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This meta-analysis investigated the efficacy, safety, and tolerability of lamotrigine versus placebo in preventing relapse and recurrence of mood episodes in women of childbearing age with bipolar I disorder. Following up to 16 weeks' open-label lamotrigine treatment, responders were randomized to double-blind treatment, including lamotrigine 100–400 mg/day or placebo, in four trials of up to 76 weeks. Women aged 18–45 years who received ≥ 1 dose of study treatment and had ≥ 1 efficacy assessment in the double-blind phase were pooled for efficacy analysis. The primary outcome was median time to intervention for any mood episode (TIME). Of 717 eligible women in the open-label phase, 287 responded and were randomized to lamotrigine (n = 153) or placebo (n = 134). The randomized group had a mean (SD) of 2.0(2.02) manic and 2.5(2.02) depressive episodes in the 3 years before screening. Median TIME was 323 days with lamotrigine and 127 days with placebo (HR 0.69; 95% CI 0.49, 0.96; p = 0.030). Lamotrigine delayed time to intervention for any depressive episode (HR 0.59; 95% CI 0.39, 0.90; p = 0.014) with no treatment difference for manic episodes (HR 0.91; 95% CI 0.52, 1.58; p = 0.732). 2/717 (< 1%) participants experienced serious rash-related adverse events (AEs) during the open-label phase, and 52/717 (7%) had non-serious rash-related events leading to study withdrawal. Incidence of AEs and AEs leading to withdrawal were similar between lamotrigine and placebo groups. Lamotrigine delayed relapse and recurrence of mood episodes, largely by preventing depressive episodes, and was well tolerated in women of childbearing age. [ABSTRACT FROM AUTHOR]

Background: Many medications used to treat schizophrenia and bipolar I disorder are linked to hyperprolactinemia. The effects of cariprazine, a dopamine D3/D2 receptor partial agonist, on prolactin levels in patients with schizophrenia or bipolar I disorder were evaluated. Methods: Effects on prolactin were evaluated using pooled data from randomized, double-blind, placebo-controlled studies in patients with schizophrenia (4 studies; 6-week duration; cariprazine 1.5– 3 mg/d, 4.5– 6 mg/d, and 9– 12 mg/d), bipolar mania (3 studies; 3-week duration; cariprazine 3– 6 and 9– 12 mg/d), and bipolar depression (3 studies; 6- to 8-week duration; cariprazine 1.5 and 3 mg/d). Long-term effects were analyzed using open-label studies in patients with schizophrenia (2 studies; 48-week duration) and patients with bipolar mania (1 study; 16-week duration). Change in prolactin levels (ng/mL) from baseline to study endpoint was evaluated in subsets of sex and prior medication use. Results: In patients with schizophrenia (male, n = 1377; female, n = 558), median prolactin changes were − 1.2 for males and − 7.4 for females on placebo, and ranged from − 4.2 to − 3.6 for males and − 12.4 to +0.2 for females in the cariprazine-treatment groups. In patients with bipolar mania (male, n = 570; female, n = 395), median prolactin changes were − 0.2 for males and − 1.1 for females on placebo and ranged from − 2.1 to − 3.0 for males and 0 to +1.8 for females in the cariprazine-treatment groups. Median decreases were also seen in the long-term studies of schizophrenia (range, − 14.6 to − 2.0) and bipolar mania (range, − 0.8 to +1.9). In patients with bipolar depression (male, n = 485; female, n = 780), median prolactin changes were +0.3 for males and +0.7 for females on placebo and ranged from +0.4 to +0.5 for males and +3.0 to +3.1 for females in the cariprazine-treatment groups. Conclusion: Treatment with cariprazine for schizophrenia or bipolar I disorder was associated with minimal effects on prolactin levels. [ABSTRACT FROM AUTHOR]

• The prevalence of Depressive Disorders was 4.73% ant the incidence rates (2015–2017) were 7.12, 7.35 and 8.02 per 1000 person-years, respectively. • The estimated societal cost of Depressive Disorders in the Spanish adult population was € 6145 million. The mean cost per patient/year was € 3402. • Indirect costs related to long-term sick leaves/permanent disabilities have the greatest weight within the total cost of depressive disorder in Spain (60,5%). • Direct costs represent only 17,5% of the total costs of depression, representing 1,1% of the total Health Care Expenditure in 2017. Depressive Disorders are the most common psychiatric diagnoses in the general population. To estimate the frequency, costs associated with Depressive Disorders in usual clinical practice, and in the whole Spanish population, a longitudinal, retrospective, observational study was carried out using data from the BIG-PAC database®. Study population: all patients aged ≥ 18 years with a diagnosis of a Depressive Disorder in 2015–2017. Prevalence was computed as the proportion of Depressive Disorder cases in the adult general population, and the incidence rate, as the number of new Depressive Disorder cases diagnosed per 1,000 person-years in the population using health services, during 2015–2017. We collected demographic variables, comorbidity, direct health costs, and indirect costs (temporary and permanent disability). Health costs related to Depressive Disorders were estimated according to the annual resource use rate (resource/patient/year). Indirect costs were calculated according to the human capital method. Using the study data and information from the Spanish National Institute of Statistics, we estimated the cost of Depressive Disorders corresponding to the Spanish adult population, including premature mortality. 69,217 Depressive Disorder patients aged ≥ 18 years who met the inclusion/exclusion criteria were studied (mean age: 56.8 years; female: 71.4%). Prevalence of Depressive Disorders in the general population was 4.73% (95% CI: 4.70–4.76%). Annual incidence rates (2015–2017) were 7.12, 7.35 and 8.02 per 1,000 person-years, respectively. Total costs observed in our Depressive Disorder patients were € 223.9 million (corresponding to a mean of € 3,235.3; mean/patient/year), of which, 18.4% were direct health care costs and 81.6%, non-health indirect costs (18% temporary occupational disability, 63.6% permanent disability). Considering also the cost of premature death , the mean cost per patient/year was € 3,402 and the estimated societal costs of Depressive Disorders in Spain were € 6,145 million. The prevalence and incidence of Depressive Disorders are consistent with other series reviewed. Resource use and total costs (especially non-health costs) were high. [ABSTRACT FROM AUTHOR]

