Approved treatments for bipolar depression are limited and associated with a spectrum of undesirable side effects. Lumateperone (lumateperone tosylate, ITI−007), a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, is FDA-approved for the treatment of schizophrenia. Lumateperone is currently being investigated for the treatment of bipolar depression (major depressive episodes [MDE] associated with bipolar I and bipolar II disorder). This Phase 3 randomized, double-blind, parallel-group, placebo-controlled multinational study (NCT03249376) investigated the efficacy and safety of lumateperone in patients with bipolar I or bipolar II disorder experiencing a MDE.

Patients (18 75 years) with a clinical diagnosis of bipolar I or bipolar II disorder who were experiencing a MDE (Montgomery-Åsberg Depression Rating Scale [MADRS] Total score =20 and a Clinical Global Impression Scale-Bipolar Version-Severity [CGI-BP-S] score =4 at screening and baseline) were randomized to lumateperone 42mg or placebo for 6 weeks. The primary and key secondary efficacy endpoints were change from baseline to Day 43 in MADRS total score and CGI-BP-S scores, respectively. Secondary efficacy outcomes included response (MADRS improvement = 50%) and remission (MADRS total score =12) at Day 43. Safety assessments included treatment emergent adverse events, laboratory parameters, vital signs, extrapyramidal symptoms (EPS), and suicidality.

In this study, 377 patients received treatment (placebo, n=189; lumateperone 42mg, n=188) and 333 completed treatment. Patients in the lumateperone 42-mg group had significantly greater mean improvement on MADRS total score change from baseline to Day 43 compared with placebo (least squares mean difference [LSMD]=-4.6; 95% confidence interval [CI]=-6.34, −2.83; effect size vs placebo [ES]=-0.56; P<.0001). Lumateperone treatment was associated with significant MADRS improvement in both patients with bipolar I (LSMD=-4.0; 95% CI=-5.92, −1.99; ES=-0.49; P<.0001) and bipolar II (LSMD=-7.0; 95% CI=-10.92, −3.16; ES=-0.81; P=.0004). The lumateperone 42-mg group also had significantly greater mean improvement in CGI-BP-S total score compared with placebo (LSMD=-0.9; 95% CI=-1.37, −0.51; ES=-0.46; P<.001). Lumateperone compared with placebo had significantly greater MADRS response rate (51.1% vs 36.7%; odds ratio=2.98; P<.001) and remission rates (P=.02) at Day 43. Lumateperone treatment was well tolerated, with minimal risk of EPS, metabolic, and prolactin side effects.

Lumateperone 42 mg significantly improved depression symptoms in both patients with bipolar I and bipolar II depression. Lumateperone was generally well tolerated. These results suggest that lumateperone 42 mg may be a promising new treatment for bipolar depression associated with bipolar I or bipolar II disorder.

Intra-Cellular Therapies, Inc.

The aim of this study is to determine if personality traits contribute to the likelihood of substance abuse in Bipolar Disorder (BD).

Fifty-nine patients meeting DSM-IV criteria for BD: 20 without any history of Substance Related Disorder (SRD), 21 with a lifetime history of SRD but without current SRD, and 18 with current SRD. Patients filled out the TCI, the differences were analyzed by ANOVA and the likelihood was obtained by Multinomial Logistic Regression.

Only Novelty Seeking (NS) is statistically different between the groups. Patients with BD with current SRD have higher rates in NS than those with past SRD, and those without a history of SRD. NS was confirmed as a predicting variable, both to current SRD (OR [CI 95%] = 1.039/1.351; p = 0.011) and past SRD (OR [CI 95%] = 1.004/1.277; p = 0.042) on patients with BD.

The results shown would appear to confirm the relationship of NS with the SRD, so long as there is no clear evidence that indicates the association of NS with BD.

There appears a greater predisposition to develop SRD in those patients with a higher degree of NS. The use of the Cloninger's TCI could be used in BD to determine the risk of developing an SRD. Early detection might help improve prognosis.

Despite their proven efficacy and tolerability, many patients are often switched among antipsychotics therapies due to the lack of therapeutic response. Many physicians begin to switching antipsychotics with the original intention to discontinue the drug, and, continue with another therapy. Several new antipsychotics available allow us to improve the long- term therapy.

