), and lifetime psychotic symptoms (ß = 1.094; p ≤ 0.005). Clinicians have to pay attention to minimize residual symptoms that may significantly impact on the course of BD and achievement of full remission between episodes.

[A brief historical approach about the concept of paranoia]. / Un breve recorrido histórico acerca del concepto de paranoia.

From the ancient Greeks (V to III centuries BC), through Hippocrates to the Roman physician Aulo Cornelius Celso (I century), the term paranoia has been used as a manifestation of mental illness. After many centuries, Robert Burton in 1621 introduces the concept with a more modern meaning. Only with Heinroth (1818) the syndrome enters into the psychiatric nosology as a disorder of thought with unaltered perceptions. French and German psychiatry agree on the concept of paranoia as a partial psychosis with a maintained level of functioning and absence of deterioration. With this meaning the term is introduced in the modern psychiatry in Kahlbaum's work (1863). Jasper contributes with the introduction of paranoid development that can be influenced by the environment or previous experiences (1910). But to Kraepelin (1921) is owed the most precise description in a specifc essay based on his clinical experience. The German psychiatrist speaks of both a psychogenic and a more biological component. In modern psychiatric classifcations gradually the syndrome has disappeared and encompassed in the generic delusional disorder, clearly distinct from schizophrenia, and only if the delusions are understandable. The consequences of the absence of a diagnostic recognition implies that there is no specific research on this syndrome with difficulties in developing psychotherapeutic and pharmacological treatments.

[Neuroprogression and cognition in Bipolar Disorders: A systematic review of cognitive performance in euthymic patients]. / Neuroprogresión y cognición en los trastornos bipolares: una revisión sistemática del rendimiento cognitivo en pacientes eutímicos.

In recent years, investigators have begun to consider the possibility of explaining the physiopathology of bipolar disorder from a neuroprogressive perspective. The evidence that supports the feasibility of such an approach is varied, and arises from neuroimaging studies, batteries of neurocognitive evaluations, and tests to identify the specific biomarkers of the disorder. The present article seeks to perform a review of the research that investigates the cognitive deficits in bipolar disorder. A bibliographic revision was performed of articles published between 1990 and 2015. Levels of cognitive performance were explored in both cross-sectional and longitudinal studies. The compiled studies signal the presence of altered cognitive function, even during periods of euthymia. However, there are contradictory results as to whether bipolar disorder presents a degenerative course. New lines of investigation suggest that only a percentage of individuals with bipolar disorder are affected in a progressive manner. It is of paramount importance to perform new longitudinal studies in high-risk populations, so as to validate or refute a neuroprogressive model of cognitive deficits in patients with bipolar disorder.

Co-occurrence of anxiety and bipolar disorders: clinical and therapeutic overview.

BACKGROUND: Anxiety commonly co-occurs with bipolar disorders (BDs), but the significance of such "co-morbidity" remains to be clarified and its optimal treatment adequately defined. METHODS: We reviewed epidemiological, clinical, and treatment studies of the co-occurrence of BD and anxiety disorder through electronic searching of Pubmed/MEDLINE and EMBASE databases. RESULTS: Nearly half of BD patients meet diagnostic criteria for an anxiety disorder at some time, and anxiety is associated with poor treatment responses, substance abuse, and disability. Reported rates of specific anxiety disorders with BD rank: panic ≥ phobias ≥ generalized anxiety ≥ posttraumatic stress ≥ obsessive-compulsive disorders. Their prevalence appears to be greater among women than men, but similar in types I and II BD. Anxiety may be more likely in depressive phases of BD, but relationships of anxiety phenomena to particular phases of BD, and their temporal distributions require clarification. Adequate treatment trials for anxiety syndromes in BD patients remain rare, and the impact on anxiety of treatments aimed at mood stabilization is not clear. Benzodiazepines are sometimes given empirically; antidepressants are employed cautiously to limit risks of mood switching and emotional destabilization; lamotrigine, valproate, and second-generation antipsychotics may be useful and relatively safe. CONCLUSIONS: Anxiety symptoms and syndromes co-occur commonly in patients with BD, but "co-morbid" phenomena may be part of the BD phenotype rather than separate illnesses.

Options for pharmacological treatment of refractory bipolar depression.

Bipolar disorders of types I and II, even when treated by currently standard options, show a marked excess of depressive morbidity. Treated, type I patients in mid-course or from the onset of illness are ill, overall, 50 % of weeks of follow-up, and 75 % of that unresolved morbidity is depressive. Currently widely held impressions are that bipolar depression typically is poorly responsive to antidepressants, that treatment-resistant depression (TRD) is characteristic of the disorder, and that risk of mania with antidepressant treatment is very high. However, none of these views is supported consistently by available research. TRD may be more prevalent in bipolar than unipolar mood disorders. Relatively intense research attention is directed toward characteristics and treatments of TRD in unipolar depression, but studies of bipolar TRD are uncommon. We found only five controlled trials, plus 10 uncontrolled trials, providing data on a total of 13 drug treatments, all of which involved one or two trials, in 87 % as add-ons to complex, uncontrolled regimens. In two controlled trials, ketamine was superior to placebo but it is short-acting and not orally active; pramipexole was weakly superior to placebo in one controlled trial; three other drugs failed to outperform controls. Other pharmacotherapies are inadequately evaluated and nonpharmacological options are virtually untested in bipolar TRD. The available research supports the view that antidepressants may be effective in bipolar depression provided that currently agitated patients are excluded, that risk of mania with antidepressants is only moderately greater than risk of spontaneous mania, and that bipolar TRD is not necessarily resistant to all treatments.

Overview of antidepressant treatment of bipolar depression.

Bipolar depression remains a major unresolved challenge for psychiatric therapeutics. It is associated with significant disability and mortality and represents the major proportion of the approximately half of follow-up time spent in morbid states despite use of available treatments. Evidence regarding effectiveness of standard treatments, particularly with antidepressants, remains limited and inconsistent. We reviewed available clinical and research literature concerning treatment with antidepressants in bipolar depression and its comparison with unipolar depression. Research evidence concerning efficacy and safety of commonly used antidepressant treatments for acute bipolar depression is very limited. Nevertheless, an updated meta-analysis indicated that overall efficacy was significantly greater with antidepressants than with placebo-treatment and not less than was found in trials for unipolar major depression. Moreover, risks of non-spontaneous mood-switching specifically associated with antidepressant treatment are less than appears to be widely believed. The findings encourage additional efforts to test antidepressants adequately in bipolar depression, and to consider options for depression in types I vs. II bipolar disorder, depression with subsyndromal hypomania and optimal treatment of mixed agitated-dysphoric states--both short- and long-term. Many therapeutic trials considered were small, varied in design, often involved co-treatments, or lacked adequate controls.