"Novel Psychopharmacology for Depressive Disorders".

Major depressive disorder carries a significant burden and a high risk for suicide. The need for more effective, safer, and faster-acting drugs is, therefore, compelling. The present chapter briefly assesses the most promising agents, focusing on non-monoamine-targeting compounds, namely, the glutamate antagonist ketamine and its enantiomer esketamine. A critical overview of the evidence and the pitfalls associated with current antidepressant drug development is likewise provided in the following text.

Prevalence and correlates of major depressive disorder, bipolar disorder and schizophrenia among nursing home residents without dementia: systematic review and meta-analysis.

BACKGROUND: The elderly population and numbers of nursing homes residents are growing at a rapid pace globally. Uncertainty exists regarding the actual rates of major depressive disorder (MDD), bipolar disorder and schizophrenia as previous evidence documenting high rates relies on suboptimal methodology. AIMS: To carry out a systematic review and meta-analysis on the prevalence and correlates of MDD, bipolar disorder and schizophrenia spectrum disorder among nursing homes residents without dementia. METHOD: Major electronic databases were systematically searched from 1980 to July 2017 for original studies reporting on the prevalence and correlates of MDD among nursing homes residents without dementia. The prevalence of MDD in this population was meta-analysed through random-effects modelling and potential sources of heterogeneity were examined through subgroup/meta-regression analyses. RESULTS: Across 32 observational studies encompassing 13 394 nursing homes residents, 2110 people were diagnosed with MDD, resulting in a pooled prevalence rate of 18.9% (95% CI 14.8-23.8). Heterogeneity was high (I2 = 97%, P≤0.001); no evidence of publication bias was observed. Sensitivity analysis indicated the highest rates of MDD among North American residents (25.4%, 95% CI 18-34.5, P≤0.001). Prevalence of either bipolar disorder or schizophrenia spectrum disorder could not be reliably pooled because of the paucity of data. CONCLUSIONS: MDD is highly prevalent among nursing homes residents without dementia. Efforts towards prevention, early recognition and management of MDD in this population are warranted.

Alexithymia, suicide ideation, affective temperaments and homocysteine levels in drug naïve patients with post-traumatic stress disorder: an exploratory study in the everyday 'real world' clinical practice.

Objective: The present exploratory study aimed to investigate relationships between alexithymia, suicide ideation, affective temperaments and homocysteine levels among drug-naïve adult outpatients with Post-Traumatic Stress Disorder (PTSD) in an everyday 'real world' clinical setting.Method: Sixty-four adult outpatients with PTSD were evaluated using the Davidson Trauma Scale (DTS), the Toronto Alexithymia Scale (TAS-20), the Scale of Suicide Ideation (SSI), the Temperament Evaluation of the Memphis, Pisa, Paris and San Diego-Autoquestionnaire. As well, homocysteine levels were measured.Results: Alexithymic subjects showed higher values on all scales but not homocysteine levels. Partial correlations showed that almost all studied variables were correlated with each other, except homocysteine levels. Regression analysis showed that higher disorder severity as measured by DTS and TAS-20 'Difficulty in Identifying Feelings' dimension was associated with higher SSI scores.Conclusions: In conclusion, alexithymic PTSD outpatients may be characterised by higher disorder severity and difficulty in identifying feelings that may be linked to increased suicide ideation, regardless of affective temperaments or homocysteine levels. Homocysteine levels were not related to any studied variable. However, study limitations are discussed and must be considered. KeypointsPatients with alexithymia showed increased PTSD severity, a higher score on TEMPS-A subscales, and more severe suicide ideation.The Difficulty in Identifying Feelings (DIF) dimension of TAS-20 was associated with suicide ideation in patients with PTSD.Homocysteine did not correlate with any studied variables.This study was exploratory and cross-sectional: further larger and prospective studies are needed.

The emergence of loss of efficacy during antidepressant drug treatment for major depressive disorder: An integrative review of evidence, mechanisms, and clinical implications.