Individuals with bipolar depression often experience functional impairment that interferes with recovery. These analyses examined the effects of cariprazine on functional outcomes in patients with bipolar I disorder. Prespecified analyses of data from a randomized, double-blind, placebo-controlled pivotal trial of cariprazine in bipolar I depression (NCT01396447) evaluated mean changes from baseline to week 8 in Functional Assessment Short Test (FAST) total score. Post hoc analyses with no adjustment for multiplicity evaluated FAST subscale scores, functional recovery and remission (FAST total score ≤11 and ≤20, respectively), and 30% or 50% improvement from baseline. There were 393 patients with bipolar I disorder (placebo = 132; cariprazine: 1.5 mg/d = 135, 3 mg/d = 126) in the FAST analysis population. Statistically significant differences were noted for cariprazine 1.5 mg/d versus placebo in mean change from baseline in FAST total score (p<.01) and on 5 of 6 subscale scores (p<.05); cariprazine 3 mg/d was significantly different than placebo on the Interpersonal Relationship subscale (p<.05). Rates of functional remission and recovery, and ≥30% or ≥50% improvement were significantly greater for cariprazine 1.5 mg/d versus placebo (p<.05 all); the percentage of patients with ≥30% improvement was significantly different for cariprazine 3 mg/d versus placebo (p<.05). At week 8, statistically significant improvements in FAST outcomes were observed for cariprazine versus placebo in patients with bipolar I depression; more consistent results were noted for 1.5 mg/d than 3 mg/d. In addition to improving bipolar depression symptoms, these results suggest that cariprazine may improve functional outcomes. [ABSTRACT FROM AUTHOR]

Background: Brexpiprazole is a dopamine/serotonin receptor partial agonist (D2, 5-HT1A) and antagonist (5-HT2A) approved for treatment of schizophrenia and major depressive disorder (adjunct to antidepressants). Aims: This study aimed to investigate brexpiprazole as monotherapy in acute mania (bipolar I disorder) in two short-term (ST) studies (study 080 and study 081) and one open-label (OL) extension (study 083). Methods: ST studies were three-week randomized, double-blind, flexible dose (2–4 mg/day), placebo-controlled studies. The primary endpoint was mean change in Young Mania Rating Scale (YMRS) total score from baseline to day 21. The OL study was a 26-week flexible dose (2–4 mg/day) study for patients completing the ST studies. Results: A total of 164 and 158 (study 080) and 170 and 162 (study 081) inpatients with DSM-5 mania with/without mixed features were randomized to placebo or brexpiprazole, respectively. The primary analyses did not show a statistically significant difference between brexpiprazole and placebo: study 080: least squares mean difference (95% confidence limits): 0.14 (−1.74, 2.03), p = 0.8797; study 081: −1.62 (−3.56, 0.32), p = 0.1011. OL study patients (n = 381) demonstrated a gradual improvement in YMRS total score. Akathisia was the only adverse event, with an incidence of ⩾5% with brexpiprazole and more than placebo in the ST studies, or ⩾5% in the OL study. Brexpiprazole was more efficacious in patients with impaired or no insight (predominantly EU patients) than in patients with excellent insight (predominantly US patients). Conclusions: Further studies are necessary to address the potential efficacy of brexpiprazole in acute mania, which should ensure that the study sample is severe enough (especially with regard to insight), and that the dose/titration schedule is not too modest. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) is a major healthcare and socio-economic challenge. Despite its substantial burden on society, the research activity in BD is much smaller than its economic impact appears to demand. There is a consensus that the accurate identification of the underlying pathophysiology for BD is fundamental to realize major health benefits through better treatment and preventive regimens. However, to achieve these goals requires coordinated action and innovative approaches to boost the discovery of the neurobiological underpinnings of BD, and rapid translation of research findings into development and testing of better and more specific treatments. To this end, we here propose that only a large-scale coordinated action can be successful in integrating international big-data approaches with real-world clinical interventions. This could be achieved through the creation of a Global Bipolar Disorder Foundation, which could bring government, industry and philanthropy together in common cause. A global initiative for BD research would come at a highly opportune time given the seminal advances promised for our understanding of the genetic and brain basis of the disease and the obvious areas of unmet clinical need. Such an endeavour would embrace the principles of open science and see the strong involvement of user groups and integration of dissemination and public involvement with the research programs. We believe the time is right for a step change in our approach to understanding, treating and even preventing BD effectively. [ABSTRACT FROM AUTHOR]

The article focuses on the Commentary on Kohne and van OS view on precision psychiatry. Topics discussed include Precision psychiatry aims to tailor pharmacological and psychological treatments to subgroups of patients; and sharing similar characteristics in terms of their susceptibility to a particular disease, outcome or their probability to respond to a specific.

