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Several psychotropic drugs, including antidepressants (AD), mood stabilizers, and antipsychotics (AP) have been suggested to have favorable effects in the treatment of COVID-19. The aim of this systematic review and meta-analysis was to collect evidence from studies concerning the scientific evidence for the repurposing of psychotropic drugs in COVID-19 treatment. Two independent authors searched PubMed-MEDLINE, Scopus, PsycINFO, and ClinicalTrials.gov databases, and reviewed the reference lists of articles for eligible articles published up to 13th December 2021. All computational, preclinical and clinical (observational and/or RCTs) studies on the effect of any psychotropic drug on Sars-CoV-2 or patients with COVID-19 were considered for inclusion. We conducted random effect meta-analyses on clinical studies reporting the effect of AD or AP on COVID-19 outcomes. 29 studies were included in the synthesis: 15 clinical, 9 preclinical, and 5 computational studies. 9 clinical studies could be included in the quantitative analyses. AD did not increase the risk of severe COVID-19 (RR= 1.71; CI 0.65-4.51) or mortality (RR=0.94; CI 0.81-1.09). Fluvoxamine was associated with a reduced risk of mortality for COVID-19 (OR=0.15; CI 0.02-0.95). AP increased the risk of severe COVID-19 (RR=3.66; CI 2.76-4.85) and mortality (OR=1.53; CI 1.15-2.03). Fluvoxamine might be a possible candidate for psychotropic drug repurposing in COVID-19 due to its anti-inflammatory and antiviral potential, while evidence on other AD is still controversial. Although AP are associated with worse COVID-19 outcomes, their use should be evaluated case to case and ongoing treatment with antipsychotics should be not discontinued in psychiatric patients.

Objectives Clinical staging is widely used in medicine to map disease progression, inform prognosis and guide treatment decisions; in psychiatry, however, staging remains a hypothetical construct. To facilitate future research in bipolar disorders (BD), a well-defined nomenclature is needed, especially since diagnosis is often imprecise with blurred boundaries, and a full understanding of pathophysiology is lacking. Methods Under the auspices of the International Society of Bipolar Disorders, a Task Force of international experts was convened to review, discuss, and integrate findings from the scientific literature relevant to the development of a consensus staging model and standardize a terminology that could be used to advance future research including staging of BD and related disorders. Results Consensus opinion and areas of uncertainty or difference were identified in regard to terms referring to staging as it may apply to BD, to at-risk status and subthresholdhold stages, and to various clinical stages of BD as it is currently diagnosed. Conclusion The use of a standardized nomenclature about the clinical stages of BD will facilitate communication about research on clinical and pathological components of this heterogeneous group of disorders. The concepts presented are based on current evidence, but the template provided allows for further refinements as etiological advances come to light.

Background: Major depressive disorder (MDD) and generalized anxiety disorder (GAD) are frequently comorbid. Aims: To assess the effectiveness of vortioxetine in patients with MDD and comorbid GAD. Methods: Open-label, 8-week study (NCT04220996) in 100 adult outpatients with severe MDD and severe comorbid GAD receiving vortioxetine as first treatment for the current depressive episode or switching to vortioxetine due to inadequate response to another drug for depression. Vortioxetine starting dosage was 10 mg/day, with forced up-titration to 20 mg/day after 1 week. Response was defined as ⩾50% decrease in Montgomery–Åsberg Depression Rating Scale (MADRS) and/or Hamilton Anxiety Rating Scale (HAM-A) total score from baseline; remission defined as MADRS and/or HAM-A total score ⩽10. Results: Clinically meaningful and statistically significant improvements from baseline in symptoms of depression and anxiety, and overall functioning and health-related quality of life, were observed after 8 weeks’ vortioxetine treatment (all changes p Conclusion: Vortioxetine demonstrates effectiveness in significantly reducing symptoms of both depression and anxiety in patients with severe MDD comorbid with severe GAD. Findings support increasing vortioxetine dosage to 20 mg/day early in the course of therapy, and show that this may be achieved without compromising tolerability.

