In the last decade, literature reports evidences of a growing number of patients diagnosed with Bipolar Disorders (BD), however, only few data are available regarding the distribution of BD diagnosis in the two genders. In fact, although many studies show differences in presentation and comorbidities of BD in the two genders, BD are commonly perceived as equally affecting both women and men. On the other hand, BD in female patients can often be misdiagnosed as MDD, especially because of the higher number of depressive episodes that characterize BD in women.

We aimed to analyse the gender composition of large samples, recently published studies on BD, in order to evaluate a possible modification of representation of BD in the two genders.

An electronic review of literature was conducted, and results were filtered by year of publication (2011-2020) and number of patients (> 1,000).

Our results show a higher number of female patients in every study evaluated (N=10). Of note, we found a higher number of females also in BD-I subsamples, in contradiction with previously published literature.

Even if with limitations connected to the design of the study, our study supports the hypothesis of a gender specific increment in BD diagnosis, and could lead the way for large epidemiological studies assessing gender specific prevalence of BD in the general population. Given the risks connected with untreated BD, and with antidepressants monotherapy, a better understanding of BD epidemiology could help physicians adequately diagnose and treat affected subjects.

The aim of this study was to investigate whether lower lithium levels (LoLi) or olanzapine doses (LoOL) are risk factors for future mood episodes in patients with bipolar I disorder.

A post-hoc analysis of the olanzapine-lithium-maintenance study [31] was performed using proportional hazards Cox regression models and marginal structural models (MSMs), adjusting for non-random assignments of dose during treatment.

The LoLi group (< 0.6 mmol/L) had a significantly increased risk of manic/mixed (hazard ratio [HR] = 1.96, p = 0.042), but not depressive (HR = 2.11, p = 0.272) episodes, compared to the combined medium (0.6–0.79 mmol/L) and high lithium level (≥ 0.8 mmol/L) groups. There was no significant difference in risk between the two higher lithium level groups (0.6-0.79 mmol/L; ≥ 0.8 mmol/L) for new manic/mixed (HR = 0.96, p = 0.893) or depressive (HR = 0.95, p = 0.922) episodes. The LoOL group (< 10 mg/day) showed a significantly increased risk of depressive (HR = 2.24, p = 0.025) episodes compared to the higher olanzapine (HiOL) dose group (HiOL: 10–20 mg/day), while there was no statistically significant difference in risk for manic/mixed episodes between the two groups (HR = 0.94, p = 0.895).

Lithium levels ≥ 0.6 mmol/L and olanzapine doses ≥ 10 mg/day may be necessary for optimal protection against manic/mixed or depressive episodes, respectively in patients with bipolar I disorder.

This unique study of treatment of the mixed state of bipolar I disorder using simultaneous depression and mania response criteria compared divalproex monotherapy versus olanzapine augmentation in a 6-week, randomized, double-blind trial.

Patients (age 18-60 years) with 14-28 days of divalproex monotherapy (blood levels of 75-125 μg/mL) were randomized to augmentation with olanzapine 5-20 mg/day or placebo. Data collected included: Hamilton Depression Rating Scale (HDRS), Young Mania Rating Scale (YMRS), Clinical Global Impression for Bipolar Illness (CGI-BP), hospitalizations, concomitant medications, and adverse events (AEs). Primary co-objectives were comparisons of baseline to endpoint changes in HDRS and YMRS. Secondary objectives included comparisons of times to onset (25% reduction) and response (50% reduction) in both HDRS and YMRS, change in CGI-BP, hospitalizations, and safety.

Patients were 59% female, 51% Caucasian, 33% African American, and 14% Hispanic with mean standard deviation (SD) HDRS and YMRS scores of 22.2 (4.5) and 20.9 (4.4). Mean standard error (SE) score changes for the olanzapine (n=100) or placebo (n=101) arms, respectively, were: HDRS, -9.37 (.55) and -7.69 (.54), p=.022; YMRS, -10.15 (.44) and -7.68 (.44), p< .001; and CGI-BP, -1.34 (.11) and -1.06 (.11), p=.056. Times-to-onset (median 7 vs 14 days) and response (median 25 vs 49 days) were significantly shorter for olanzapine augmentation. One olanzapine patient required hospitalization (p=1.0). Treatment-emergent AEs were consistent with previously-published rates.

Six-week olanzapine treatment augmentation was associated with greater and earlier reduction of manic and depressive symptoms in mixed episode patients on divalproex treatment.

Recent research indicates intramuscular ziprasidone produces a significant, early (within 24 hours) improvement in psychotic symptoms. In this analysis, we evaluated the potential for an early antipsychotic response to oral ziprasidone in subjects with acute bipolar mania.

We conducted a pooled analysis of two 3-week, randomized, double-blind, placebo-controlled trials of ziprasidone (40-160 mg/d) in hospitalized patients (N=415) with bipolar I disorder, and a current manic (N=257) or mixed episode (N=158), with (N=151) or without (N=245) psychotic features. Efficacy assessments included the Mania Rating Scale (MRS, derived from the SADS-C). Remission was defined as achieving a MRS score <= 12. Improvement in psychosis was evaluated by a sum of the three SADS-C psychosis items (delusions, hallucinations, and suspiciousness). MMRM and logistic regression analyses were applied to estimate the time course of response.

Significantly greater response rate (>50% decrease from baseline) and improvement in the SADS-C psychosis score were observed in the ziprasidone group (versus placebo) as early as Day 4 (p<0.01), and the magnitude of improvement increased with time (p<0.003). At Day 21, remission rate with ziprasidone monotherapy was 49% versus 36% in the placebo group (p=0.02). Early antipsychotic response at Day 4 was an accurate predictor of remission at Day 21 (p<0.01, ROC=0.76).