DSM-5 and ICD-11 define mixed depression as the presence of non-overlapping symptoms of opposite polarity during a major depressive episode. However, such a definition has generated controversy. 2720 patients with major depression, enrolled in BRIDGE–II–MIX cross-sectional study, were subdivided in clusters using a k-medoids algorithm based on 32 clinical features. Clinical variables were compared among clusters. Stepwise logistic regression and random forest predictor importance estimates were used to identify which features best predicted cluster membership. Data-driven criteria were compared with DSM-5 mixed specifier and previously proposed research-based criteria (RBDC). Two clusters were identified (MDE ± MX), mainly reflecting differences in current manic symptoms. As expected, MDE + MX showed higher rates of comorbidities and bipolar features, more previous depressive episodes and suicide attempts, shorter duration of current MDE and lower age at onset. Seven clinical features among the original 32 proved to be the best predictors of cluster membership. Derived criteria perfectly allocated subjects in clusters, requiring at least four features out of the following seven: irritability, emotional lability, psychomotor agitation, distractibility, mood reactivity, absence of reduced appetite, and absence of psychomotor retardation. RBDC showed a better performance than DSM-5 in identifying MDE + MX subjects. Our results strongly suggest a predominant role for overlapping "manic" symptoms in defining mixed depressive states. Mixed depression is better identified by the presence of excitatory features shared with mania and atypical features rather than by non-overlapping manic symptoms. [ABSTRACT FROM AUTHOR]

AbstractObjective:Method:Results:Conclusion:To develop and validate a very brief version of the 24-item Real Relationship Inventory–Client (RRI-C) form.Two independent samples of individual psychotherapy patients (Nsample1 = 700, Nsample2 = 434) completed the RRI-C along with other measures. Psychometric scale shortening involved exploratory factor analysis, item response theory analysis, confirmatory factor analysis (CFA), and multigroup CFA. Reliability and convergent and discriminant validity of the scale and subscales were also assessed.The 8-item RRI-C (RRI-C-SF) preserves the two-factor structure: Genuineness (k = 4, α = .86) and Realism (k = 4, α = .87), which were correlated at r = .74. CFA provided the following fit indices for the bifactor model: X2/df = 2.16, CFI = .99, TLI = .96, RMSEA = .07, and SRMR = .03. Multigroup CFA showed that the RRI-C-SF was invariant across in-person and remote session formats. The RRI-C-SF demonstrated high reliability (α = .91); high correlation with the full-length scale (r = .96); and excellent convergent and discriminant validity with measures of other elements of the therapeutic relationship, personality characteristics, current mental health state, and demographic-clinical variables. Clinical change benchmarks were calculated to serve as valuable tools for both research and clinical practice.The RRI-C-SF is a reliable measure that can be used for both research and clinical purposes. It enables a nuanced assessment of the genuineness and the realism dimensions of the real relationship. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to estimate all-cause mortality in patients after a first-episode mania (FEM) and examine whether six guideline-recommended medications can reduce mortality. Methods: The cohort included population-based FEM samples and matched controls from Taiwan, spanning 2007 to 2018. The primary outcomes assessed were all-cause/suicide-related mortality, while the secondary outcome focused on mortality associated with pharmacological treatments. We compared mortality in post-FEM patients and age-/sex-matched controls without any diagnosed bipolar disorders and patients with and without psychopharmacological treatment using Cox regression analysis, respectively. Statistics were presented with time-to-event adjusted hazard ratios (AHRs) and 95% confidence intervals (CIs). Results: The study included 54,092 post-FEM patients and 270,460 controls, totaling 2,467,417 person-years of follow-up. Post-FEM patients had higher risks of all-cause mortality (AHR 2.38, 95% CI: 2.31–2.45) and suicide death (10.80, 5.88–19.84) than controls. Lithium (0.62, 0.55–0.70), divalproex (0.89, 0.83–0.95), and aripiprazole (0.81, 0.66–1.00) were associated with reduced all-cause mortality compared to non-users. There were no significant all-cause mortality differences for quetiapine (0.95, 0.89–1.01), risperidone (0.92, 0.82–1.02), and paliperidone (1.24, 0.88–1.76) users. When accounting for drug action onset times in sensitivity analyses, only lithium significantly reduced all-cause mortality (AHR range 0.65–0.72). There were 35 and 16 suicide deaths in post-FEM patients and controls, respectively. No drug had a significant effect on suicide deaths (lithium: 6; divalproex: 7; aripiprazole: 0; quetiapine: 10; risperidone: 4; paliperidone: 1). Conclusion: Post-FEM patients had a higher risk of all-cause/suicide-related mortality, and lithium treatment might reduce all-cause mortality. [ABSTRACT FROM AUTHOR]

Traditionally, the focus of psychiatry has been to assess the clinical presentation of so-called "disorders of the mind" and define diagnoses in order to establish successful therapeutic strategies. Interestingly, Kessing et al.4 in a recent nationwide population-based longitudinal study identified that the rates of presentation of any psychiatric disorder in siblings of patients suffering from bipolar disorder (BD) were increased not only in their 20 s but also above 60 years of age. Therefore, therapeutic interventions aimed at enhancing resilience,10 healthy life-style behaviours,11 coping strategies12 and peaceful family environment might have important implications in terms of mental health outcomes, not only in those patients already suffering from a psychiatric condition but also in the general population. [Extracted from the article]

