Risk of manic switch and suicidal outcomes in bipolar depression treated with esketamine: A one-year retrospective cohort study of 2126 patients.

Trends in Use of Antipsychotics and Mood Stabilizers Among Medicaid Beneficiaries With Bipolar Disorder, 2001-2004

Modafinil Add-On in the Treatment of Bipolar Depression

To identify demographic and clinical characteristics of bipolar depressed patients who require antidepressant (AD) augmentation, and to evaluate the short- and long-term effectiveness and safety of this therapeutic strategy. One hundred twenty-two bipolar depressed patients were consecutively recruited, 71.7% of them received mood stabilizers (MS)/second-generation antipsychotics (SGA) with AD-augmentation and 28.3% did not. Patients were evaluated at baseline, and after 12weeks and 15months of treatment. The AD-augmentation was significantly higher in patients with bipolar II compared with bipolar I diagnosis. Patients with MS/SGA+AD had often a seasonal pattern, depressive polarity onset, depressive index episode with anxious features, a low number of previous psychotic and (hypo)manic episodes and of switch. They had a low irritable premorbid temperament, a low risk of suicide attempts, and a low number of manic symptoms at baseline. After 12weeks of treatment, 82% of patients receiving ADs improved, 58% responded and 51% remitted, 3.8% had suicidal thoughts or projects, 6.1% had (hypo)manic switch, and 4.1% needed hospitalization. During the following 12months, 92% of them remitted from index episode, 25.5% did not relapse, and 11% needed hospitalization. Although at the start advantaged, patients with AD-augmentation, compared with those without AD-augmentation, did not significantly differ on any outcome as well on adverse events in the short- and long-term treatment. Our findings indicate that ADs, combined with MS and/or SGA, are short and long term effective and safe in a specific subgroup for bipolar depressed patients.

Antidepressants remain among the most widely used class of drugs in treating bipolar disorder, despite their minimal efficacy in randomized clinical trials and concern for association with manic episodes. This study sought to evaluate the outcomes of antidepressant treatment in bipolar depression in a large naturalistic cohort study, STEP-BD, in terms of symptomatic remission as well as emergence of mania, using a propensity score (PS) analysis to reduce indication bias. Propensity scores were developed to estimate the probability of antidepressant exposure using multivariate logistic regression models; these scores were then used to match antidepressant-exposed and non-exposed individuals. Cox regression models were used to estimate hazard ratios for manic switch and time to remission, adjusted for these scores in the matched population. Total sample included 2166 individuals, of whom 1085 were exposed to AD and 1081 were unexposed to AD; mean follow-up duration was 182.5 (SD: 44.6) days (median = 126, ICR: 87.4). Cox regression models for manic switch with antidepressant exposure versus non-exposure yielded an unadjusted hazard ratio (HR) of 0.93 (95% CI 0.67-1.14) and PS-adjusted HR of 0.77 (95% CI 0.51-1.08), neither of which was statistically significantly different from 1. Probability of symptomatic remission was also not significantly associated with antidepressant exposure, with unadjusted and PS-adjusted HR of 1.15 (95% CI 0.97-1.37) and 1.02 (95% CI 0.87-1.23), respectively. With PS adjustment, there was no evidence of increased likelihood of manic switch or achievement of symptomatic remission associated with antidepressant use in bipolar depression. Our results underscore the ongoing need to identify alternative strategies for effective treatment of bipolar depression.