The re-emergence (i.e. 'breakthrough') of depressive symptoms despite maintenance treatment of depression with antidepressant drugs is a complex clinical phenomenon referred to as tolerance. Herein we critically appraise evidence from both pre-clinical and clinical studies, focusing on putative mechanisms as well as clinical correlates and implications of the emergence tolerance during antidepressant treatment for major depressive disorder (MDD). It is firstly unclear to what extent this phenotype reflects a pharmacological effect of an antidepressant, is driven by non-adherence, is a marker of latent bipolarity or another comorbidity, a marker of neuroprogression of the underlying disorder or the intrusion of the impact of psychosocial variables into the clinical course. The operational definitions of tolerance and its related phenomena have also been largely inconsistent. Several protective clinical indicators have been proposed, including a rapid-cycling course and comorbid chronic anxiety, whilst poor treatment adherence, proneness to emotional blunting and sub-threshold bipolarity have been identified as possible correlates of tolerance to antidepressant treatment in MDD. Putative neurobiological underpinnings include adaptations in the hypothalamic-pituitary-adrenal (HPA) axis and the serotonergic system. Due to the clinical and diagnostic challenges imposed by the emergence of tolerance to antidepressants, there is an urgent need for upcoming international guidelines to reach a consensus on operational definitions for this complex clinical phenomenon, thus enabling a more precise appreciation of the incidence and correlates of tolerance to antidepressants. Taken together, the present review underscores the need to cautiously weight benefits and risks prior to considering long-term antidepressant treatment for patients with MDD as tolerance may emerge in a subset of patients.

Incidence, prevalence and clinical correlates of antidepressant-emergent mania in bipolar depression: a systematic review and meta-analysis.

BACKGROUND: Treatment-emergent mania (TEM) represents a common phenomenon inconsistently reported across primary studies, warranting further assessment. METHODS: A systematic review and meta-analysis following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines were conducted. Major electronic databases were searched from inception to May 2017 to assess the incidence and prevalence rates and clinical features associated with manic switch among bipolar depressed patients receiving antidepressants, using meta-regression and subgroup analysis. RESULTS: Overall, 10 098 depressed patients with bipolar disorder (BD) across 51 studies/arms were included in the quantitative analysis. The cumulative incidence of cases (TEM+ ) among 4767 patients with BD over 15 retrospective studies was 30.9% (95% confidence interval [CI] 19.6-45.0%, I2  = 97.9%). The cumulative incidence of TEM+ among 1929 patients with BD over 12 prospective open studies was 14.4% (95% CI 7.4-26.1%, I2  = 93.7%). The cumulative incidence of TEM+ among 1316 patients with BD over 20 randomized controlled trials (RCTs) was 11.8% (95% CI 8.4-16.34%, I2  = 73.46%). The pooled prevalence of TEM+ among 2086 patients with BD over four cross-sectional studies was 30.9% (95% CI 18.1-47.4%, I2  = 95.6%). Overall, concurrent lithium therapy predicted the lowest TEM rates. Inconsistent operational definitions of TEM were recorded, and the lack of information about age, sex, co-occurring anxiety, and other clinically relevant moderators precluded further stratification of the results. CONCLUSIONS: Rates of TEM vary primarily depending on study setting, which is concordant with the high degree of heterogeneity of the included records. Forthcoming RCT studies should adopt consistent operational definitions of TEM and broaden the number of moderators, in order to contribute most effectively to the identification of clear-cut sub-phenotypes of BD and patient-tailored pharmacotherapy.

Transcranial direct current stimulation for obsessive-compulsive disorder: A randomized, controlled, partial crossover trial.

BACKGROUND: Presupplementary motor area (pre-SMA) hyperactivity has been detected in obsessive-compulsive disorder (OCD) patients. However, it is not understood whether this is a putative primary cause or a compensatory mechanism in OCD pathophysiology. Considering the polarity-dependent effects on cortical excitability of transcranial direct current stimulation (tDCS), we applied cathodal and/or anodal tDCS to the pre-SMA of OCD patients to test which current polarity might better improve symptoms. METHODS: Twelve OCD patients received initially 10 anodal (n = 6) or cathodal (n = 6) daily consecutive 2 mA/20 min tDCS sessions with the active electrode placed bilaterally on the pre-SMA. In case of improvement or no change in symptoms severity, the subjects were maintained on the same current polarity for 10 more sessions. In case of symptoms worsening after the first 10 sessions they were switched to the other polarity for 10 more sessions to test the hypothesis of a polarity-dependent effect. Therefore, each subject received 20 tDCS sessions. The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and the Sheehan Disability Scale (SDS) were administered biweekly to assess changes in symptoms severity. RESULTS: After 10 sessions, 50% of patients who initially received anodal stimulation were switched to cathodal, while 100% of patients initially assigned to cathodal stimulation continued on the same polarity. At the end of the study, a statistically significant decrease was observed in the mean Y-BOCS scores of those patients who underwent cathodal tDCS. No pre-post difference was found in the scores of patients following anodal tDCS. CONCLUSIONS: Cathodal but not anodal tDCS over the pre-SMA significantly improved OCD symptoms.

Polarity-dependent effects of transcranial direct current stimulation in obsessive-compulsive disorder.