Association between selective serotonin reuptake inhibitors and violent crime - could underlying psychopathology be the cause? Fuelling the discussion regarding the safety of selective serotonin reuptake inhibitors (SSRIs), the present large Swedish nationwide cohort registry study ([5]) tries to answer whether treatment with SSRIs is associated with increased risk of committing a violent crime. However, it should be emphasised that causality cannot be inferred from such studies, that the indication confounder is extremely likely in an observational study, and that the vast majority (97%!) of patients prescribed SSRI will not commit violent crimes either before, during or after the therapy. [Extracted from the article]

The author discusses an article by Gin S. Malhi and colleagues, published within the issue, in which they called for the removal of the term bipolar II from the "Diagnostic and Statistical Manual of Mental Disorders, 4th Edition" (DSM-IV). Topics covered include how the original bipolar II disorder was aimed at hospitalized depressed patients with a history of hypomania, frequent hypomanic and depressive episodes with morbidity and mortality, and the difference between mania and hypomania.

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]

Objectives: Although clinically highly relevant, the recognition and treatment of bipolar mixed states has played only an underpart in recent guidelines. This WFSBP guideline has been developed to supply a systematic overview of all scientific evidence pertaining to the acute and longterm treatment of bipolar mixed states in adults. Methods: Material used for these guidelines is based on a systematic literature search using various data bases. Their scientific rigour was categorised into six levels of evidence (A-F), and different grades of recommendation to ensure practicability were assigned. We examined data pertaining to the acute treatment of manic and depressive symptoms in bipolar mixed patients, as well as data pertaining to the prevention of mixed recurrences after an index episode of any type, or recurrence of any type after a mixed index episode. Results: Manic symptoms in bipolar mixed states appeared responsive to treatment with several atypical antipsychotics, the best evidence resting with olanzapine. For depressive symptoms, addition of ziprasidone to treatment as usual may be beneficial; however, the evidence base is much more limited than for the treatment of manic symptoms. Besides olanzapine and quetiapine, valproate and lithium should also be considered for recurrence prevention. Limitations: The concept of mixed states changed over time, and recently became much more comprehensive with the release of DSM-5. As a consequence, studies in bipolar mixed patients targeted slightly different bipolar subpopulations. In addition, trial designs in acute and maintenance treatment also advanced in recent years in response to regulatory demands. Conclusions: Current treatment recommendations are still based on limited evidence, and there is a clear demand for confirmative studies adopting the DSM-5 specifier with mixed features concept. [ABSTRACT FROM AUTHOR]

Bipolar disorder places a significant burden on the affected individuals, their family, healthcare systems and the overall economy. More treatment options are needed, especially those with better efficacy and tolerability. Asenapine is a second-generation antipsychotic approved in Europe (brand name Sycrest®) for the treatment of moderate-to-severe manic episodes associated with bipolar I disorder in adults, and in the US (brand name Saphris®) for the treatment of manic or mixed episodes of bipolar I disorder in adults and children aged 10–17 years. It is the antagonistic activity at the D2 receptor that is likely responsible for the antimanic properties of asenapine. Clinical trials have demonstrated that asenapine mono- and add-on therapy is effective in the short- and long-term treatment of mania associated with bipolar I disorder in adult and paediatric patients. In addition, post hoc and pooled data analyses have shown that asenapine is effective in reducing clinically significant depressive symptoms in patients with bipolar I disorder. The most common adverse events associated with asenapine are somnolence, dizziness, extrapyramidal symptoms, increased bodyweight and oral hypoesthesia. However, the incidence of these events, particularly weight gain, is generally lower than with olanzapine. In one study, asenapine has been shown to improve health-related quality of life. Economic analyses indicate that the use of asenapine can, over time, lead to a reduction in the costs of treatment. [ABSTRACT FROM AUTHOR]

Background: Major Depressive Disorder (MDD) is a heterogeneous disease characterized by emotional, physical and cognitive symptoms. This study explored the effects of vortioxetine versus escitalopram on outcomes of cognition, functioning and mood symptoms in depressed patients with inadequate response to current antidepressant treatment.Methods: In this parallel-group, active-comparator study, adult patients (18-65 years, N = 101) with MDD, with inadequate response to current antidepressant monotherapy, were randomized 1:1 to 8 weeks' double-blind treatment with flexible doses (10-20mg/day) of either vortioxetine or escitalopram. Primary and key secondary efficacy measures were the Digit Symbol Substitution Test (DSST), analyzed using a mixed model for repeated measurements, and the University of San Diego Performance-based Skills Assessment - Brief (UPSA-B), analyzed using analysis of covariance (last observation carried forward method).Results: At week 8, DSST and UPSA-B performance had improved in both treatment groups, with no statistically significant treatment differences. Numerical improvements across measures of cognition, functioning and mood symptoms generally favored vortioxetine. Most adverse events were mild or moderate, with nausea being the most common adverse event.Limitations: This was an exploratory study with small sample sizes implying limited statistical power.Conclusion: Although this explorative study did not meet primary endpoints, the results confirm vortioxetine in doses of 10-20mg/day as an efficacious and well-tolerated antidepressant switch treatment. The overall direction of numerical effect sizes across cognition endpoints support previous findings that vortioxetine specifically benefits cognitive function in MDD. [ABSTRACT FROM AUTHOR]