The purpose of this study was to assess the risk of manic switch associated with antidepressants in Medicaid-enrolled pediatric patients with bipolar depression. This retrospective cohort study involved 2003-2007 Medicaid Analytic eXtract (MAX) data from four geographically diverse states. The study sample included children and adolescents (ages 6-18 years) who had received a diagnosis of bipolar disorder on two or more separate occasions or during a hospital discharge, followed by a diagnosis of depression. According to the pharmacotherapy received by these patients in the 30 days around the index bipolar depression diagnosis, patients were categorized into five mutually exclusive groups. Manic switch was defined as having received a diagnosis of mania within 6 weeks after the initiation of bipolar depression treatment. Relative risks of manic switch between antidepressant monotherapy/polytherapy and their alternatives were assessed using Cox proportional hazards model. The robustness of the conventional Cox proportional hazards model toward possible bias caused by unobserved confounders was tested using instrumental variable analysis, and the uncertainty regarding manic switch definition was tested by altering the duration of follow-up. After applying all the selection criteria, 179 antidepressant monotherapy, 1047 second-generation antipsychotic (SGA) monotherapy, 570 mood stabilizer monotherapy, 445 antidepressant polytherapy, and 1906 SGA-mood stabilizer polytherapy users were identified. In Cox proportional hazard analyses, both antidepressant monotherapy and polytherapy exhibited higher risk of manic switch than their alternatives (antidepressant monotherapy vs. SGA monotherapy, hazard ratio [HR]=2.87 [95% CI: 1.10-7.49]; antidepressant monotherapy vs. mood stabilizer monotherapy, HR=1.41 [95% CI: 0.52-3.80); antidepressant polytherapy vs. SGA-mood stabilizer polytherapy, HR=1.61 [95% CI: 0.90-2.89]). However, only the comparison between antidepressant monotherapy and SGA monotherapy was statistically significant. The instrumental variable analysis did not detect endogeneity of the treatment variables. Extending the follow-up period from 6 weeks to 8 and 12 weeks generated findings consistent with the main analysis. Study findings indicated a higher risk of manic switch associated with antidepressant monotherapy than with SGA monotherapy in pediatric patients with bipolar depression. The finding supported the clinical practice of cautious prescribing of antidepressants for brief periods.

Suicide and suicide attempts are persistent and increasing public health problems. Observational studies and meta-analyses of randomized clinical trials have suggested that lithium may prevent suicide in patients with bipolar disorder or depression. To assess whether lithium augmentation of usual care reduces the rate of repeated episodes of suicide-related events (repeated suicide attempts, interrupted attempts, hospitalizations to prevent suicide, and deaths from suicide) in participants with bipolar disorder or depression who have survived a recent event. This double-blind, placebo-controlled randomized clinical trial assessed lithium vs placebo augmentation of usual care in veterans with bipolar disorder or depression who had survived a recent suicide-related event. Veterans at 29 VA medical centers who had an episode of suicidal behavior or an inpatient admission to prevent suicide within 6 months were screened between July 1, 2015, and March 31, 2019. Participants were randomized to receive extended-release lithium carbonate beginning at 600 mg/d or placebo. Time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide. The trial was stopped for futility after 519 veterans (mean [SD] age, 42.8 [12.4] years; 437 [84.2%] male) were randomized: 255 to lithium and 264 to placebo. Mean lithium concentrations at 3 months were 0.54 mEq/L for patients with bipolar disorder and 0.46 mEq/L for patients with major depressive disorder. No overall difference in repeated suicide-related events between treatments was found (hazard ratio, 1.10; 95% CI, 0.77-1.55). No unanticipated safety concerns were observed. A total of 127 participants (24.5%) had suicide-related outcomes: 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and 3 in the placebo group. In this randomized clinical trial, the addition of lithium to usual Veterans Affairs mental health care did not reduce the incidence of suicide-related events in veterans with major depression or bipolar disorders who experienced a recent suicide event. Therefore, simply adding lithium to existing medication regimens is unlikely to be effective for preventing a broad range of suicide-related events in patients who are actively being treated for mood disorders and substantial comorbidities. ClinicalTrials.gov Identifier: NCT01928446.