Resumen: Introducción: La comorbilidad médica en pacientes con trastornos del estado de ánimo tiende a convertirse en un problema de salud pública clínica y global cada vez más importante. Varias patologías médicas específicas están asociadas con un mayor riesgo de padecer trastornos del estado de ánimo y, por otra parte, los trastornos del estado de ánimo están asociados con un aumento de la morbilidad y mortalidad debidas a condiciones médicas comórbidas. En este artículo se revisan las comorbilidades médicas que más comúnmente se asocian a los trastornos afectivos (enfermedades cardiovasculares, obesidad y síndrome metabólico) examinando sus posibles implicaciones bidireccionales. Métodos: Se ha realizado una revisión no sistemática y búsqueda de la literatura científica sobre la asociación entre las tres enfermedades médicas más frecuentes en trastorno depresivo mayor y trastorno bipolar (enfermedades cardiovasculares, obesidad, síndrome metabólico) entre enero de 1995 y noviembre de 2019. Resultados: La evidencia sugiere que la comorbilidad entre estas tres enfermedades médicas y los trastornos del estado de ánimo es muy frecuente; la presencia de las primeras empeora significativamente el pronóstico y el manejo terapéutico de las segundas y viceversa, comparten mecanismos fisiopatológicos e implican una etiología aparentemente bidireccional. Conclusiones: La presencia de estas enfermedades médicas concurrentes en un individuo con un trastorno del estado de ánimo se asocia con una presentación de enfermedad más compleja. En muchos casos, estas comorbilidades pueden preceder a la aparición de los trastornos del estado de ánimo, aunque en la mayoría de los casos parecen seguir a la aparición de los trastornos del estado de ánimo. Para los profesionales, la evidencia apoya inequívocamente las recomendaciones para la vigilancia rutinaria de las comorbilidades según un enfoque multidisciplinar. Summary: Introduction: Medical comorbidity in patients with mood disorders tends to become an increasingly important clinical and global public health problem. On one hand, several specific medical pathologies are associated with an increased risk of mood disorders and on the other hand, mood disorders are associated with increased morbidity and mortality due to comorbid medical conditions. This article reviews the medical comorbidities that are most commonly associated with affective disorders (cardiovascular diseases, obesity and metabolic syndrome) examining their possible bidirectional implications. Methods: A non-systematic review about the association between the three most common medical diseases in major depressive disorder and bipolar affective disorder (cardiovascular diseases, obesity, metabolic syndrome) has been carried out from January 1995 to November 2019. Results: The evidence suggests that comorbidity between these three medical diseases and mood disorders is very prevalent. The presence of medical disease significantly worsens the prognosis and therapeutic management of the mood disorders and vice versa. In many cases, these comorbidities may precede the onset of mood disorders, although in most cases they appear to follow the onset of mood disorders. Conclusions: The presence of these concurrent medical diseases in an individual with a mood disorder is associated with a more complex disease presentation. For professionals, the evidence unequivocally supports recommendations for routine surveillance of comorbidities according to a multidisciplinary approach. Palabras clave: Trastorno bipolar, Trastorno depresivo mayor, Comorbilidad médica, Enfermedad cardiovascular, Obesidad, Síndrome metabólico, Keywords: Bipolar disorder, Major depressive disorder, Comorbidities, cardiovascular disease, Obesity, Metabolic syndrome

Substance use disorder (SUD) is a common comorbidity in individuals with bipolar disorder (BD), and it is associated with a severe course of illness, making early identification of the risk factors for SUD in BD warranted. We aimed to identify, through machine-learning models, the factors associated with different types of SUD in BD. We recruited 508 individuals with BD from a specialized unit. Lifetime SUDs were defined according to the DSM criteria. Random forest (RF) models were trained to identify the presence of (i) any (SUD) in the total sample, (ii) alcohol use disorder (AUD) in the total sample, (iii) AUD co-occurrence with at least another SUD in the total sample (AUD+SUD), and (iv) any other SUD among BD patients with AUD. Relevant variables selected by the RFs were considered as independent variables in multiple logistic regressions to predict SUDs, adjusting for relevant covariates. AUD+SUD could be predicted in BD at an individual level with a sensitivity of 75% and a specificity of 75%. The presence of AUD+SUD was positively associated with having hypomania as the first affective episode (OR = 4.34 95% CI = 1.42–13.31), and the presence of hetero-aggressive behavior (OR = 3.15 95% CI = 1.48–6.74). Machine-learning models might be useful instruments to predict the risk of SUD in BD, but their efficacy is limited when considering socio-demographic or clinical factors alone.

This article reviews the most common non-psychiatric comorbidities associated with affective disorders, examining the implications of their possible bidirectional link. A narrative review was conducted on the association among the three most common non-psychiatric diseases in major depressive disorder and bipolar disorder (obesity, metabolic syndrome, and cardiovascular diseases) in articles published from January 1994 to April 2020. The evidence suggests that obesity, metabolic syndrome, and cardiovascular diseases are highly prevalent in patients diagnosed with affective disorders. The presence of non-psychiatric comorbidities significantly worsens the therapeutic management and prognosis of affective disorders and vice versa. In many cases, these comorbidities may precede the onset of affective disorders, although in most cases they appear after it. The presence of these concurrent non-psychiatric diseases in an individual diagnosed with an affective disorder is associated with a more complex disease presentation and management. For professionals, the evidence unequivocally supports routine surveillance of comorbidities from a multidisciplinary approach.