Background: Psychomotor agitation (PMA) is a state of motor restlessness and mental tension that requires prompt recognition, appropriate assessment and management to minimize anxiety for the patient and reduce the risk for escalation to aggression and violence. Standardized and applicable protocols and algorithms can assist healthcare providers to identify patients at risk of PMA, achieve timely diagnosis and implement minimally invasive management strategies to ensure patient and staff safety and resolution of the episode. Methods: Spanish experts in PMA from different disciplines (psychiatrists, psychologists and nurses) convened in Barcelona for a meeting in April 2016. Based on recently issued international consensus guidelines on the standard of care for psychiatric patients with PMA, the meeting provided the opportunity to address the complexities in the assessment and management of PMA from different perspectives. The attendees worked towards producing a consensus for a unified approach to PMA according to the local standards of care and current local legislations. The draft protocol developed was reviewed and ratified by all members of the panel prior to its presentation to the Catalan Society of Psychiatry and Mental Health, the Spanish Society of Biological Psychiatry (SEPB) and the Spanish Network Centre for Research in Mental Health (CIBERSAM) for input. The final protocol and algorithms were then submitted to these organizations for endorsement. Results: The protocol presented here provides guidance on the appropriate selection and use of pharmacological agents (inhaled/oral/IM), seclusion, and physical restraint for psychiatric patients suspected of or presenting with PMA. The protocol is applicable within the Spanish healthcare system. Implementation of the protocol and the constituent algorithms described here should ensure the best standard of care of patients at risk of PMA. Episodes of PMA could be identified earlier in their clinical course and patients could be managed in the least invasive and coercive manner, ensuring their own safety and that of others around them. Conclusion: Establishing specialized teams in agitation and providing them with continued training on the identification of agitation, patient management and therapeutic alternatives might reduce the burden of PMA for both the patient and the healthcare system. [ABSTRACT FROM AUTHOR]

To investigate the effectiveness, safety, and tolerability of vortioxetine in patients treated at therapeutic doses (5–20 mg/day) for both acute and maintenance treatment, patient-level data were pooled from 5 long-term (52-week), open-label extension studies of major depressive disorder. The mean (±standard deviation) MADRS total score improved from 17.1±10.2 at the start of maintenance therapy to 7.6±8.2 (observed cases [OC]) or 10.3±9.9 (last observation carried forward [LOCF]) at week 52. The mean HAM-A total scores improved from 11.3±6.9 to 6.0±6.0 (OC) or 7.5±6.7 (LOCF) and the mean CGI-S score improved from 3.11±1.20 to 1.94±1.08 (OC) or 2.27±1.26 (LOCF) at week 52. Response and remission rates increased over time. At week 52, the total response rate was 75.4% ( n =916/1215, LOCF) and the total remission rate was 60.7% ( n =738/1215, LOCF). There were no differences in effectiveness as assessed by MADRS total scores at week 52 in subgroups based on gender, age (<55 vs ≥55 years), baseline HAM-A total score (<20 vs ≥20), baseline MADRS total score (<30 vs ≥30), previous major depressive episodes (MDEs) (<3 vs ≥3) or current MDE duration (<6 vs ≥6 months) at the start of the lead-in studies, or response status (≥50% decrease in MADRS total score during the lead-in study). The most commonly reported adverse event during the maintenance period was nausea. [ABSTRACT FROM AUTHOR]

This article discusses the development and preliminary validation of a self-report inventory of the patient's perception of, and affective reaction to, their therapist during a psychotherapy session. First, we wrote a pool of 131 items, reviewed them based on subject matter experts' review, and then collected validation data from a clinical sample of adult patients in individual therapy (N = 701). We used exploratory factor analysis and item response theory graded response models to select items, confirmatory factor analysis (CFA) to test the factor structure, and k-fold cross-validation to verify model robustness. Multi-group CFA examined measurement invariance across patients with different diagnoses (unipolar depression, bipolar disorder, and neither of these). Three factors produced short scales retaining the strongest items. The in-Session Patient Affective Reactions Questionnaire (SPARQ) has a two-factor structure, yielding a four-item Negative affect scale and a four-item Positive affect scale. The Relationship In-Session Questionnaire (RISQ) is composed of four items from the third factor with dichotomized responses. Both scales showed excellent psychometric properties and evidence of metric invariance across the three diagnostic groups: unipolar depression, bipolar disorder, and neither of these. The SPARQ and the RISQ scale can be used in clinical or research settings, with particular value for capturing the patient's perspectives about their therapist and session-level emotional processes. [ABSTRACT FROM AUTHOR]

Objective: As the older population increases, it is important to identify factors that may reduce the risks of dementia in the general population. One such factor is the concept of cognitive reserve (CR). The present study analyzed the psychometric properties of the Cognitive Reserve Assessment Scale in Health (CRASH) in the Brazilian population. This scale was originally developed to measure CR in individuals with severe mental illness. We also investigated the relationship between the CRASH and clinical or sociodemographic variables. Methods: This study was conducted with 398 individuals. We assessed sociodemographic variables and depression, anxiety, and stress symptoms (Depression, Anxiety and Stress Scale [DASS-21]) using a web-based survey. We constructed a confirmatory factor analysis (CFA) model in order to test the goodness of fit of the factor structure proposed in the original CRASH study. Results: The McDonald's hierarchical co for CRASH using CFA parameters was 0.61, and the Cronbach's alpha coefficient indicated good internal consistency when considering all items (alpha = 0.7). Conclusions: Our results suggest that CRASH can be used to assess CR in the general population in Brazil. [ABSTRACT FROM AUTHOR]

