Suicide Risk and Mood Disorders in Women in the Postpartum Period: a Longitudinal Study.

Suicide associated with severe psychiatric illnesses is considered the leading cause of maternal deaths. We aimed to assess the suicide risk in women who experienced depressive or mixed episodes of mood change during the postpartum period and to determine which disorder is more related to suicide risk in the same period. We conducted a longitudinal study with 706 women whose children were born from April 2007 to May 2008 in a southern city in Brazil, and received prenatal care by the Brazilian National System of Public Health. The first assessment occurred during the prenatal period and the second within 30 to 60 days postpartum. The incidence of suicide risk was 10.9%. The odds of postpartum suicide risk were 6.50 (95% CI: 2.73; 15.48) higher in mothers with postpartum depression and 41.50 (95% CI: 12.11; 142.16) higher in those with mixed episodes than those who did not suffer from any mood disorder. Women with chronic episodes (who had depressive or mixed episodes during pregnancy and postpartum) were at increased odds of 4.94 (95% CI: 1.46; 16.69) of a postpartum suicide risk. The postpartum seems to be a critical period in the women's mental health. The impact of mental disorders in this period, especially mixed episodes, can increase the odds of a suicide risk onset. A good psychiatric evaluation and support during the prenatal and postpartum care may prevent the subsequent risk of suicide.

Treatment of Mixed Features in Bipolar Disorder: an Updated View.

PURPOSE OF REVIEW: Mixed presentations in bipolar disorder have long posed clinical and nosological challenges. The DSM-5 mixed features specifier was developed to provide a more flexible and clinically relevant definition of mixed presentations compared with narrowly defined DSM-IV mixed episodes. However, there is little guidance on treating such presentations. Here, we summarize the evidence for biological treatments of DSM-5 and similarly defined mixed features (MFs). RECENT FINDINGS: The literature on treating MFs is almost exclusively based on post hoc analyses. Within this limited evidence base is preliminary positive data for aripiprazole, asenapine, cariprazine, olanzapine, risperidone, and ziprasidone in treating acute mania with MFs, and cariprazine, lurasidone, olanzapine, and ziprasidone for depressive symptoms in depression with MFs. Divalproex may also be efficacious for acute mania with MFs. The few extant maintenance studies suggest that divalproex and olanzapine may have long-term efficacy in those with index MFs or for the prevention of MFs, respectively. The existing evidence suggests that clinicians consider atypical antipsychotics and divalproex for treating acute mixed presentations. However, adequately powered treatment trials-and studies of maintenance and neurostimulation therapies-are needed. Additionally, data-driven techniques to identify relevant symptom clusters may help improve our conceptualization of mixed presentations.

Comparison of the complete blood count-derived inflammatory markers in bipolar patients with manic and mixed episodes.

OBJECTIVES: We aimed to compare altered inflammatory status between patients with bipolar manic and mixed episodes through neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) levels. BACKGROUND: NLR, PLR, and MLR are systemic inflammation biomarkers that have recently studied in bipolar disorder (BD) manic and depressive episodes. Immunological biomarker signature of mixed episodes and MLR levels in BD have less been studied. DESIGN AND SETTING: Our study included 48 bipolar patients in a mood episode (28 manic, 20 mixed) and 32 controls. Study-specific form including sociodemographic and clinical variables with laboratory findings were filled for all participants. METHODS: Red cell distribution width (RDW), mean platelet volume (MPV) neutrophil, lymphocyte and platelet count, NLR, PLR, and MLR were recorded. RESULTS: PLR and MLR were found significantly higher in bipolar patients compared to controls while NLR and MLR were significantly higher in manic patients than in mixed patients. RDW was found higher in mixed episode compared to controls. CONCLUSIONS: One can interpret these findings as MLR would be considered as a novel state biomarker for bipolar mood episodes and greater inflammatory activation may be involved in mania rather than mixed episode (Tab. 2, Fig. 1, Ref. 35).

Superior anti-suicidal effects of electroconvulsive therapy in unipolar disorder and bipolar depression.