Whether or not to use antidepressants in patients with bipolar disorder is a matter of debate. Antidepressant treatment of bipolar depression has been associated with manic switch and cycle acceleration. Furthermore, recent studies have argued against the efficacy of antidepressants in the treatment of bipolar depression. Nevertheless, many clinicians continue to employ antidepressants, especially in the management of severe depression that is unresponsive to mood stabilizers alone. Because of the unclear risk-to-benefit ratio of antidepressants in bipolar disorder, we have performed an updated review of the relevant literature. In this article we examine (1) all randomized controlled trials (RCTs) evaluating the use of antidepressants in the treatment of acute bipolar depression and assessing the risk of antidepressant-induced manic switch and (2) non-RCT trials that evaluate the impact of antidepressant discontinuation after acute antidepressant response. A MEDLINE search of journals, covering the period from January 1966 to July 2007 and supplemented by bibliographic cross-referencing, was performed to identify the relevant studies. The keywords used were antidepressant, bipolar depression, bipolar disorder, switch, manic switch, antidepressant-induced mania, predictors, and antidepressant discontinuation. Criteria used to select studies included (1) English language and (2) studies published in peer-reviewed journals. Randomized, double-blind, placebo-controlled studies have demonstrated that antidepressants exert some efficacy in the treatment of bipolar depression in some populations of patients. Moreover, the risk of manic switch, although not totally countered, appears to be strongly reduced when antidepressants are given in combination with a mood stabilizer and when new-generation antide-pressants are preferred over old tricyclic antidepressants. Finally, some studies have proven that the continuous use of antidepressants after the remission of a major depressive episode helps to prevent further depressive relapses without causing a significant increase in manic relapses. Clearly, there is a place for antidepressants in bipolar disorder; however, it is important to be cautious and evaluate their use on a case-by-case basis. Looking at specific depressive symptoms might help physicians in making the choice of whether to prescribe or not prescribe antidepressants.

Bupropion-Induced Mania and Hypomania: A Report of Two Cases

Treatment Patterns for Schizoaffective Disorder and Schizophrenia Among Medicaid Patients

This study compared background characteristics, pharmacologic treatment, and service use of adults treated for schizoaffective disorder and adults treated for schizophrenia. Medicaid claims data from two states were analyzed with a focus on adults treated for schizoaffective disorder or schizophrenia. Patient groups were compared regarding demographic characteristics, pharmacologic treatment, and health service use during 180 days before and after a claim for either schizophrenia or schizoaffective disorder. A larger proportion of patients were treated for schizophrenia (N=38,760; 70.1%) than for schizoaffective disorder (N=16,570; 29.9%). During the 180 days before the index diagnosis claim, significantly more patients with schizoaffective disorder than those with schizophrenia were treated for depressive disorder (19.6% versus 11.4%, p<.001), bipolar disorder (14.8% versus 5.8%, p<.001), substance use disorder (11.8% versus 9.7%, p<.001), and anxiety disorder (6.9% versus 5.3%, p<.001). After the index claim, a similar proportion of both diagnostic groups were treated with antipsychotic medications (schizoaffective disorder, 87.3%; schizophrenia, 87.0%), although patients with schizoaffective disorder were significantly more likely than patients with schizophrenia to receive antidepressants (61.7% versus 44.0%, p<.001), mood stabilizers (55.2% versus 34.4%, p<.001), and anxiolytics (43.2% versus 35.1%, p<.001). Patients with schizoaffective disorder were also significantly more likely than patients with schizophrenia to receive psychotherapy (23.4% versus 13.0%, p<.001) and inpatient mental health care (9.4% versus 6.2%, p<.001), although the latter was not significant after the analysis controlled for background characteristics. Schizoaffective disorder is commonly diagnosed among Medicaid beneficiaries. These patients often receive complex pharmacologic regimens, and many also receive treatment for mood disorders. Differences in service use patterns between schizoaffective disorder and schizophrenia argue for separate consideration of their health care needs.

Psychotropic Medications for Patients With Bipolar Disorder in the United States: Polytherapy and Adherence

Patterns of Psychotropic Drug Prescription for U.S. Patients With Diagnoses of Bipolar Disorders