Jessica Madera,1 Pedro Such,2 Peter Zhang,1 Ross A Baker,1 Iria Grande31Medical Affairs, Otsuka Pharmaceutical Development and Commercialization Inc, Princeton, NJ, USA; 2Medical Affairs, H. Lundbeck A/S, Valby, Denmark; 3Bipolar and Depression Disorders Unit, Hospital Clinic, Institute of Neurosciences, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, SpainPurpose: There is growing agreement that definitions of “recovery” in bipolar-I disorder (BP-I) should include functional outcomes beyond sustained symptomatic remission. In this post-hoc analysis, we assessed functional recovery rates according to the validated Functioning Assessment Short Test (FAST) in participants with BP-I after 52 weeks of maintenance treatment with aripiprazole once monthly (AOM).Patients and methods: Rates of functional recovery with AOM 400 were investigated in two 52-week studies. NCT01567527 was a placebo-controlled, double-blind, randomized-withdrawal study and NCT01710709 was an open-label study. Functional recovery, assessed at the end of the respective maintenance phases, was defined as a total FAST score of ≤11 for 8 consecutive weeks.Results: Post-hoc analyses included 229 patients from the randomized-withdrawal study (AOM 400 n=116; placebo n=113). The open-label study included 402 patients (including 321 de novo patients and 81 rollover patients who had completed the randomized-withdrawal study). In the randomized-withdrawal study, functional recovery was achieved by 30.2% (n=35) of the AOM 400 group compared with 24.8% (n=28) in the placebo group. The difference was not statistically significant (p=0.39). In the open-label study, 36% (n=116) of de novo patients and 43% (n=35) of rollover patients had functionally recovered after 52 weeks of AOM 400 treatment.Conclusion: These data highlight the utility of a sustained FAST total score of ≤11 as a definition of recovery and emphasize the possibility of achieving this ambitious treatment goal with effective long-term treatment.Keywords: bipolar disorder, aripiprazole, long-acting injectable, maintenance, functioning, recovery

Clinical and epidemiological research suggests that behavioral addictions (BA) are associated with a wide range of psychiatric disorders. However, the relationship between BA and bipolar disorders (BD) has not been thoroughly explored. The aim of this systematic review was to critically summarize and evaluate the current available evidence regarding a possible association between BA and BD. A systematic review of major electronic databases according to PRISMA guidelines was conducted from inception to 31st December 2017. We sought quantitative studies data concerning prevalence of comorbidity, features and treatment related to BA-BD comorbidity. Data were narratively synthesized. Of the 1250 studies returned from the search, a total of 28 articles were included in this review. BA may be overrepresented in BD samples, and the other way around. Pathological gambling and kleptomania were the most prevalent conditions followed by compulsive buying, compulsive sexual behavior and internet addiction. BA was also associated with other mood disorders, anxiety disorders and substance use disorder. BD-BA comorbidity was related with more severe course of illness. Studies on treatment strategies for BD–BA comorbidity are rather limited; only one randomized controlled trial that fulfilled inclusion criteria was identified. Methodological heterogeneity in terms of design and results among studies was found. BD-BA commonly co-occurs although there is a need for rigorous studies. Routine screening and adequate assessment may be helpful in BD patients to identify individuals at risk for BA and to effectively manage the complex consequences associated with BA-BD comorbidity.

Introduction: Early recognition of bipolar disorder improves the prognosis and decreases the burden of the disease. However, there is a significant delay in diagnosis. Multiple risk factors for bipolar disorder have been identified and a population at high-risk for the disorder has been more precisely defined. These advances have allowed the development of risk calculators to predict individual risk of conversion to bipolar disorder. This review aims to identify the risk calculators for bipolar disorder and assess their clinical applicability. Methods: A systematic review of original studies on the development of risk calculators in bipolar disorder was performed. The studies' quality was evaluated with the Newcastle-Ottawa Quality Assessment Form for Cohort Studies and according to recommendations of the Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis Initiative. Results: Three studies met the inclusion criteria; one developed a risk calculator of conversion from major depressive episode to bipolar disorder; one of conversion to new-onset bipolar spectrum disorders in offspring of parents with bipolar disorder; and the last one of conversion in youths with bipolar disorder not-otherwise-specified. Conclusions: The calculators reviewed in this article present good discrimination power for bipolar disorder, although future replication and validation of the models is needed. info:eu-repo/semantics/publishedVersion

Purpose of review Previous studies suggest an association between depression and increased risk of various type of infections, including acute bacterial skin and skin structure infections (ABSSSI). Here, we review the latest advancement in our understanding of immunity in patients with depression and its relevance to disease management and diagnosis, with a special focus on patients suffering from ABSSSI. Recent findings Recent studies have highlighted the role of hypothalamic-pituitary-adrenal axis, neuro-endocrine stress signaling pathways and behavioral attitudes (substance abuse and homelessness) in the pathogenesis of infections in depressed patients. Furthermore, acute bacterial infections, in turn, have emerged as a possible risk for depression development because of different mechanisms including antibiotic-driven changes in the microbiota. Summary Recent evidences have emphasized the threat that comanagement of depression and infection pose to infectious disease physician and psychiatrist. Depressed patients with ABSSSI must be closely monitored for drug side-effects, drug-drug interactions, toxicity, and adequate compliance. New management strategies including new long-acting antibiotics (e.g., dalbavancin) are welcome.

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 ).