OBJECTIVES: Electroconvulsive therapy (ECT) has long been believed to reduce suicidal tendencies in patients with affective disorders; however, ECT recipients, who constitute the most severely ill and suicidal patients, are not eligible to participate in head-to-head randomized controlled trials. Large-scale studies are required to investigate the anti-suicidal effects of ECT vs psychopharmacotherapy. METHODS: A nationwide retrospective cohort study design was used. Data were obtained from the Taiwan National Health Insurance Research Database. Inpatients with unipolar disorder or bipolar disorder who received ECT (n = 487) were observed from 1 January 2000 to 31 December 2013 for suicide events. The non-ECT control cohort consisted of inpatients with psychopharmacotherapy randomly matched (ratio, 1:4) by age, sex, and diagnosis. RESULTS: After potential confounds had been accounted for, the adjusted hazard ratio (HR) was 0.803, indicating that ECT recipients showed a 19.7% lower risk of suicide than control individuals. The stratum-specific adjusted HR was 0.79 in patients with unipolar disorder (P = .041) and 0.923 in patients with bipolar disorder (P = .254). Upon further stratification of the patients with bipolar disorder by their affective states, the adjusted HR was 0.805 (P = .046) for bipolar depression, 1.048 for bipolar mania (P = .538), and 0.976 for mixed bipolar state (P = .126). CONCLUSIONS: Compared with psychopharmacotherapy, ECT exerted superior anti-suicidal effects in patients with unipolar disorder and bipolar depression; however, there was a lack of superior anti-suicidal effects of ECT in the treatment of patients with bipolar mania and mixed state.

Childhood trauma and mixed episodes are associated with poor response to lithium in bipolar disorders.

OBJECTIVES: Reliable predictors of response to lithium are still lacking in bipolar disorders (BDs). However, childhood trauma has been hypothesized to be associated with poor response to lithium. METHODS: We included 148 patients with BD, euthymic when retrospectively and clinically assessed for response to lithium and childhood trauma using reliable scales. RESULTS: According to the 'Alda scale', the sample consisted in 20.3% of excellent responders, 49.3% of partial responders and 30.4% of non-responders to lithium. A higher level of physical abuse significantly correlated with a lower level of response to lithium (P = 0.009). As compared to patients not exposed to any abuse, patients with at least two trauma abuses (emotional, physical or sexual) were more at risk of belonging to the non-responders group (OR = 4.91 95% CI (1.01-27.02)). Among investigated clinical variables, lifetime presence of mixed episodes and alcohol misuse were associated with non-response to lithium. Multivariate analyses demonstrated that physical abuse and mixed episodes were independently associated with poor response to lithium (P = 0.005 and P = 0.013 respectively). CONCLUSIONS: Childhood physical abuse might be involved in a poor future response to lithium prophylaxis, this effect being independent of the association between clinical expression of BD and poor response to lithium.

Treating mixed mania/hypomania: a review and synthesis of the evidence.

The DSM-5 incorporates a broad concept of mixed states and captured ≥3 nonoverlapping symptoms of the opposite polarity using a "with mixed features" specifier to be applied to manic/hypomanic and major depressive episodes. Pharmacotherapy of mixed states is challenging because of the necessity to treat both manic/hypomanic and depressive symptoms concurrently. High-potency antipsychotics used to treat manic symptoms and antidepressants can potentially deteriorate symptoms of the opposite polarity. This review aimed to provide a synthesis of the current evidence for pharmacotherapy of mixed states with an emphasis on mixed mania/hypomania. A PubMed search was conducted for randomized controlled trials (RCTs) that were at least moderately sized, included a placebo arm, and contained information on acute-phase and maintenance treatments of adult patients with mixed episodes or mania/hypomania with significant depressive symptoms. Most studies were post-hoc subgroup and pooled analyses of the data from RCTs for acute manic and mixed episodes of bipolar I disorder; only two prospectively examined efficacy for mixed mania/hypomania specifically. Aripiprazole, asenapine, carbamazepine, olanzapine, and ziprasidone showed the strongest evidence of efficacy in acute-phase treatment. Quetiapine and divalproex/valproate were also efficacious. Combination therapies with these atypical antipsychotics and mood stabilizers can be considered in severe cases. Olanzapine and quetiapine (alone or in combination with lithium/divalproex) showed the strongest evidence of efficacy in maintenance treatment. Lithium and lamotrigine may be beneficial given their preventive effects on suicide and depressive relapse. Further prospective studies primarily focusing on mixed states are needed.

The Mixed Tendency in Bipolar Disorder: An Operational Proposal for the Integration of Mixed Episodes in Predominant Polarity.