Nineteen year open label study in ‘real world’ setting in 121 inpatients with schizophrenia (DSM-III -> DSM-IV-TR) observed first time in 1992 in a neuropsychiatric centre and subsequently clinically evaluated until 2011; data collected and compared to switching between antipsychotics (from haloperidol to clozapine, risperidone, olanzapine, quetiapine, aripiprazole). At baseline: epidemiogical and biological parameters, PANSS, QLindex and, subsequently, with CGI-S scores during every clinical visit of control [T1 → T7]. The overall analysis carried out with EZAnalyze(c) ver.3.0.

In the clozapine group remission rates were higher than other groups; Interrupted therapy: 27.62% of patients with risperidone, 34.85% with quetiapine. A consistent number of patients (8.04%), who have suspended the ‘first’ therapy with haloperidol, have assumed again the therapy with haloperidol toT7. Outcome was good in 28.4%,intermediate in 50,1% and poor in 21%. CGI-S T7 vs T0 (Severity of illness= p: 0,0066; Global improvement = p: 0,02844; Efficacy index =p: 0,00597)

Study suggested that most clinically stable outpatients with schizophrenia maintain remission states after being switched to atypical antipsychotics; a T7 (19 years) a consistent number of patients assumed again haloperidol with satisfactory rate of 51.18% then previous pharmacological treatments with a atypical antipsychotics.

The use of atypical antipsychotics (SGAs) is hindered by the frequent occurrence of metabolic side effects, resulting in worsened quality of life and greater mortality as a result of increased risk factors for metabolic syndrome [2] [3] in schizophrenic patients compared with general population [1].

To establish the relationship between antipsychotic efficacy and side effects, especially the impact of various antipsychotics on metabolic parameters after 20-year treatment with atypical (SGAs) and typical antipsychotics (FGAs)

To identify advantages and disvantages of SGAs in terms of quality of life, costs and benefits.

Forty-five psychiatric inpatients diagnosed with schizophrenia or schizoaffective disorder (DSM-IV-TR diagnosis), treated with typical (haloperidol) and atypical (clozapine, risperidone, olanzapine, quetiapine, aripiprazole) antipyschotics, were studied retrospectively during 20 years. We use data at baseline, follow-up: 1, 5, 10, 20 years. Rating scales administered: CGI-I, SAPS, SANS, PANSS.

The results have underlined a statistically significant variations(p value <.05) of the lipidic and glicidic profile. We have also found a reduction of the recorded values at endpoint vs baseline in aripiprazole and haloperidol groups. The glicemic values, were not statistically different in quetiapine, aripiprazole, risperidone and haloperidol groups. No significant statistical variations were observed in complete blood count, electrocardiogram, liver enzymes blood pressure and body weight.

The results confirm studies on efficacy and effectiveness of both SGAs and FGAs, and their influence on metabolic profile and other biological parameters. These data can represent a’real world’ study in patients observed during our daily out-patient practice.

Immune system markers may predict affective disorder treatment response, but whether an overall immune system marker predicts bipolar disorder treatment effect is unclear.

Bipolar CHOICE (N = 482) and LiTMUS (N = 283) were similar comparative effectiveness trials treating patients with bipolar disorder for 24 weeks with four different treatment arms (standard-dose lithium, quetiapine, moderate-dose lithium plus optimised personalised treatment (OPT) and OPT without lithium). We performed secondary mixed effects linear regression analyses adjusted for age, gender, smoking and body mass index to investigate relationships between pre-treatment white blood cell (WBC) levels and clinical global impression scale (CGI) response.

Compared to participants with WBC counts of 4.5–10 × 109/l, participants with WBC < 4.5 or WBC ≥ 10 showed similar improvement within each specific treatment arm and in gender-stratified analyses.

An overall immune system marker did not predict differential treatment response to four different treatment approaches for bipolar disorder all lasting 24 weeks.

To characterize the multiple dimensions and benefits of the Mediterranean diet as a sustainable diet, in order to revitalize this intangible food heritage at the country level; and to develop a multidimensional framework – the Med Diet 4.0 – in which four sustainability benefits of the Mediterranean diet are presented in parallel: major health and nutrition benefits, low environmental impacts and richness in biodiversity, high sociocultural food values, and positive local economic returns.

A narrative review was applied at the country level to highlight the multiple sustainable benefits of the Mediterranean diet into a single multidimensional framework: the Med Diet 4.0.

We included studies published in English in peer-reviewed journals that contained data on the characterization of sustainable diets and of the Mediterranean diet. The methodological framework approach was finalized through a series of meetings, workshops and conferences where the framework was presented, discussed and ultimately refined.