Objectives The Bipolar Disorders: Improving Diagnosis, Guidance, and Education ( BRIDGE- II-Mix) study aimed to estimate the frequency of mixed states in patients with a major depressive episode ( MDE) according to different definitions and to compare their clinical validity, looking into specific features such as suicidality. Methods A total of 2,811 subjects were enrolled in this multicenter cross-sectional study. Psychiatric symptoms, and sociodemographic and clinical variables were collected. The analysis compared the characteristics of patients with MDE with ( MDE- SA group) and without ( MDE- NSA) a history of suicide attempts. Results The history of suicide attempts was registered in 628 patients (22.34%). In the MDE- SA group, women (72.5%, p = 0.028), (hypo)mania in first-degree relatives (20.5%, p < 0.0001), psychotic features (15.1%, p < 0.0001), and atypical features (9.2%, p = 0.009) were more prevalent. MDE- SA patients' previous responses to treatment with antidepressants included more (hypo)manic switches [odds ratio ( OR) = 1.97, 95% confidence interval ( CI): 1.58-2.44, p < 0.0001], treatment resistance ( OR = 2.07, 95% CI: 1.72-2.49, p < 0.0001), mood lability ( OR = 1.98, 95% CI: 1.65-2.39, p < 0.0001), and irritability ( OR = 1.80, 95% CI: 1.48-2.17, p < 0.0001). Multivariate analysis evidenced that risky behavior, psychomotor agitation and impulsivity, and borderline personality and substance use disorders were the variables most frequently associated with previous suicide attempts. In the MDE- SA group, 75 patients (11.9%) fulfilled Diagnostic and Statistical Manual (DSM)-5 criteria for MDE with mixed features, and 250 patients (39.8%) fulfilled research-based diagnostic criteria for a mixed depressive episode. Conclusions Important differences between MDE- SA and MDE-NSA patients have emerged. Early identification of symptoms such as risky behavior, psychomotor agitation, and impulsivity in patients with MDE, and treatment of mixed depressive states could represent a major step in suicide prevention. [ABSTRACT FROM AUTHOR]

The article focuses on the Misunderstanding precision psychiatry. Topics discussed include some of these advances were presented in our previous commentary; and Kohne question the foundations of precision psychiatry by doing so, they question the very foundations of current psychiatric practice and how we understand mental processes.

The use of combination therapy with mood stabilizers and antipsychotics in acute mania in bipolar disorder (BD) is widespread, although most treatment guidelines recommend monotherapy as the first option, and reserve combination therapy, which is associated with more frequent and more severe side effects, for when patients do not respond to the former treatment option. Reasons to prescribe combination therapy include the lack of efficacy of the current treatment (either real or due to undisclosed poor adherence), psychiatric comorbidities, severe previous course of illness, slow cross-tapering during treatment switching, and potential benefits from particular combinations. The decision to start with monotherapy or combination therapy may depend on the patient characteristics, and is still under debate. Clinical trials designed to ascertain whether combination therapy or monotherapy is more advantageous for patients in acute mania and beyond, according to illness severity, are urgently needed. Adding a third monotherapy arm to the conventional two-arm, adjunctive-design trials or initiating combination therapy from the beginning may help to shed some light on the issue. [ABSTRACT FROM AUTHOR]

Background The present study aims to evaluate cognitive tolerability profile of SSRIs in long-term treatment. The secondary aim is to explore differences of side effects profile between patients with major depression (MD) and anxiety disorders (AD). Methods Sixty-seven consecutive patients, successfully treated with SSRIs in monotherapy for at least six months for MD or AD, were assessed for side effects, with a special focus on cognition. Results Over 20% of MD and AD patients in long term treatment with SSRIs reported cognitive symptoms including fatigue, inattentiveness, lack of concentration, memory impairment and apathy. Recall memory impairment, attention deficit and somnolence were most frequently rated as moderate or severe. There were no significant differences in SSRI cognitive side effects profile between MD and AD patients. Limitations Subjective measure of cognitive functioning, limited sample size, lack of a control group. Conclusions A large proportion of depressed and anxious patients treated successfully with SSRIs for over six months reported cognitive, affective, motivational symptoms. These symptoms are likely to represent SSRI side effects rather than residual depressive symptomatology. [ABSTRACT FROM AUTHOR]