Over the last decade, there has been a growing appreciation of the importance of identifying and treating cognitive impairment associated with bipolar disorder, since it persists in remission periods. Evidence indicates that neurocognitive dysfunction may significantly influence patients’ psychosocial outcomes. An ever-increasing body of research seeks to achieve a better understanding of potential moderators contributing to cognitive impairment in bipolar disorder in order to develop prevention strategies and effective treatments. This review provides an overview of the available data from studies examining treatments for cognitive dysfunction in bipolar disorder as well as potential novel treatments, from both pharmacological and psychological perspectives. All these data encourage the development of further studies to find effective strategies to prevent and treat cognitive impairment associated with bipolar disorder. These efforts may ultimately lead to an improvement of psychosocial functioning in these patients.

BackgroundCognitive reserve (CR) reflects the capacity of the brain to endure neuropathology, minimize clinical manifestations and successfully complete cognitive tasks. The present study aims to determine whether high CR may constitute a moderator of cognitive functioning in bipolar disorder (BD).MethodsOne hundred and two patients with BD and 32 healthy controls were enrolled. All patients met DSM-IV criteria for I or II BD and were euthymic (YMRS ≤ 6 and HDRS ≤ 8) during a 6-month period. All participants were tested with a comprehensive neuropsychological battery, and a Cerebral Reserve Score (CRS) was estimated. Subjects with a CRS below the group median were classified as having low CR, whereas participants with a CRS above the median value were considered to have high CR.ResultsParticipants with BD with high CR displayed a better performance in measures of attention (digits forward: F = 4.554, P = 0.039); phonemic and semantic verbal fluency (FAS: F = 9.328, P = 0.004; and Animal Naming: F = 8.532, P = 0.006); and verbal memory (short cued recall of California Verbal Learning Test: F = 4.236, P = 0.046), after multivariable adjustment for potential confounders, including number of admissions and prior psychotic symptoms.ConclusionsHigh cognitive reserve may therefore be a valuable construct to explore for predicting neurocognitive performance in patients with BD regarding premorbid status.Disclosure of interestDr. I. Grande has received a Juan Rodés Contract (JR15/00012), Instituto de Salud Carlos III, Spanish Ministry of Economy and Competiveness, Barcelona, Spain and has served as a consultant for Ferrer and as a speaker for AstraZeneca, Ferrer and Janssen-Cilag.Disclosure of interestDr. I. Grande has received a Juan Rodés Contract (JR15/00012), Instituto de Salud Carlos III, Spanish Ministry of Economy and Competiveness, Barcelona, Spain and has served as a consultant for Ferrer and as a speaker for AstraZeneca, Ferrer and Janssen-Cilag.

(1) Background: bipolar disorder (BD) is a chronic disease that often leads to functional impairment. The objective of this study is to elucidate which variables are associated with better functional outcomes in a sample of euthymic patients with BD. (2) Methods: patients were recruited at the Hospital Clinic of Barcelona and they underwent a clinical interview, a functional assessment, and a comprehensive neuropsychological evaluation. After that, patients were divided into two groups according to the Functioning Assessment Short Test total score: functionally remitted vs. functionally impaired. Following this, a multivariate logistic regression was run in order to identify clinical, demographic and cognitive factors associated with functional remission. (3) Results: a total of 420 euthymic patients with BD were assessed for this study, distributed as follows: functionally remitted (n = 221) and functionally impaired (n = 199). Finally, the multivariate logistic regression revealed that only five variables significantly contributed to the model, including: lifetime history of psychotic symptoms (the variable that contributed the most to the model), followed by the Hamilton Depression total score, and cognitive performance (executive functions and verbal memory). (4) Conclusions: treatments to ensure a good functional outcome in BD should specially prevent psychosis, target subthreshold depressive symptoms and enhance cognition, more specifically executive functions and verbal memory.

OBJECTIVE The aim of this study was to identify predisposing factors and clinical features at baseline that might help predict diagnosis of bipolar disorder vs schizophrenia in a first-episode psychosis (FEP) cohort. METHODS In this prospective, naturalistic study, we evaluated a cohort of 335 subjects with FEP recruited from April 2009 to April 2012. Baseline features were compared between subjects with a final DSM-IV diagnosis of bipolar disorder and schizophrenia at 12-month follow-up. A binary logistic regression model was used to assess predictors of diagnosis of bipolar disorder at follow-up. RESULTS At 12-month follow-up, 47 of the 335 subjects included in the study received the diagnosis of bipolar disorder and 105, of schizophrenia. Subjects with a final diagnosis of bipolar disorder had a higher prevalence of family history of mood disorders (38.2% vs 18.0%, P = .02), better baseline premorbid adjustment (Premorbid Adjustment Scale [PAS]: 38.4 vs 50.6, P < .01) and psychosocial functioning (Functional Assessment Short Test [FAST]: 23.6 vs 33.7, P = .001), better cognitive flexibility (number of perseverative errors on the Wisconsin Card Sorting Test [WCST]: 14.2 vs 19.7, P = .01), more manic symptoms (Young Mania Rating Scale [YMRS]: 14.1 vs 7.3, P < .01), lesser negative symptoms (Positive and Negative Syndrome Scale negative scale [PANSS-N]: 15.0 vs 22.3, P < .001), and shorter duration of untreated psychosis (144.2 vs 194.7 days, P < .01) than subjects with a schizophrenia diagnosis. Binary logistic regression model revealed that lower FAST scores (odds ratio [OR] = 0.956; P = .015), lower PANSS-N scores (OR = 0.93; P = .048), and lower number of perseverative errors on the WCST (OR = 0.946; P = .035) were significantly related to diagnosis of bipolar disorder at follow-up. CONCLUSIONS In our FEP cohort, better psychosocial functioning, lesser negative symptoms, and better cognitive flexibility were related to diagnosis of bipolar disorder at 12-month follow-up.