The Med Diet 4.0 provides a conceptual multidimensional framework to characterize the Mediterranean diet as a sustainable diet model, by applying principles of sustainability to the Mediterranean diet.

By providing a broader understanding of the many sustainable benefits of the Mediterranean diet, the Med Diet 4.0 can contribute to the revitalization of the Mediterranean diet by improving its current perception not only as a healthy diet but also a sustainable lifestyle model, with country-specific and culturally appropriate variations. It also takes into account the identity and diversity of food cultures and systems, expressed within the notion of the Mediterranean diet, across the Mediterranean region and in other parts of the world. Further multidisciplinary studies are needed for the assessment of the sustainability of the Mediterranean diet to include these new dimensions.

This study examined healthcare utilization in the past year by subjects who screened positive for bipolar versus unipolar depression.

A self-administered survey was completed in 2002 by a United States population-based sample. Respondents were categorized into one of three subgroups: bipolar depressed screen positive (BP DEP+, n=394); unipolar depressed screen positive (UP DEP+, n=794); and control subjects (n=1,612).

For depressive symptoms in the past year, BP DEP+ respondents were significantly more likely than UP DEP+ respondents to report a healthcare visit to a number of diverse care providers. In analyses controlled for demographics and depression severity, the differences in psychiatric hospitalization, psychologist/counselor outpatient visit, substance abuse/social services visit, and number of emergency room visits remained significant between BP DEP+ and UP DEP+ respondents.

Subjects with self-reported bipolar depression sought care more often from a number of diverse healthcare resources than subjects with self-reported unipolar depression. These findings underscore the morbidity associated with bipolar depression.

There have been no previous factor analytic studies of the Hamilton Depression Rating Scale (HDRS) in samples with bipolar I depression, and no investigations of the utility of any derived factors in determining treatment response in this condition. This study aimed to identify and compare factors of a 31-item version of the HDRS (HDRS-31) in large samples of patients with bipolar depression and Major Depressive Disorder (MDD), then examine the responsiveness of such factors to lamotrigine compared with placebo in the bipolar depressed sample.

This multivariate analytical study was performed on 2 large depressed samples (one bipolar and the other MDD) that had been recruited for separate, contemporaneous, double-blind placebo-controlled trials of lamotrigine. The 2 studies had similar designs and assessment tools, the major measures being the Montgomery–Asberg Depression Rating Scale (MADRS) and HDRS-31. To identify the constructs underlying the scale, exploratory factor analyses were conducted using HDRS-31 baseline scores. Treatment responsiveness in the bipolar depressed sample—as indicated by improvement in the total MADRS and HDRS-31, as well as HDRS factors—were examined using both a mixed-effects analysis and individual time-point t-tests.

Seven factors of the HDRS-31 were identified: I—“depressive cognitions,” II—“psychomotor retardation,” III—“insomnia,” IV—“hypersomnia,” V—“appetite and weight change,” VI—“anxiety,” and VII—“anergia.” A significant therapeutic effect of lamotrigine in bipolar depression was found for the “depressive cognitions” factor (from week 3) and “psychomotor retardation” (from week 4).

This study has identified 7 factors of the HDRS in a large sample of patients with bipolar depression. The results suggest that that the clinical benefits of lamotrigine in acute bipolar depression are primarily upon depressive cognitions and psychomotor slowing.

Lack of coordination between screening studies for common mental disorders in primary care and community epidemiological samples impedes progress in clinical epidemiology. Short screening scales based on the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI), the diagnostic interview used in community epidemiological surveys throughout the world, were developed to address this problem.

Expert reviews and cognitive interviews generated CIDI screening scale (CIDI-SC) item pools for 30-day DSM-IV-TR major depressive episode (MDE), generalized anxiety disorder (GAD), panic disorder (PD) and bipolar disorder (BPD). These items were administered to 3058 unselected patients in 29 US primary care offices. Blinded SCID clinical reinterviews were administered to 206 of these patients, oversampling screened positives.