Predominant Polarity (PP) is an established specifier of Bipolar Disorder (BD), holding significant clinical implications. Nevertheless, there exists no consensus on how to incorporate mixed states into PP, leaving patients prone to mixed recurrences that are unclassified. In a comprehensive study involving 701 euthymic BD patients, we sought to redefine PP by introducing a novel metric, the "mixed tendency", and establish a practical threshold to identify patients with a "mixed phenotype". Furthermore, we investigated potential associations between the mixed phenotype and specific PP categories. Our findings revealed that the mixed tendency correlated significantly with early BD type I, lifetime suicide attempts, self-aggressive behaviour, and lifetime number of affective episodes (>5). Using a ROC curve analysis, we determined an optimal cut-off point for the mixed tendency at 0.228, suggesting that patients with ~25% of lifetime mixed episodes relative to total affective episodes should be identified as having a mixed phenotype. Notably, the mixed phenotype was positively associated with undetermined PP and negatively with manic and depressive PP. This study introduces a promising approach to incorporating mixed episodes into the PP definition, potentially enabling tailored interventions for patients with a substantial history of mixed episodes. However, further research in large, longitudinal cohorts is essential to validate these findings.

Comparing the metabolic pathways of different clinical phases of bipolar disorder through metabolomics studies.

This study identified the metabolic biomarkers for different clinical phases of bipolar disorder (BD) through metabolomics. BD patients were divided into three groups: patients with BD and depressive episodes (BE, n = 59), patients with BD and mania/hypomania episodes (BH, n = 16), patients with BD and mixed episodes (BM, n = 10), and healthy controls (HC, n = 10). Serum from participants was collected for metabolomic sequencing, biomarkers from each group were screened separately by partial least squares analysis, and metabolic pathways connected to the biomarkers were identified. Compared with the controls, 3-D-hydroxyacetic acid and N-acetyl-glycoprotein showed significant differences in the BE, BH, and BM groups. This study suggests that different clinical types of BD share the same metabolic pathways, such as pyruvate, glycolysis/gluconeogenesis, and ketone body metabolisms. In particular, abnormal glycine, serine, and threonine metabolism was specific to BM; ß-glucose, glycerol, lipids, lactate, and acetoacetate metabolites were specific to depressive episodes; the guanidine acetic acid metabolites specific to BH; and the acetic and ascorbic acids were metabolites specific to manic and BM. We screened potential biomarkers for different clinical phases of BD, which aids in BD typing and provides a theoretical basis for exploring the molecular mechanisms of BD.

Cariprazine for the treatment of bipolar mania with mixed features: A post hoc pooled analysis of 3 trials.

BACKGROUND: When bipolar I disorder (BP-I) mania is accompanied by subsyndromal depressive symptoms, a more complicated illness presentation results. To qualify for the mixed features specifier during mania, the DSM-5 requires ≥3 "non-overlapping" depressive symptoms (DS); notwithstanding, concerns of this definition's ecological validity and implications for timely diagnosis remain. METHODS: Herein, patients were pooled from three similarly-designed pivotal trials of cariprazine compared to placebo for BP-I mania (NCT00488618/NCT01058096/NCT01058668) in post hoc analyses of mixed features using three criteria: ≥3 DS (DSM-5), ≥2 DS, and Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥10. Efficacy of cariprazine compared to placebo was assessed (Week 3) by Young Mania Rating Scale (YMRS) and MADRS scores and rates of mania response and remission. RESULTS: In pooled patients (N = 1037), cariprazine significantly improved mean YMRS scores compared to placebo for each criterion; LSMDs were ≥3 DS = -3.79 (P = .0248), ≥2 DS = -2.91 (P = .0207), and ≥10 MADRS = -5.49 (P < .0001). More cariprazine- than placebo-treated patients met YMRS response and remission criteria, reaching significance for response in ≥2 DS (34% versus 47%; number-needed-to-treat [NNT] = 8, P = .0483) and ≥10 MADRS (31% versus 57%, NNT = 4, P < .0001) and for remission in ≥2 DS (27% versus 39%, NNT = 9, P = .0462), ≥10 MADRS (23% versus 44%, NNT = 5, P < .0001). Depressive symptoms were improved compared to placebo, reaching statistical significance in the MADRS ≥10 subgroup (LSMD = -1.59, P = .0082). LIMITATIONS: Post hoc analysis, MADRS  < 18 entry criterion may have prevented assessment of MADRS changes. CONCLUSIONS: Cariprazine significantly reduced manic and depressive symptoms in patients with mixed features with differential efficacy across the subgroups analyzed herein.

