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Objective: Uncertainty surrounds the risks of lithium use during pregnancy in women with bipolar disorder. The authors sought to provide a critical appraisal of the evidence related to the efficacy and safety of lithium treatment during the peripartum period, focusing on women with bipolar disorder and their offspring.Methods: The authors conducted a systematic review and random-effects meta-analysis assessing case-control, cohort, and interventional studies reporting on the safety (primary outcome, any congenital anomaly) or efficacy (primary outcome, mood relapse prevention) of lithium treatment during pregnancy and the postpartum period. The Newcastle-Ottawa Scale and the Cochrane risk of bias tools were used to assess the quality of available PubMed and Scopus records through October 2018.Results: Twenty-nine studies were included in the analyses (20 studies were of good quality, and six were of poor quality; one study had an unclear risk of bias, and two had a high risk of bias). Thirteen of the 29 studies could be included in the quantitative analysis. Lithium prescribed during pregnancy was associated with higher odds of any congenital anomaly (N=23,300, k=11; prevalence=4.1%, k=11; odds ratio=1.81, 95% CI=1.35-2.41; number needed to harm (NNH)=33, 95% CI=22-77) and of cardiac anomalies (N=1,348,475, k=12; prevalence=1.2%, k=9; odds ratio=1.86, 95% CI=1.16-2.96; NNH=71, 95% CI=48-167). Lithium exposure during the first trimester was associated with higher odds of spontaneous abortion (N=1,289, k=3, prevalence=8.1%; odds ratio=3.77, 95% CI=1.15-12.39; NNH=15, 95% CI=8-111). Comparing lithium-exposed with unexposed pregnancies, significance remained for any malformation (exposure during any pregnancy period or the first trimester) and cardiac malformations (exposure during the first trimester), but not for spontaneous abortion (exposure during the first trimester) and cardiac malformations (exposure during any pregnancy period). Lithium was more effective than no lithium in preventing postpartum relapse (N=48, k=2; odds ratio=0.16, 95% CI=0.03-0.89; number needed to treat=3, 95% CI=1-12). The qualitative synthesis showed that mothers with serum lithium levels <0.64 mEq/L and dosages <600 mg/day had more reactive newborns without an increased risk of cardiac malformations.Conclusions: The risk associated with lithium exposure at any time during pregnancy is low, and the risk is higher for first-trimester or higher-dosage exposure. Ideally, pregnancy should be planned during remission from bipolar disorder and lithium prescribed within the lowest therapeutic range throughout pregnancy, particularly during the first trimester and the days immediately preceding delivery, balancing the safety and efficacy profile for the individual patient. [ABSTRACT FROM AUTHOR]

Objective: About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants. This study compared the efficacy and safety of switching patients with treatment-resistant depression from an ineffective antidepressant to flexibly dosed esketamine nasal spray plus a newly initiated antidepressant or to a newly initiated antidepressant (active comparator) plus placebo nasal spray.Methods: This was a phase 3, double-blind, active-controlled, multicenter study conducted at 39 outpatient referral centers. The study enrolled adults with moderate to severe nonpsychotic depression and a history of nonresponse to at least two antidepressants in the current episode, with one antidepressant assessed prospectively. Confirmed nonresponders were randomly assigned to treatment with esketamine nasal spray (56 or 84 mg twice weekly) and an antidepressant or antidepressant and placebo nasal spray. The primary efficacy endpoint, change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) score, was assessed by a mixed-effects model using repeated measures.Results: Of 435 patients screened, 227 underwent randomization and 197 completed the 28-day double-blind treatment phase. Change in MADRS score with esketamine plus antidepressant was significantly greater than with antidepressant plus placebo at day 28 (difference of least square means=-4.0, SE=1.69, 95% CI=-7.31, -0.64); likewise, clinically meaningful improvement was observed in the esketamine plus antidepressant arm at earlier time points. The five most common adverse events (dissociation, nausea, vertigo, dysgeusia, and dizziness) all were observed more frequently in the esketamine plus antidepressant arm than in the antidepressant plus placebo arm; 7% and 0.9% of patients in the respective treatment groups discontinued study drug because of an adverse event. Adverse events in the esketamine plus antidepressant arm generally appeared shortly after dosing and resolved by 1.5 hours after dosing.Conclusions: Current treatment options for treatment-resistant depression have considerable limitations in terms of efficacy and patient acceptability. Esketamine is expected to address an unmet medical need in this population through its novel mechanism of action and rapid onset of antidepressant efficacy. The study supports the efficacy and safety of esketamine nasal spray as a rapidly acting antidepressant for patients with treatment-resistant depression. [ABSTRACT FROM AUTHOR]