About one third of patients with obsessive-compulsive disorder (OCD) fail to experience significant clinical benefit from currently available treatments. Hyperactivity of the presupplementary motor area (pre-SMA) has been detected in OCD patients, but it is not clear whether it is the primary cause or a secondary compensatory mechanism in OCD pathophysiology. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique with polarity-dependent effects on motor cortical excitability. A 33-year-old woman with treatment-resistant OCD received 20 daily consecutive 2 mA/20 min tDCS sessions with the active electrode placed on the pre-SMA, according to the 10-20 EEG system, and the reference electrode on the right deltoid. The first 10 sessions were anodal, while the last 10 were cathodal. Symptoms severity was assessed using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) severity score. In the end of anodal stimulation, OCD symptoms had worsened. Subsequent cathodal stimulation induced a dramatic clinical improvement, which led to an overall 30% reduction in baseline symptoms severity score on the Y-BOCS. Our study supports the hypothesis that pre-SMA hyperfunction might be responsible for OCD symptoms and shows that cathodal inhibitory tDCS over this area might be an option when dealing with treatment-resistant OCD.

Premorbid circadian profile of patients with major depression and panic disorder.

AIMS: This study aims to compare some behavioural characteristics related to circadian functions in healthy subjects, in patients with major depressive disorder (MDD) and panic disorder (PD) during adulthood (disease period) and during the premorbid age (between 12 and 20 years old). METHODS: 132 adult patients with MDD, 144 with PD and 151 adult healthy controls were enrolled in the study. All subjects completed a retrospective questionnaire. RESULTS: Several behaviours (such as falling asleep, awakening, having, appetite, perceiving energy and cognitive functioning) showed a phase delay or a phase advance in MDD and PD patients compared to healthy controls. Behavioural differences where found in patients even before the clinical onset of the disease. CONCLUSIONS: Circadian profiles of MDD and PD patients diverge from those of healthy controls not only during the disorder but also in the ages preceding its clinical onset. The analysis of these circadian patterns may aid physicians to early identify subjects with specific psychiatric vulnerabilities.

[Facial Action Coding System (FACS): an instrument for the objective evaluation of facial expression and its potential applications to the study of schizophrenia]. / Facial Action Coding System (FACS): uno strumento di valutazione obiettiva dell'espressività mimica facciale e le sue potenziali applicazioni allo studio della schizofrenia.

INTRODUCTION: Affective flattening and the consequent anomalous expression of emotions are considered as key elements of the negative symptoms of schizophrenia. The purpose of this work is to assess how a survey instrument based on objective evaluation of emotional facial expressiveness (FACS) and a method of elicitation of emotions (film clips) can provide psychopathological manifestations about schizophrenia. METHODS: Relevant literature was identified through a search of Medline, PsychInfo and PubMed. Search terms included: "elicitation of emotions", "facial action coding system" and "schizophrenia". The research was limited to English-language publications and studies conducted exclusively in humans. RESULTS: The overall evaluation of the studies analyzed in this work show that the FACS is a useful tool to highlight specific clinical characteristics of schizophrenic patients with significant deficits in the expression and recognition of emotions, such as the status of hospitalization, the age of onset, the treatment with antipsychotic drugs, the SANS, SAPS and BPRS scores. CONCLUSIONS: Even if we have preliminary and incomplete data, the FACS and the elicitation of emotions through film clips can give an original contribution to the development of knowledge on pathophysiological events and interpretive models of schizophrenia.

The prevalence, odds and predictors of lifespan comorbid eating disorder among people with a primary diagnosis of bipolar disorders, and vice-versa: Systematic review and meta-analysis.

BACKGROUND: There are scarce and discrepant data about the prevalence and correlates of co-occurring eating disorders (EDs) among people with a primary diagnosis of bipolar disorder (BD), and vice-versa, compelling a systematic review and meta-analysis on the matter. METHODS: MEDLINE/PsycINFO databases were systematically searched for original studies documenting BD⇌ED comorbidity across the lifespan, from inception up until April 20th, 2020. Random-effects meta-analysis and meta-regression analyses were conducted, accounting for multiple moderators. RESULTS: Thirty-six studies involved 15,084 primary BD patients. Eleven studies encompassed 15,146 people with primary EDs. Binge eating disorder (BED) occurred in 12.5% (95%C.I.=9.4-16.6%, I2=93.48%) of BDs, while 9.1% (95%C.I.=3.3-22.6%) of BEDs endorsed BD. Bulimia Nervosa (BN) occurred in 7.4% (95%C.I.=6-10%) of people with BD, whereas 6.7% (95%C.I.=12-29.2%) of subjects with BN had a diagnosis of BD. Anorexia Nervosa (AN) occurred in 3.8% (95%C.I.=2-6%) of people with BDs; 2% (95%C.I.=1-2%) of BD patients had a diagnosis of AN. Overall, BD patients with EDs had higher odds of being female vs. non-ED controls. Several moderators yielded statistically significant differences both within- and between different types of BDs and EDs. LIMITATIONS: Scant longitudinal studies, especially across different EDs and pediatric samples. High heterogeneity despite subgroup comparisons. Limited discrimination of the quality of the evidence. CONCLUSIONS: The rates of BD⇌ED comorbidity vary across different diagnostic groups, more than they do according to the "direction" of BD⇌ED. Further primary studies should focus on the risks, chronology, clinical impact, and management of the onset of intertwined BD⇌ED across different ages, promoting a continuum approach.