(1) Background: The cognitive reserve (CR) concept has not been precisely defined in severe mental disorders and has been estimated using heterogeneous methods. This study aims to investigate and develop the psychometric properties of the Cognitive Reserve Assessment Scale in Health (CRASH), an instrument designed to measure CR in people with severe mental illness; (2) Methods: 100 patients with severe mental illness (non-affective psychoses and affective disorders) and 66 healthy controls were included. The internal consistency and convergent validity of CRASH were assessed. Spearman’s correlations coefficients were also performed to examine the relationship between CRASH and neuropsychological tests, psychosocial functioning, and clinical course; (3) Results: The internal consistency was high (Cronbach’s alpha coefficient = 0.903). The CRASH global score had a large positive correlation with the Cognitive reserve questionnaire total score (r = 0.838, p < 0.001), demonstrating good convergent validity. The correlation coefficients between the CRASH total scores and clinical, functional, and neuropsychological performance were different between groups. In order to provide clinical interpretation, severity classification based on diagnosis (non-affective psychotic disorders, affective disorders, and healthy controls) have been created; (4) Conclusions: CRASH is the first CR measure developed specifically for patients with severe mental illness, facilitating reliable and valid measurement of this construct. The scale may aid in the stratification of patients and the implementation of personalized interventions.

Background Patients with bipolar disorder (BD) differ in their relative predominance of types of episodes, yielding predominant polarity, which has important treatment implications. However, few prospective studies of predominant polarity exist. Methods In the Jorvi Bipolar Study (JoBS), a regionally representative cohort of 191 BD I and BD II in- and outpatients was followed for five years using life-chart methodology. Differences between depressive (DP), manic (MP), and no predominant polarity (NP) groups were examined regarding time ill, incidence of suicide attempts, and comorbidity. Results At baseline, 16% of patients had MP, 36% DP, and 48% NP. During the follow-up the MP group spent significantly more time euthymic, less time in major depressive episodes, and more time in manic states than the DP and NP groups. The MP group had significantly lower incidence of suicide attempts than the DP and NP group, lower prevalence of comorbid anxiety disorders but more psychotic symptoms lifetime and more often (hypo)manic first phase of the illness than the DP group. Classification of predominant polarity was influenced by the timeframe used. Limitations The retrospective counting of former phases is vulnerable to recall bias. Assignment of dominant polarity may necessitate a sufficient number of illness phases. Conclusions Predominant polarity has predictive value in predicting group differences in course of illness, but individual patients’ classification may change over time. Patients with manic polarity may represent a more distinct subgroup than the two others regarding illness course, suicide attempts, and psychiatric comorbidity.

Background:Asenapine is the most recent compound that has been FDA- and EMA-approved for treatment of mania. Its efficacy and safety have been assessed in placebo-controlled trials, but little is known about its performance in routine clinical conditions. In this study, we compared features of patients treated with adjunctive asenapine or other adjunctive antipsychotics and the costs of the treatment.Methods:A combined prospective and retrospective data collection and analysis was conducted from January 2011 to December 2013 following a clinical interview and assessment of manic and depressive symptoms (YMRS, HDRS-17), clinical state (CGI-BP-M), psychosocial functioning (FAST), sexual dysfunction (PRSexDQ) and health resource costs associated with treatment with adjunctive asenapine versus other adjunctive antipsychotics.Results:Hundred and fifty-two patients from different university hospitals were included. Fifty-three patients received adjunctive asenapine and 99 received other adjunctive antipsychotics concomitantly to mood stabilizers. Considering inpatients, those treated with adjunctive asenapine presented a significantly less severe manic episode (P = 0.001), less psychotic symptoms (P = 0.030) and more comorbid personality disorder (P = 0.002). Regarding outpatients, those treated with adjunctive asenapine showed significantly less severe manic episode (P = 0.046), more previous mixed episodes (P = 0.013) and more sexual dysfunction at baseline (P = 0.036). No significant differences were found in mean total costs per day.Conclusion:Clinicians tended to use adjunctive asenapine in patients with less severe manic symptoms but more complex clinical profile, including more mixed episodes in the past, concomitant personality disorder, and sexual problems. Treatment with adjunctive asenapine was not associated with higher costs when compared to other options.