Tikslai. Šios Gairės remiasi pirmuoju leidimu, kuris buvo išleistas 2002 m., buvo redaguotas ir atnaujintas iki 2009 m. rugsėjo mėn. turimais moksliniais įrodymais. Jų paskirtis -- pateikti sistematizuotą visų mokslinių įrodymų, susijusių su suaugusiųjų bipolinės depresijos gydymu, apžvalgą. Metodai. Duomenys, panaudoti rengiant šias rekomendacijas, paimti iš MEDLINE ir EMBASE duomenų bazių, klinikinių tyrimų duomenų bazės: www.clinicaltrials.gov, svarbiausių pastarojo meto konferencijų bei įvairių nacionalinių ir tarptautinių gydymo rekomendacijų. Jų mokslinis pagrįstumas buvo suskirstytas į šešis įrodymų lygius (nuo A iki F). Kadangi šios rekomendacijos skirtos klinikiniam darbui, moksliniai įrodymai buvo suskirstyti į skirtingų lygių rekomendacijas siekiant užtikrinti praktiškumą. Rezultatai. Nustatėme 10 farmakologinių monoterapijos arba kompleksinio gydymo variantų, turinčių bent ribotus teigiamus įrodymus dėl poveikio gydant bipolinę depresiją, keletas iš jų vis dar eksperimentiniai ir paremti tik vienu tyrimu. Tik vienas vaistas pakankamai ištirtas. Išvados. Nuo pirmojo šių gairių leidimo 2002 m. buvo padaryta didelė pažanga, tačiau yra daug sričių, kuriose vis dar reikia intensyvių tyrimų siekiant optimizuoti gydymą. Dauguma gydymo rekomendacijų vis dar remiasi ribotais duomenimis ir palieka nemažai neapibrėžtumo sričių. Raktažodžiai: bipolinis sutrikimas, depresija, ūminės fazės gydymas, įrodymais pagrįstos rekomendacijos, farmakoterapija, antipsichotikai, antidepresantai, nuotaikos stabilizatoriai, elektrotraukulinė terapija, psichoterapija. [ABSTRACT FROM AUTHOR]

The need to support clinical decision making and cost-effectiveness analyses in medicine, despite a dearth of head-to-head treatment comparisons, has encouraged the development of methods enabling indirect comparisons of treatment alternatives, including network meta-analysis (NMA). Valid application of NMA requires close similarity of compared trials, including their design, patient characteristics, and methods of diagnosis and symptomatic assessment. When biological or other objective measures of outcomes are not available, as is the case in psychiatric disorders, subtle differences in characteristics of trials or participants may lead to unrecognized incoherence within a network and thus to inconsistent results. By considering comparative-efficacy analyses of psychotropic drugs in major psychiatric disorders as working examples, we underscore the risks of violating the fundamental transitivity assumption in the context of NMA and suggest precautions for creating a coherent network. We conclude that with thoughtful and critical application, NMA can add useful information concerning the comparative benefits, risks, and costs of specific treatments in psychiatry. [ABSTRACT FROM AUTHOR]

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

Malhi and coworker's editorial1 offers several reasons explaining the decline in the use of lithium to treat Bipolar Disorder (BD) against the recommendation of most international guidelines. For instance, lithium monotherapy was superior than valproate monotherapy in preventing both manic and depressive relapses in the BALANCE study,2 a multicentre 2-year randomized open-label trial including 330 patients with type-I BD (BD-I). Comparative efficacy and tolerability of pharmacological treatments in the maintenance treatment of bipolar disorder: a systematic review and network meta-analysis. [Extracted from the article]

An introduction is presented in which the editor discusses various reports within the issue on topics including biomarkers, comorbidity and treatment of bipolar disorders.

Abstract: This paper reports the efficacy and tolerability of the nicotinic channel modulator TC-5214 (dexmecamylamine) as adjunct therapy for patients with major depressive disorder who have an inadequate response to initial antidepressant treatment in 2 Phase III studies. These double-blind, placebo-controlled studies (NCT01157078, D4130C00002 [Study 002] conducted in the US and India; NCT01180400, D4130C00003 [Study 003] conducted in Europe) comprised 8 weeks of open-label antidepressant treatment followed by 8 weeks of active treatment during which patients were randomized to flexibly-dosed TC-5214 1–4mg twice daily (BID) or placebo as an adjunct to ongoing therapy with SSRI/SNRI. The primary efficacy endpoint in both studies was change in Montgomery Åsberg Depression Rating Scale (MADRS) total score from randomization (week 8) to treatment end (week 16). Secondary endpoints included change in Sheehan Disability Scale and Hamilton Depression Rating Scale 17-item scores. Study 002 randomized 319 patients and Study 003 randomized 295 patients to TC-5214 or placebo. At treatment end, no significant differences were seen for change in MADRS total score with TC-5214 versus placebo. Furthermore, there were no significant differences in any of the secondary endpoints. The most commonly reported (≥10%) adverse events with TC-5214 in these studies were constipation and headache. In these 2 flexibly-dosed studies, no specific therapeutic effects were observed for TC-5214 (1–4mg BID) adjunct to antidepressant in the primary endpoint or any secondary endpoint; however, TC-5214 was generally well tolerated. In conclusion, no antidepressant effect of TC-5214 was observed in these studies. [Copyright &y& Elsevier]

Abstract: Background: The aim of this study was to describe the phenomenology of mania and depression in bipolar patients experiencing a manic episode with mixed features as defined in the new Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Methods: In this multicenter, international on-line survey (the IMPACT study), 700 participants completed a 54-item questionnaire on demographics, diagnosis, symptomatology, communication of the disease, impact on life, and treatment received. Patients with a manic episode with or without DSM-5 criteria for mixed features were compared using descriptive and inferential statistics. Results: Patients with more than 3 depressive symptoms were more likely to have had a delay in diagnosis, more likely to have experienced shorter symptom-free periods, and were characterized by a marked lower prevalence of typical manic manifestations. All questionnaire items exploring depressive symptomatology, including the DSM-5 criteria defining a manic episode as “with mixed features”, were significantly overrepresented in the group of patients with depressive symptoms. Anxiety associated with irritability/agitation was also more frequent among patients with mixed features. Limitations: Retrospective cross-sectional design, sensitive to recall bias. Two of the 6 DSM-5 required criteria for the specifier “with mixed features” were not explored: suicidality and psychomotor retardation. Conclusions: Bipolar disorder patients with at least 3 depressive symptoms during a manic episode self-reported typical symptomatology. Anxiety with irritability/agitation differentiated patients with depressive symptoms during mania from those with “pure” manic episodes. The results support the use of DSM-5 mixed features specifier and its value in research and clinical practice. [Copyright &y& Elsevier]