Bipolar disorder is a recurrent disorder that affects more than 1% of the world population and usually has its onset during youth. Its chronic course is associated with high rates of morbidity and mortality, making bipolar disorder one of the main causes of disability among young and working-age people. The implementation of early intervention strategies may help to change the outcome of the illness and avert potentially irreversible harm to patients with bipolar disorder, as early phases may be more responsive to treatment and may need less aggressive therapies. Early intervention in bipolar disorder is gaining momentum. Current evidence emerging from longitudinal studies indicates that parental early-onset bipolar disorder is the most consistent risk factor for bipolar disorder. Longitudinal studies also indicate that a full-blown manic episode is often preceded by a variety of prodromal symptoms, particularly subsyndromal manic symptoms, therefore supporting the existence of an at-risk state in bipolar disorder that could be targeted through early intervention. There are also identifiable risk factors that influence the course of bipolar disorder, some of them potentially modifiable. Valid biomarkers or diagnosis tools to help clinicians identify individuals at high risk of conversion to bipolar disorder are still lacking, although there are some promising early results. Pending more solid evidence on the best treatment strategy in early phases of bipolar disorder, physicians should carefully weigh the risks and benefits of each intervention. Further studies will provide the evidence needed to finish shaping the concept of early intervention. AJP AT 175 Remembering Our Past As We Envision Our Future April 1925: Interpretations of Manic-Depressive Phases Earl Bond and G.E. Partridge reviewed a number of patients with manic-depressive illness in search of a unifying endo-psychic conflict. They concluded that understanding either phase of illness was "elusive" and "tantalizing beyond reach." (Am J Psychiatry 1925: 81: 643-662 ). [ABSTRACT FROM AUTHOR]

Objective: The authors evaluated the efficacy, safety, and tolerability of cariprazine, an atypical antipsychotic candidate, in adult patients with acute bipolar I depression.Method: This was an 8-week multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study in adult patients with bipolar I disorder experiencing a current major depressive episode. Patients were randomly assigned (1:1:1:1) to receive placebo or cariprazine at 0.75, 1.5, or 3.0 mg/day. The primary and secondary efficacy parameters were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impressions severity subscale (CGI-S), respectively, analyzed using a mixed-effects model for repeated measures on the modified intent-to-treat population.Results: The intent-to-treat population comprised 571 patients (141 in the placebo group and 140, 145, and 145 in the cariprazine 0.75-, 1.5-, and 3.0-mg/day groups). Cariprazine at 1.5 mg/day showed significantly greater improvement on MADRS total score change from baseline to week 6 compared with placebo; the least squares mean difference was -4.0 (95% CI=-6.3, -1.6; significant after adjustment for multiple comparisons). Cariprazine at 3.0 mg/day showed greater MADRS score reduction than placebo (-2.5, 95% CI=-4.9, -0.1; not significant when adjusted for multiple comparisons). The 0.75 mg/day dosage was similar to placebo. A similar pattern for significance was observed on the CGI-S (1.5 mg/day: least squares mean difference=-0.4, 95% CI=-0.6, -0.1; 3.0 mg/day: -0.3, 95% CI=-0.5, -0.0). The most common adverse events (≥10%) in cariprazine-treated patients were akathisia and insomnia; weight gain was slightly higher with cariprazine than with placebo.Conclusions: Cariprazine at 1.5 mg/day demonstrated consistent efficacy compared with placebo across outcomes and was generally well tolerated, suggesting efficacy for the treatment of bipolar I depression. [ABSTRACT FROM AUTHOR]

The article presents a research study on clinical use of intranasal ketamine for treatment-resistant or acutely suicidal patients with depression. Topics discussed include the therapeutic effect of overusing ketamines for mood elevation; the guidelines made for marketing and distribution of ketamine by the Food & Drug Administration (FDA) in U.S.; and education of the public and physicians about the risk of drug abuse.

An introduction to the journal is presented in which the editor discusses the use of antidepressant monotherapy in bipolar disorder.

The author reflects on the standards used for psychiatric investigation in the methods of reliability. It states that the commonly used method for analysis, the kappa statistic, is not known to most clinicians. It mentions that in situations of actual treatment, future tests must be considered in terms of clinical utility, reliability, and practicality in the application of new criteria even outside medical centers.