Ziprasidone was associated with a rapid onset of response in psychotic symptoms in patients with acute bipolar mania. This early reduction in psychotic symptoms was found to mediate overall improvement in manic symptoms and predict remission at endpoint.

The objective of this post-hoc analysis was to evaluate recovery-related outcomes in patients with bipolar depression treated with lurasidone.

Subjects meeting DSM-IV-TR criteria for bipolar I depression, with or without rapid cycling, were randomized to 6 weeks of once-daily, double-blind treatment with either lurasidone 20-60 mg (LUR20-60), lurasidone 80-120 mg (LUR80-120) or placebo (PBO), followed by a 6-month, open-label, continuation study of lurasidone.

At end of the 6-week acute phase, a significantly higher proportion of subjects met both symptomatic (MADRS total score ≤ 12) and functional (mean SDS total score ≤ 3 and all SDS domain scores ≤ 3 for mildly impairment) remission criteria in the lurasidone group (33%,N=273 pooling the LUR20-60 and LUR80-120 groups) compared to the placebo group (15%, N=143,p<0.05, NNT = 6). In the 6-month continuation study, the proportion of subjects achieving symptomatic and functional remission at both week 19 and week 32 (month 3 and month 6 of the continuation study, respectively) was 61% (85/140) in subjects who continued lurasidone treatment (LUR-LUR) and 45% (31/69) in subjects who switched from placebo to lurasidone (PBO-LUR). Multivariate logistic modeling revealed that statistically significant predictors of symptomatic and functional recovery included: lower baseline symptom severity, non-white race, and taking lurasidone (rather than placebo) during the acute phase.

Our findings support the potential for attainment of remission in patients with bipolar I depression treated with lurasidone, which might lead to clinical and functional recovery.

Assess prevalence and clinical relevance of 'with mixed features” using a more liberal (2 opposite pole symptoms) compared to the more conservative DSM-5 (3 opposite pole symptoms) threshold in depressed bipolar disorder (BD) patients.

BD outpatients were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. Prevalence and clinical correlates of baseline depressive episodes 'with mixed features” were compared using a more liberal threshold and the more conservative DSM-5 threshold.

Among 503 BD patients, 151 (30.8%) had baseline syndromal major depressive episodes, among whom 'with mixed features” occurred in 22.5% (34/151) using a more liberal threshold, but in only 9.9% (15/151) using the more conservative DSM-5 threshold. Hence, the rate of 'with mixed features” for depressive episodes using the more liberal compared to the conservative threshold was more than twice (2.3 times) as high (Chi-square=8.8, p=0.004). Moreover, the more liberal threshold yielded more important statistically significant clinical correlates of 'with mixed features” compared to pure depressive episodes, which were not significant using the more conservative DSM-5 threshold. Specifically, using the more liberal threshold, mixed compared to pure depression was associated with more anxiety disorder comorbidity and alcohol use disorder comorbidity, and less antidepressant use.

Further studies are warranted to assess our preliminary observation that a more liberal 'with mixed features” threshold for bipolar depression may be more inclusive and have more clinical relevance.

Rapid cycling (RC) worsens the course of bipolar disorder (BD) being associated with poor response to pharmacotherapy. Previous results about clinical variables potentially associated with RCBD were discordant or unreplicated.

An early diagnosis should be the goal to properly treat RCBD patients.

To compare clinical variables between RC and non-RC bipolar patients and to identify related risk factors.

A sample of 238 bipolar patients was enrolled from three different community mental health centers. Descriptive analyses were performed on total sample and patients were compared in terms of sociodemographic and clinical variables according to the presence of RC by multivariate analyses of variance (MANOVAs, continuous variables) or χ2 tests (qualitative variables). Binary logistic regression was performed to calculate odds ratios.

Overall, 28 patients (11.8%) had RC. The two groups were not different in terms of age, age at onset, gender distribution, type of family history, type of substance use disorder, history of antidepressant therapy, main antidepressant, psychotic symptoms, comorbid anxiety disorders, suicide attempts, thyroid diseases, diabetes, type of BD, duration of untreated illness, illness duration, duration of antidepressant treatment and GAF scores. In contrast, RC patients had more often a history of obstetric complications (P < 0.05), obesity (P < 0.05) and a trend to hypercholesterolemia (P = 0.08). In addition, RC bipolar patients presented more frequently lifetime MDMA misuse (P < 0.05) than patients without RC.

Obesity and obstetric complications are risk factors for the development of RC in BD. Lifetime MDMA misuse may be more frequent in RC bipolar patients.

The authors have not supplied their declaration of competing interest.

Few controlled studies examine the treatment of depressive features in mania.

To evaluate the efficacy of olanzapine, in combination with lithium or valproate, for treating depressive symptoms associated with mania.

Secondary analysis of a 6-week, double-blind, randomised study of olanzapine (5–20 mg/day) or placebo combined with ongoing valproate or lithium open treatment for 344 patients in mixed or manic episodes. This analysis focused on a dysphoric subgroup with baseline Hamilton Rating Scale for Depression (HRSD) total scores of 20 or over contrasted with non-dysphoric patients.

In the dysphoric subgroup (n=85) mean HRSD total score improvement was significantly greater in olanzapine co-therapy patients than in those receiving placebo plus lithium or valproate (P<0.001). Substantial contributors to this superiority included the HRSD Maier sub-scale (P=0.013) and the suicide item (P=0.001). Total Young Mania Rating Scale improvement was also superior with olanzapine co-therapy.

In patients with acute dysphoric mania, addition of olanzapine to ongoing lithium or valproate monotherapy significantly improved depressive symptom, mania and suicidality ratings.