Background: Persistent low-grade immune-inflammatory processes, oxidative and nitrosative stress (O&NS), and hypothalamic-pituitary-adrenal axis activation are integral to the pathophysiology of major depressive disorder (MDD). The microbiome, intestinal compositional changes, and resultant bacterial translocation add a new element to the bidirectional interactions of the gut-brain axis; new evidence implicates these pathways in the patho-aetiology of MDD. In addition, abnormalities in the gut-brain axis are associated with several chronic non-communicable disorders, which frequently co-occur in individuals with MDD, including but not limited to irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), obesity, and type 2 diabetes mellitus (T2DM). Methods: We searched the PubMed/MEDLINE database up until May 1, 2016 for studies which investigated intestinal dysbiosis and bacterial translocation (the ‘leaky gut') in the pathophysiology of MDD and co-occurring somatic comorbidities with an emphasis on IBS, CFS, obesity, and T2DM. Results: The composition of the gut microbiota is influenced by several genetic and environmental factors (e.g. diet). Several lines of evidence indicate that gut-microbiota-diet interactions play a significant pathophysiological role in MDD and related medical comorbidities. Gut dysbiosis and the leaky gut may influence several pathways implicated in the biology of MDD, including but not limited to immune activation, O&NS, and neuroplasticity cascades. However, methodological inconsistencies and limitations limit comparisons across studies. Conclusions: Intestinal dysbiosis and the leaky gut may constitute a key pathophysiological link between MDD and its medical comorbidities. This emerging literature opens relevant preventative and therapeutic perspectives.

Objective: Patients diagnosed with bipolar disorder (BD) are reported to have significant work impairment during interepisode intervals. This study was carried out to assess potential predictors of occupational disability in a longitudinal follow-up of euthymic patients. Method: We included 327 euthymic patients diagnosed with BD type I or type II, 226 of whom were employed and 101 were receiving a severe disablement benefit (SDB). Sociodemographic data were studied and episode recurrence was assessed along a 1-year follow-up. Logistic regression analysis was applied to determine predictors of receiving SDB. Cox regression was built to study recurrences. Results: Predictors of receiving SDB were: axis II comorbidity [Odds Ratio (OR) = 2.94, CI: 1.26–6.86, P = 0.013], number of manic episodes (OR = 1.21, CI: 1.10–1.34, P < 0.001), being without stable partner (OR = 2.44, CI: 1.34–4.44, P = 0.004) and older age (OR = 1.08, CI: 1.05–1.12, P < 0.001). Bipolar patients receiving SDB presented more episodic recurrences regardless of polarity than employed bipolar patients (P = 0.002). The time until recurrence in 25% of the bipolar patients receiving SDB was 6.08 months (CI: 4.44– 11.77) being 13.08 months (CI: 9.60 to –) in the employed group. Conclusion: Occupational disability in bipolar patients is associated with axis II comorbidity, more previous manic episodes, not having a stable relationship, older age, and more recurrences at 1-year followup.

Brain-derived neurotrophic factor (BDNF) plays a critical role in neurodevelopment and neuroplasticity. Altered BDNF signaling is thought to contribute to the pathogenesis of schizophrenia (SZ) especially in relation to cognitive deficits. Clozapine (CLZ) has been shown a beneficial effect on cognition in SZ in some studies and a detrimental effect in others. To examine serum BDNF, two groups of chronically medicated DSM-IV SZ patients (n = 44), on treatment with clozapine (n = 31) and typical antipsychotics (n = 13) had 5 ml blood samples collected by venipuncture. Serum BDNF levels were significantly correlated with CLZ daily dose (r = 0.394, p = 0.028), but not with typical antipsychotic daily dose (r = 0.208, p = 0.496). This study suggests that serum BDNF levels are correlated with CLZ daily dose, and this may lead to the cognitive enhancement as seen in patients with SZ under CLZ. Despite the strong evidence that chronic administration of CLZ is effective for patients with SZ, it is still unknown whether atypical antipsychotic drugs regulate BDNF expression. Serum BDNF levels concentration in SZ merits further investigations with regard to the role of neurotrophins in the cognitive response to treatment with CLZ and other atypical antipsychotics.

Objective: Staging models for medical diseases are widely used to guide treatment and prognosis. Bipolar disorder (BD) is a chronic condition and it is among the most disabling disorders in medicine. The staging model proposed by Kapczinski in 2009 presents four progressive clinical stages of BD. Our aim was to evaluate pharmacological maintenance treatment across these stages in patients with BD. Methods: One hundred and twenty-nine subjects who met DSM-IV criteria for BD were recruited from the Bipolar Disorders Program at Hospital de Clı´nicas de Porto Alegre, Brazil. All patients were in remission. The subjects were classified according to the staging model: 31 subjects were classified as stage I, 44 as stage II, 31 as stage III, and 23 as stage IV. Results: Patterns of pharmacological treatment differed among the four stages (p = 0.001). Monotherapy was more frequent in stage I, and two-drug combinations in stage II. Patients at stages III and IV needed three or more medications or clozapine. Impairment in functional status (Functioning Assessment Short Test [FAST] scale scores) correlated positively with the number of medications prescribed. Conclusions: This study demonstrated differences in pharmacological treatment in patients with stable BD depending on disease stage. Treatment response can change with progression of BD. Clinical guidelines could consider the staging model to guide treatment effectiveness.