Stepwise regression selected optimal screening items to predict clinical diagnoses. Excellent concordance [area under the receiver operating characteristic curve (AUC)] was found between continuous CIDI-SC and DSM-IV/SCID diagnoses of 30-day MDE (0.93), GAD (0.88), PD (0.90) and BPD (0.97), with only 9–38 questions needed to administer all scales. CIDI-SC versus SCID prevalence differences are insignificant at the optimal CIDI-SC diagnostic thresholds (χ21 = 0.0–2.9, p = 0.09–0.94). Individual-level diagnostic concordance at these thresholds is substantial (AUC 0.81–0.86, sensitivity 68.0–80.2%, specificity 90.1–98.8%). Likelihood ratio positive (LR+) exceeds 10 and LR− is 0.1 or less at informative thresholds for all diagnoses.

CIDI-SC operating characteristics are equivalent (MDE, GAD) or superior (PD, BPD) to those of the best alternative screening scales. CIDI-SC results can be compared directly to general population CIDI survey results or used to target and streamline second-stage CIDIs.

There is uncertainty about the efficacy of lamotrigine in bipolar depressive episodes.

To synthesise the evidence for the efficacy of lamotrigine in bipolar depressive episodes.

Systematic review and meta-analysis of individual patient data from randomised controlled trials comparing lamotrigine with placebo.

Individual data from 1072 participants from five randomised controlled trials were obtained. More individuals treated with lamotrigine than placebo responded to treatment on both the Hamilton Rating Scale for Depression (HRSD) (relative risk (RR)=1.27, 95% CI 1.09–1.47, P=0.002) and Montgomery– åsberg Depression Rating Scale (MADRS) (RR=1.22, 95% CI 1.06–1.41, P=0.005). There was an interaction (P=0.04) by baseline severity of depression: lamotrigine was superior to placebo in people with HRSD score >24 (RR=1.47, 95% CI 1.16–1.87, P=0.001) but not in people with HRSD score 24 (RR=1.07, 95% CI 0.90–1.27, P=0.445).

There is consistent evidence that lamotrigine has a beneficial effect on depressive symptoms in the depressed phase of bipolar disorder. The overall pool effect was modest, although the advantage over placebo was larger in more severely depressed participants.

Previous studies have reported prefrontal cortex (PFC) pathophysiology in bipolar disorder.

We examined the hemodynamics of the PFC during resting and cognitive tasks in 29 patients with bipolar disorder and 27 healthy controls, matched for age, verbal abilities and education. The cognitive test battery consisted of letter and category fluency (LF and CF), Sets A and B of the Raven's Colored Progressive Matrices (RCPM-A and RCPM-B) and the letter cancellation test (LCT). The tissue oxygenation index (TOI), the ratio of oxygenated hemoglobin (HbO2) concentration to total hemoglobin concentration, was measured in the bilateral PFC by spatially resolved near-infrared spectroscopy. Changes in HbO2 concentration were also measured.

The bipolar group showed slight but significant impairment in performance for the non-verbal tasks (RCPM-A, RCPM-B and LCT), with no significant between-group differences for the two verbal tasks (LF and CF). A group×task×hemisphere analysis of variance (ANOVA) on the TOI revealed an abnormal pattern of prefrontal oxygenation across different types of cognitive processing in the bipolar group. Post hoc analyses following a group×task×hemisphere ANOVA on HbO2 concentration revealed that the bipolar group showed a greater increase in HbO2 concentration in the LCT and in RCPM-B, relative to controls.

Both indices of cortical activation (TOI and HbO2 concentration) indicated a discrepancy in the PFC function between verbal versus non-verbal processing, indicating task-specific abnormalities in the hemodynamic control of the PFC in bipolar disorder.

Sub-syndromal symptoms in bipolar disorder impair functioning and diminish quality of life.

To examine factors associated with time spent with sub-syndromal symptoms and to characterise how these symptoms influence outcomes.

In a double-blind randomised maintenance trial, patients received either olanzapine or lithium monotherapy for 1 year. Stepwise logistic regression models were used to identify factors that were significant predictors of percentage time spent with sub-syndromal symptoms. The presence of sub-syndromal symptoms during the first 8 weeks was examined as a predictor of subsequent relapse.

Presence of sub-syndromal depressive symptoms during the first 8 weeks significantly increased the likelihood of depressive relapse (relative risk 4.67, P<0.001). Patients with psychotic features and those with a greater number of previous depressive episodes were more likely to experience sub-syndromal depressive symptoms (RR=2.51, P<0.001 and RR=2.35, P=0.03 respectively).

These findings help to identify patients at increased risk of affective relapse and suggest that appropriate therapeutic interventions should be considered even when syndromal-level symptoms are absent.

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.