Background To determine the efficacy and safety of quetiapine combined with lithium or divalproex for preventing mood events in patients with bipolar I disorder. In this pooled analysis of two similar long-term studies (D1447C00126 [NCT00107731] and D1447C00127 [NCT00081380]), lithium and divalproex treatment groups were analyzed separately. Methods Patients received open-label quetiapine (400-800 mg/d) plus lithium or divalproex to achieve ≥12 weeks of clinical stability before being randomized to double-blind combination treatment with quetiapine (400-800 mg/d) or placebo plus lithium or divalproex for up to 104 weeks. The primary endpoint was time to first mood event postrandomization following open stabilization. Results Of 3,414 patients in the stabilization phase, 1,326 were randomized. There were no differences in the risk of recurrence of mood, mania, or depression between quetiapine plus lithium or quetiapine plus divalproex. Among patients co-treated with placebo and lithium, the risk of recurrence of a mania event was significantly higher than among patients co-treated with placebo and divalproex. In patients with an index episode of mania, placebo plus lithium was associated with a significantly higher risk of recurrence of a mania event than placebo plus divalproex. Safety data were generally consistent with recognized safety profiles. Conclusions In patients with bipolar I disorder previously stabilized on quetiapine and lithium or divalproex, maintenance therapy with quetiapine significantly increased the time to recurrence of a mood event (mania or depression) versus placebo, regardless of whether it was combined with lithium or divalproex. [ABSTRACT FROM AUTHOR]

Abstract: Background: Clinical trials are not generally powered to analyze outcomes such as sustained response. We evaluated sustained response rates for patients with major depressive disorder receiving quetiapine XR as monotherapy or adjunct therapy. Method: Post hoc analyses of pooled data from four previously reported randomized, placebo-controlled studies of quetiapine XR 150 and 300mg/day as monotherapy or adjunct therapy to ongoing antidepressant. Sustained response rates (≥50% reduction in MADRS total score at specific timepoint and each subsequent visit until Week 6) were calculated at Weeks 1, 2, and 4; rates were compared using a Cochran–Mantel–Haenszel analysis. Results: In the monotherapy studies, the proportion of patients experiencing sustained response was greater with quetiapine XR 150mg/day versus placebo at Week 2 (20.0% vs. 13.3%; p<0.05) and Week 4 (33.3% vs. 23.3%; p<0.01) (observed cases [OC]). The corresponding sustained response rates for quetiapine XR 300mg/day were 18.0% (p=0.104) and 29.7% (p=0.063), respectively (OC). The proportion of patients experiencing sustained response was greater in the adjunct studies versus placebo at Weeks 2 and 4 for quetiapine XR 150 (Week 2, 30.1% vs. 15.2%, p<0.001; Week 4, 40.1% vs. 32.0%, p<0.05) and 300mg/day (Week 2, 29.0% vs. 15.2%, p<0.001; Week 4, 42.0% vs. 32.0%, p<0.05) (OC). Limitations: Post hoc analyses, acute treatment period; no active comparator. Conclusions: Quetiapine XR as monotherapy (150mg/day at Weeks 2 and 4) or adjunct to ongoing antidepressant therapy (150 and 300mg/day at Weeks 2 and 4) increased sustained response rates versus placebo. [Copyright &y& Elsevier]

Although the most distinctive clinical feature of bipolar disorder is the pathologically elevated mood, it does not usually constitute the prevalent mood state of bipolar illness. The majority of patients with bipolar disorder spend much more time in depressive episodes, including subsyndromal depressive symptoms, and bipolar depression accounts for the largest part of the morbidity and mortality of the illness. The pharmacological treatment of bipolar depression mostly consists of combinations of at least two drugs, including mood stabilizers (lithium and anticonvulsants), atypical antipsychotics, and antidepressants. Antidepressants are the most frequently prescribed drugs, but recommendations from evidence-based guidelines are not conclusive and do not overtly support their use. Among antidepressants, best evidence exists for fluoxetine, but in combination with olanzapine. Although some guidelines recommend the use of selective serotonin reuptake inhibitors or bupropion in combination with antimanic agents as first-choice treatment, others do not, based on the available evidence. Among anticonvulsants, the use of lamotrigine is overall recommended as a first-line choice, but acute monotherapy studies have failed. Valproate is generally mentioned as a second-line treatment. Lithium monotherapy is also suggested by most guidelines as a first-line treatment, but its efficacy in acute use is not totally clear. Amongst atypical antipsychotics, quetiapine, in monotherapy or as adjunctive treatment, is recommended by most guidelines as a first-line choice. Olanzapine monotherapy is also suggested by some guidelines and is approved in Japan. Armodafinil, pramipexole, ketamine, and lurasidone are recent proposals. Long-term treatment in bipolar disorder is strongly recommended, but guidelines do not recommend the use of antidepressants as a maintenance treatment. Lithium, lamotrigine, valproate, olanzapine, quetiapine, and aripiprazole are the recommended first-line maintenance options. [ABSTRACT FROM AUTHOR]