In the field of bipolar disorder, some proposals of a staging model have been suggested considering the progressive features of the disorder. The staging model regards special features of the patients and further draws a route to define the prognosis and treatment as well as the neurobiological background of the disorder. The aim of this model is to identify rational therapeutic targets and provide the most effective and less toxic intervention in a time-sensitive manner. Advocating for a model of staging in bipolar disorder that can group the patients according to quantitative cut-offs of common practice clinical variables as well as defining a biochemical correlation seems to be a further step towards an operative and valid model of staging in bipolar disorder.Disclosure of interestDr. I. Grande has received a Juan Rodés Contract (JR15/00012), Instituto de Salud Carlos III, Spanish Ministry of Economy and Competiveness, Barcelona, Spain and has served as a consultant for Ferrer and as a speaker for AstraZeneca, Ferrer and Janssen-Cilag.

Maintenance therapy in bipolar disorder (BD) is usually required to prevent relapses and improve residual symptoms. Therefore, in this study, we describe patterns of pharmacological maintenance treatment and identify associated clinical features. This prospective multicentre epidemiological study recruited a cohort of 739 consecutive out-patients with clinically stable BD. Clinical stability was assessed at baseline with the Clinical Global Impression scale for BD and depressive symptoms with the Hamilton Depression Rating Scale. Psychotropic medications were classified and analysed according to their mechanism as well as use. Logistic regression models were used to examine the associations between pharmacological strategies and clinical features. Longer time since last episode [odds ratio (OR) 1.002, p < 0.0001] and family history of psychiatric disorders (OR 1.911, p = 0.028) were associated with lithium in monotherapy; manic polarity of the most recent episode (OR 3.300, p = 0.006) and longer duration of clinical stability (OR 1.009, p = 0.034) with antipsychotic in monotherapy; depressive polarity of the most recent episode (OR 2.567, p = 0.003) and bipolar II disorder diagnosis (OR 2.278, p = 0.008) with antidepressant combination; no ongoing psychiatric co-morbidity (OR 0.230, p = 0.004) with lithium and anticonvulsant; manic polarity of the most recent episode (OR 3.774, p < 0.0001) with lithium and antipsychotic; manic polarity of the most recent episode (OR 2.907, p = 0.028) with lithium, anticonvulsant and antipsychotic. The pharmacological patterns followed published recommendations, except for the excessive use of antidepressants. This study reveals clinical factors closely related to prescription patterns.

BackgroundAllostatic load (AL) relates to the neural and bodily “wear and tear” that emerge in the context of chronic stress. This paper aims to provide clinicians with a comprehensive overview of the role of AL in patophysiology of bipolar disorder (BD) and its practical implications.MethodsPubMed searches were conducted on English-language articles published from 1970 to June 2011 using the search terms allostatic load, oxidative stress, staging, and bipolar disorder cross-referenced with cognitive impairment, comorbidity, mediators, prevention.ResultsProgressive neural and physical dysfunction consequent to mood episodes in BD can be construed as a cumulative state of AL. The concept of AL can help to reconcile cognitive impairment and increased rates of clinical comorbidities that occur over the course of cumulative BD episodes.ConclusionsData on transduction of psychosocial stress into the neurobiology of mood episodes converges to the concept of AL. Mood episodes prevention would not only alleviate emotional suffering, but also arrest the cycle of AL, cognitive decline, physical morbidities and, eventually, related mortality. These objectives can be achieved by focusing on effective prophylaxis from the first stages of the disorder, providing mood-stabilizing agents and standardized psychoeducation and, potentially, addressing cognitive deficits by the means of specific medication and neuropsychological interventions.

Background Asenapine is the most recent compound that hasbeen FDA- and EMA-approved for treatment of mania. Its efficacy and safety havebeen assessed in placebo-controlled trials, but little is known about itsperformance in routine clinical conditions. The MANACOR study assessed costsassociated with treatment of mania in several hospital settings acrossCatalonia, Spain. As part of the protocol, we compared cost-effectiveness ofasenapine versus other treatment options. Methods A combined prospective and retrospective datacollection and analysis was conducted from January 2011 to December 2013following a clinical interview and assessment of manic and depressive symptoms(YMRS, HDRS-17), clinical state (CGI-BP-M), psychosocial functioning (FAST),sexual dysfunction (PRSexDQ) and health resource costs associated withtreatment with asenapine versus other antipsychotics. Results 152 patients from different university hospitalswere included. 53 patients received asenapine and 99 received otherantipsychotics. Considering inpatients (N=117), those treated with asenapinepresented a significantly less severe manic episode (p=0.001), less psychoticsymptoms (p=0.030) and, more comorbid personality disorder (p=0.002). Regardingoutpatients, those treated with asenapine showed significantly less severemanic episode (p=0.046), more previous mixed episodes (p= 0.013) and, moresexual dysfunction at baseline (p=0.036). No significant differences were foundin mean total costs per day. Limitations Non-randomized study design. Conclusion Clinicians tended to use asenapine in patientswith less severe manic symptoms but more complex clinical profile, includingmore mixed episodes in the past, concomitant personality disorder, and sexualproblems. Treatment with asenapine was not associated with higher costs when comparedto other options.