The rising suicide rates in the US emphasize the need for effective prevention. While telehealth has transformed access to mental health care, the impact of telehealth on suicide outcomes is unknown. To evaluate the association of virtual mental health services with individual-level suicide-related events (SREs). This retrospective cohort study using broadband access as an instrumental variable assessed a national sample of Veterans Health Administration patients who received mental health care between March 1, 2020, and December 31, 2021. Participants were recently separated (ie, discharged or released from active duty) veterans who completed their active duty service between March 1, 2019, and December 31, 2020, and who received at least 2 outpatient or inpatient diagnoses related to major depressive disorder, substance use disorder, or posttraumatic stress disorder within the year before their most recent separation date. Data were analyzed May 1 to October 31, 2023. Percentage of a patient's total mental health visits that were conducted virtually by psychiatrists, psychologists, or social workers within a calendar month. Binary measure indicating whether the patient had experienced an SRE (defined as a nonfatal suicide attempt, intentional self-harm, or suicide death) in a specific month and year as evaluated an instrumental variable probit model. The sample included 66 387 data points from 16 236 unique recently separated veterans. Among these entries, 44 766 were for male veterans (67.4%), the mean (SD) age across the sample was 32.9 (8.9) years, and the sample was representative of the US veteran population. There were 929 SREs (1.4%). Virtual mental health visits comprised a mean (SD) of 44.6% (46.1%) of all mental health visits. In instrumental variable probit analyses accounting for factors simultaneously associated with use of virtual mental health care and SRE risk, a 1% increase in the probability of virtual mental health visits was associated with a 2.5% decrease in SREs. Findings from this cohort study using a retrospective quasi-experimental design found that an increase in virtual mental health visits relative to total visits was associated with a statistically significant decrease in SREs, suggesting that providing virtual mental health services may reduce suicide-related outcomes.

This study examined longitudinal trends in the use of mood stabilizers and antipsychotics for treatment of bipolar disorder in a large public mental health system and whether trends differed by age, gender, and race-ethnicity. Data were from Medicaid beneficiaries with bipolar disorder receiving services in the San Diego County public mental health system from 2001 to 2004. For each year the proportion of clients receiving any pharmacotherapy and the proportion receiving antipsychotics alone, mood stabilizers alone, or antipsychotics plus mood stabilizers were determined. Pharmacotherapy use was examined by age, gender, and race-ethnicity. A total of 1,473 clients were identified who were continuously enrolled in Medicaid during the four years. Seventy-five percent received mood stabilizers or antipsychotics. Of this group, 33% received antipsychotics alone, 23% mood stabilizers alone, and 44% both antipsychotics and mood stabilizers. The percentage receiving mood stabilizers or antipsychotics increased significantly, from 71% in 2001 to 77% in 2004, primarily because of increased use among women. Use of mood stabilizers alone declined from 25% to 20%, and use of antipsychotics alone increased from 32% to 36%. African Americans and Latinos were less likely than non-Latino whites to receive mood stabilizers or antipsychotics; this pattern was stable over time. Antipsychotics were prescribed for a larger percentage of clients than mood stabilizers. Persons from ethnic minority groups were less likely to receive either medication type. Research is needed to examine factors affecting pharmacotherapy in bipolar disorder and mechanisms underlying racial-ethnic disparities in pharmacotherapy, including their persistence over time.

To investigate the short-term effectiveness and the short-term and long-term safety of acute antidepressant (AD) treatment of bipolar depression in a naturalistic setting. Patients with bipolar (n=86) or unipolar (n=111) depression were consecutively recruited and treated with AD (combined with mood stabilizer [MS] and/or second-generation antipsychotics in bipolar depression). Exclusion criteria were mixed depression, high mood instability, previous predominantly mixed depression (both bipolar and unipolar depression), rapid cycling course and previous switch AD-emerging (bipolar depression). After 12 weeks of treatment, no difference was found in remission, response and improvement rates between bipolar and unipolar depression. Concerning short-term safety, switching and suicidality did not differ significantly between the two groups, and no suicide attempt was observed. Concerning long-term safety, patients with bipolar depression had a significant reduction of depressive and total recurrences during the year of follow-up, compared to the year before entering the study, without significant changes in (hypo)mania and mixed depression recurrences, and suicide rates. Acute AD treatment of bipolar depression is effective in the short-term and safe in the short- and long-term, when administered in combination with MSs and/or second-generation antipsychotics, with a low risk of switch, mixed depression and cycle acceleration.