Management of asenapine treatment in clinical practice: Recommendations from a panel of experts. / Uso de asenapina en la práctica clínica: recomendaciones de un panel de expertos.

INTRODUCTION: The choice of an antipsychotic should be based on bipolar disorder (BD) symptoms and the particular needs of each patient, as well as the adverse events potentially associated with treatment. Asenapine is an atypical antipsychotic indicated for the management of type-I BD, with distinct pharmacokinetic and receptor affinity profiles. MATERIAL AND METHODS: Recommendations document developed by a panel of experts with extensive experience in the use of asenapine in psychiatric care, including emergency department, hospital, and outpatient care. Recommendations were discussed in a single meeting and were based on both the clinical experience of the panel of experts and the empirical evidence provided in the scientific literature. RESULTS: The present document describes the patient profile that best suits the pharmacodynamic characteristics of asenapine, as well as the advantages and limitations of the pharmacokinetics associated with the sublingual route. The document also addresses the main safety issues of asenapine and suggests interventions aimed at mitigating the most frequent adverse reactions associated with asenapine treatment. Finally, the article provides advice on dosing and overall management of asenapine treatment, including the combination with other treatments and the switch from other antipsychotics to asenapine. CONCLUSIONS: In this recommendations document, we provide clinicians with guidance on the use of asenapine in real-life practice, including the identification of patients who best suit the characteristics of this antipsychotic.

Bipolar Disorder Mixed Episodes: A Pragmatic Trial of a Public Health Treatment Effectiveness.

OBJECTIVES: To evaluate the effectiveness of an algorithm for the treatment of mixed episodes in bipolar disorder (BD) using the medications available under the Unified Health System (Sistema Único de Saúde) in Brazil. METHODS: The study included 107 individuals with BD in a current mixed episode, assessed biweekly for the outcomes of response and remission. The subjects were randomly assigned to start treatment with lithium, valproic acid, or carbamazepine, following a clinical protocol at a public outpatient clinic. Eligibility screening instruments, semistructured interview, and clinical psychiatric evaluation were used for diagnosis. To measure response and remission, the Hamilton Rating Scale for Depression and the Young Mania Rating Scale were used. A parameter of 50% or less in the symptom scales was used to define responses, as assessed by Kaplan-Meier time-event analysis. RESULTS: For the main outcome, response to treatment, all interventions proposed were proven to be effective, with no difference in response time for any of them. There was a lack of placebo control and blinding for intervention or outcomes. Individuals with mixed episodes in BD often face contradictory symptoms, and these inherent difficulties are the main obstacles to stabilize such a condition. CONCLUSIONS: The findings presented in this study show that the treatments available under the Unified Health System are able to reduce the overall burden of disease in terms of symptom reduction.

Long-term safety and tolerability of asenapine: A double-blind, uncontrolled, long-term extension trial in adults with an acute manic or mixed episode associated with bipolar I disorder.

BACKGROUND: Asenapine (ASN) is approved in the United States as monotherapy and adjunctive therapy (to lithium or valproate) in adults with bipolar mania, and as monotherapy in pediatric patients with bipolar mania. This is the first long-term study evaluating safety and tolerability of ASN fixed doses in this population. METHODS: After completing a 3-week, randomized, placebo (PBO)-controlled acute trial, patients could enroll in this 26-week, fixed-dose (5 or 10mg twice daily), double-blind extension study. Select predefined treatment-emergent adverse events (TEAEs) and metabolic parameters were reported. RESULTS: Overall, 164 patients were treated; 88 completed the study. The incidence of ≥1 TEAE was greater for PBO/ASN 5mg (68.3%) versus ASN 5mg/ASN 5mg (54.7%) and ASN 10mg/ASN 10mg (51.0%) with sedation, headache, somnolence, akathisia, and dizziness occurring as the most prevalent TEAEs. Predefined TEAEs were more common for PBO/ASN 5mg (33.3%) versus ASN 5mg/ASN 5mg (15.1%) and ASN 10mg/ASN 10mg (15.7%). Weight gain (≥7% increase from baseline to endpoint) was more frequent for ASN 10mg/ASN 10mg (16.3%) versus ASN 5mg/ASN 5mg (13.7%) and PBO/ASN 5mg (8.9%). No clinically significant metabolic changes were observed. The incidence of serious AEs was low and primarily related to underlying bipolar I disorder. LIMITATIONS: This study lacked a comparator group and was not powered for direct comparisons of ASN regimens. Results may not be applicable to the general bipolar population. CONCLUSIONS: ASN was generally safe and well tolerated in adults with an acute manic or mixed episode associated with bipolar I disorder.