Introduction Different proposals of the staging model in bipolar disorder (BD) have been launched suggesting a progression from prodromal to more severe and refractory presentations. Biochemical variations in BD are receiving attention as they may help to understand the neurobiological correlates of the disorder and its neuroprogression. Objectives Study pro-inflammatory factors, such as interleukins along the progression of the disorder. Aims To investigate a) the role of interleukin-6 (IL-6) in the model of staging and b) to detect clinical predictors of variations in IL-6 levels. Methods This is a case-control study matched for age and gender. Patients required the diagnosis confirmation by SCID, being in euthymia (HDRS, YMRS scores ≤ 7 in last month), and were classified in Kapczinski et al. clinical stages. At the end, 109 patients and 25 controls were eligible for the study. Serum IL-6 levels were determined by ELISA. Results Seventy-six (69.7%) patients were female and the mean age was 44.2 (SD= 12.9) years. A significant increase in IL- 6 was found in patients compared to controls ( t =2.33, p =0.02) and among the four groups of patients ( F =2.85, p =0.04). Results from linear regression analysis revealed that number of episodes per year, age at first episode, and age were significantly associated with IL-6 (β=0.025, CI: 0.005-0.044, p=0.012; β=-0.016, CI:(-0.031)-(-0.001),p=0.033; β=0.042, CI:0.027-0.058, p=0.0001, respectively). Conclusions Interleukin-6 may be a useful biomarker in the model of staging in bipolar disorder and could be related to the number of episode per year and early onset of the disorder.

Introduction Despite therapeutic advances, we still have difficulties in predicting response to treatment in bipolar disorder (BD). Brain-Derived Neurotrophic Factor (BDNF) has been put forward as a potential peripheral marker of treatment response. Objective To prospectively study the relation between clinical response to treatment and serum BDNF levels. Aims To investigate a) a possible association between serum BDNF levels and clinical response along 16 week follow-up and b) the role of val66met polymorphism in clinical response in a sample of drug-free patients with BD going through a mood episode. Methods This is a naturalistic, open-label prospective nested case control study matched for age, gender and ethnicity. Patients were 18 years or older, required BD diagnosis, undergoing a current manic, mixed or depressive episode and be off-medication for at least 2 weeks. Clinical assessment and blood withdrawn were conducted along follow-up. At the end of the study, patients were classified according to clinical response. Results 25 of 36 (69.4%) of the patients were female and the mean age was 37.8 (SD 11.8) years old. Baseline serum BDNF levels did not show any difference between patients and controls ( p = 0.075).There was a significant negative correlation between differences in serum BDNF levels and in CGI score along follow-up ( r = −.372, p = 0.028). Serum BDNF levels were significant higher in responders compared to non-responders at week 4, 8 and 16 ( p = 0.026, p = 0.009, p = 0.001 respectively). Val66met polymorphism did not seem to interfere in clinical response. Conclusions Changes in serum BDNF levels may help in monitoring treatment response.

ObjectivesCardiovascular side effects of antipsychotics are been studied both in typical and atypical antipsychotics but, in particular, with clozapine few systematic studies of these effects have been performed. In this study, we reviewed electrocardiographic (ECG) data from patients treated with clozapine.MethodsObservational, retrospective study in our Clozapine Day Clinic from 2000 to 2008. We recluted 197 patients (70% men) with mean age 31,75 ± 9,0 years who began treatment with clozapine. All of them had an electrocardiogram taken before starting treatment and after 18 weeks of follow-up. None suffered from heart diseases. QTc was evaluated by Bazett formula (QT/ (R-R’)1/2). Treatment prescribed was taken down and drug serum levels were detected. Statistical analysis was executed by SPSS 17.0.ResultsThere was significant correlation between doses prescribed and levels of clozapine and norclozapine (r=.304, p=.023; r=.354 p=.007), between levels of clozapine, norclozapine and QTc enlargement (r=.348, p=.008; r=.268 p=.046) and between levels of clozapine, norclozapine and heart rate (r=.390, p=.003; r=.326 p=.014). There were no differences between QTc and treatment with clozapine or other antipsychotic (p=0.902), between sex or if polypharmacy existed. ECG alterations were a case of supraventricular extrasystoles, another of Wolf-Parkinson -White Syndrome and other inespecific alterations like repolarizations or left hypertrophy.ConclusionWe did not find either major incidence on cardiological effects or significative QTc enlargement during treatment with clozapine in contrast to other antipsychotic previously prescribed. Therefore clozapine may be in the same cardiologic safety rank than other antipsychotics.