Objective: The authors evaluated the efficacy and safety of quetiapine plus lithium or divalproex in the prevention of recurrent mood events in patients with stabilized bipolar I disorder. Method: A total of 1,953 patients received open-label quetiapine (400-800 mg/day in flexible, divided doses) with either lithium or divaiproex (target serum concentrations 0.5-i .2 meq/liter and 50125 μg/ml, respectively) for up to 36 weeks. After at least 12 weeks-of clinical stability, 628 patients were randomly assigned to double-blind treatment with quetiapine or placebo, in combination with lithium or divalproex, for up to 104 weeks. The primary efficacymeasure was time to recurrence of any mood event (mania, depression, or a mixed episode). Results: Fewer patients in the quetiapine group experienced a mood event compared with the placebo group (20.3% versus 52.1%). The hazard ratio for time to recurrence of a mood event was 0.32. Hazard ratios were similar for mania and depression events (0.30 and 0.33, respectively). Sedation, weight increase, and hypothyroidism occurred more frequently in the quetiapine group, as did discontinuations due to adverse events. The incidence and incidence density of a single emergent blood glucose value ⩾126 mg/dl were higher in the quetiapine group (12.6% versus 5.4%; 18.44 versus 9.56 patients per 100 patient-years). Adverse events were generally consistent with the known tolerability profile of quetiapine. Conclusions: In patients stabilized on quetiapine plus lithium or divalproex, continued treatment was associated with a significant risk reduction in the time to recurrence of any mood event compa red with placebo and lithium ordivalproex. [ABSTRACT FROM AUTHOR]

Objective: The authors evaluated the efficacy and safety of adjunctive aripiprazole in bipolar I patients with mania partially nonresponsive to lithium/valproate monotherapy. Method: This multicenter, randomized, placebo-controlled study included outpatients experiencing a manic or mixed episode (with or without psychotic features). Patients with partial nonresponse to lithium/valproate monotherapy (defined as a Young Mania Rating Scale total score ⩾16 at the end of phases 1 and 2, with a decrease of ⩽25% between phases) with target serum concentrations of lithium (0.61.0 mmol/liter) or valproate (50-125 μg/ ml) were randomly assigned in a 2:1 ratio to adjunctive aripiprazole (N=253; 15 or 30 mg/day) or placebo (N=131) for 6 weeks. Results: Mean improvement from baseline in Young Mania Rating Scale total score at week 6 (primary endpoint) was significantly greater with aripiprazole (-13.3) than with placebo (-10.7). Significant improvements in Young Mania Rating Scale total score with aripiprazole versus placebo occurred from week 1 onward. In addition, the mean improvement in Clinical Global Impression Bipolar Version (CGI-BP) severity of illness (mania) score from baseline to week 6 was significantly greater with aripiprazole (-1.9) than with placebo (-1.6). Discontinuation rates due to adverse events were higher with aripiprazole than with placebo (9% versus 5%, respectively). Akathisia was the most frequently reported extrapyramidal symptom-related adverse event and occurred significantly more frequently among those receiving aripiprazole (18.6%) than among those receiving placebo (5.4%). There were no significant differences between treatments in weight change from baseline to week 6 (+0.55 kg and +0.23 kg for aripiprazole and placebo, respectively; last observation carried forward). Conclusions: Adjunctive aripiprazole therapy showed significant improvements in mania symptoms as early as week 1 and demonstrated a tolerability profile similar to that of monotherapy studies. [ABSTRACT FROM AUTHOR]

Objective: The study aims were to address neuropsychological functioning across different states of bipolar illness and to determine relationships among clinical features, neuropsychological performance, and psychosocial functioning. Method: Several domains of cognitive function were examined in 30 depressed bipolar patients (DSM-IV criteria for major depression, Hamilton Depression Rating Scale score ≥17), 34 manic or hypomanic bipolar patients (DSM-IV criteria for manic or hypomanic episode, Young Mania Rating Scale score ≥12), and 44 euthymic bipolar patients (6 months of remission, Hamilton depression scale score ≤8, and Young Mania Rating Scale score &gle;6). The comparison group consisted of 30 healthy subjects without history of neurological or psychiatric disorders. A neuropsychological battery assessed executive function, attention, and verbal and visual memory. Results: The three groups showed cognitive dysfunction in verbal memory and frontal executive tasks in relation to the comparison group. Low neuropsychological performance was associated with poor functional outcome. Impairment of verbal memory was related to the duration of illness and the numbers of previous manic episodes, hospitalizations, and suicide attempts. Conclusions: A poorer performance was observed in all bipolar groups regarding executive function and verbal memory in relation to the healthy comparison subjects. These cognitive difficulties, especially related to verbal memory, may help explain the impairment regarding daily functioning, even during remission. Further studies should focus on testing, whether optimizing prophylactic pharmacological treatment and psychoeducation might reduce cognitive impairment, and whether bipolar patients would benefit from neuropsychological rehabilitation in order to reduce the impact of cognitive impairment in their overall functioning. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Maintenance treatment for patients with bipolar I disorder: results from a North American study of quetiapine in combination with lithium or divalproex (trial 127)," by Dr. Suppes and colleagues in the 2009 issue.