Cost-effectiveness of asenapine in the treatment of bipolar I disorder patients with mixed episodes.

OBJECTIVE: Around one-third of patients with bipolar I disorder (BD-I) experience mixed episodes, characterized by both mania and depression, which tend to be more difficult and costly to treat. Atypical antipsychotics are recommended for the treatment of mixed episodes, although evidence of their efficacy, tolerability, and cost in these patients is limited. This study evaluates, from a UK National Health Service perspective, the cost-effectiveness of asenapine vs olanzapine in BD-I patients with mixed episodes. METHODS: Cost-effectiveness was assessed using a Markov model. Efficacy was informed by a post-hoc analysis of two short-term clinical trials, with response measured as a composite Young Mania Rating Score and Montgomery-Åsberg Depression Rating Scale end-point. Probabilities of discontinuation and relapse to manic, mixed, and depressive episodes were sourced from published meta-analyses. Direct costs (2012-2013 values) included drug acquisition, monitoring, and resource use related to bipolar disorder as well as selected adverse events. Benefits were measured as quality-adjusted life years (QALYs). RESULTS: For treating mixed episodes, asenapine generated 0.0187 more QALYs for an additional cost of £24 compared to olanzapine over a 5-year period, corresponding to a £1302 incremental cost-effectiveness ratio. The higher acquisition cost of asenapine was roughly offset by the healthcare savings conferred through its greater efficacy in treating these patients. The model shows that benefits were driven by earlier response to asenapine during acute treatment and were maintained during longer-term follow-up. RESULTS were sensitive to changes in key parameters including short and longer-term efficacy, unit cost, and utilities, but conclusions remained relatively robust. CONCLUSIONS: RESULTS suggest that asenapine is a cost-effective alternative to olanzapine in mixed episode BD-I patients, and may have specific advantages in this population, potentially leading to healthcare sector savings and improved outcomes. Limitations of the analysis stem from gaps in clinical and economic evidence for these patients and should be addressed by future clinical trials.

Efficacy of second generation antipsychotics in treating acute mixed episodes in bipolar disorder: a meta-analysis of placebo-controlled trials.

BACKGROUND: The literature on the treatment mixed episodes in Bipolar Disorder [BD] is sparse. Second generation antipsychotics [SGA] have documented efficacy in mania, but not mixed episodes. The objective of this meta-analysis was to ascertain the efficacy of SGA, either as mono- and/or adjunctive therapy, in the treatment of acute mixed episodes of BD, compared to placebo. METHODS: A MEDLINE search for English language publications of randomized controlled trials [RCTs] comparing SGA with placebo in the treatment of an acute manic/mixed episode of BD, during the period 1990-2012, was performed using the terms 'atypical antipsychotics', 'SGA', 'mixed episodes', 'dysphoric mania' and each SGA independently. 9 RCTs reporting data on 1289 mixed episode patients treated with aripiprazole, asenapine, olanzapine, paliperidone-ER, risperidone, and ziprasidone, either as monotherapy or as adjunctive therapy, versus placebo, for 3-6 weeks, were included in the meta-analysis. We extracted data on the number of patients, SGA, duration of study and mean change in mania and depression scores from baseline to endpoint. Standardized mean difference between SGA and placebo for the mean baseline-to-endpoint change in mania and depression rating scores was calculated, with a 95% confidence limit. RESULTS: SGA, either alone or in combination with mood stabilizers, had superior efficacy in treating manic symptoms of mixed episodes compared to placebo (-0.41, 95% CI -0.53, -0.30; overall effect p<0.00001). SGA were equally effective for manic symptoms in mixed episodes and pure mania (p=0.99). SGA had superior efficacy in treating depressive symptoms of mixed episodes (-0.30, 95% CI -0.47, -0.13; p<0.001) compared to placebo in two trials reporting this information. LIMITATIONS: Thirteen relevant studies could not be included as data for mixed-episodes were not presented separately. CONCLUSIONS: SGA are effective in treating acute mixed episodes of BD, with predominant manic symptoms. Their efficacy in treating depressed mixed episodes remains unclear.