The concept and management of acute episodes of treatment-resistant bipolar disorder: a systematic review and exploratory meta-analysis of randomized controlled trials.

BACKGROUND: The definitions of treatment-resistant bipolar disorder (TRBD) have varied across studies. Additionally, its management is clinically challenging. An updated synthesis and appraisal of the available evidence is needed. METHODS: A systematic search of major electronic databases from inception up to May 25th, 2020, was conducted to identify randomized controlled trials (RCTs) of pharmacological and non-pharmacological interventions for the management of TRBD. When sufficient evidence was available, a meta-analysis was conducted. RESULTS: Seventeen studies (n = 928 patients) were included in the qualitative synthesis. Fourteen studies (n = 803) assessed treatment-resistant acute bipolar depression (TRBD-De), including five neuromodulatory and nine pharmacological trials. Rapid- vs. standard up-titration of clozapine showed promising efficacy for TRBD mania, without significant adverse events. Electroconvulsive therapy (ECT) was confirmed to be similarly effective for TRBD-De as for treatment-resistant unipolar depression: odd ratio, OR = 0.919 (95%C.I. = 0.44-1.917), I2 = 13.98, p = .822. TRBD-De patients exposed to ketamine at day one post-infusion had high odds of response: OR = 10.682 (95%C.I. = 2.142-53.272), I2 = 0, p = <.005. The pooled drop-out rate in the ketamine trials was 21.2%. Additional evidence is warranted to confirm the potential efficacy of pramipexole or stimulants for TRBD-De. LIMITATIONS: Publication/measurement bias; exploratory nature of the meta-analyses for interventions that included participants solely with TRBD-De. CONCLUSIONS: Overall, a few interventions are available for TRBD, including pramipexole, ECT, and clozapine, among others. Larger and better-designed trials for TRBD are warranted and should be based on more uniform operational definitions. PROSPERO registration number: CRD42018114567.

Predictors of Treatment Resistance Across Different Clinical Subtypes of Depression: Comparison of Unipolar vs. Bipolar Cases.

OBJECTIVE: Treatment-resistant depression (TRD) and treatment-resistant bipolar depression (TRBD) poses a significant clinical and societal burden, relying on different operational definitions and treatment approaches. The detection of clinical predictors of resistance is elusive, soliciting clinical subtyping of the depressive episodes, which represents the goal of the present study. METHODS: A hundred and thirty-one depressed outpatients underwent psychopathological evaluation using major rating tools, including the Hamilton Rating Scale for Depression, which served for subsequent principal component analysis, followed-up by cluster analysis, with the ultimate goal to fetch different clinical subtypes of depression. RESULTS: The cluster analysis identified two clinically interpretable, yet distinctive, groups among 53 bipolar (resistant cases = 15, or 28.3%) and 78 unipolar (resistant cases = 20, or 25.6%) patients. Among the MDD patients, cluster "1" included the following components: "Psychic symptoms, depressed mood, suicide, guilty, insomnia" and "genitourinary, gastrointestinal, weight loss, insight". Altogether, with broadly defined "mixed features," this latter cluster correctly predicted treatment outcome in 80.8% cases of MDD. The same "broadly-defined" mixed features of depression (namely, the standard Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition-DSM-5-specifier plus increased energy, psychomotor activity, irritability) correctly classified 71.7% of BD cases, either as TRBD or not. LIMITATIONS: Small sample size and high rate of comorbidity. CONCLUSIONS: Although relying on different operational criteria and treatment history, TRD and TRBD seem to be consistently predicted by broadly defined mixed features among different clinical subtypes of depression, either unipolar or bipolar cases. If replicated by upcoming studies to encompass also biological and neuropsychological measures, the present study may aid in precision medicine and informed pharmacotherapy.

Prominent autistic traits and subthreshold bipolar/mixed features of depression in severe anorexia nervosa.

OBJECTIVE: Autistic traits are associated with a burdensome clinical presentation of anorexia nervosa (AN), as is AN with concurrent depression. The aim of the present study was to explore the intertwined association between complex psychopathology combining autistic traits, subthreshold bipolarity, and mixed depression among people with AN. METHOD: Sixty patients with AN and concurrent major depressive episode (mean age, 22.2±7 years) were cross-sectionally assessed using the Autism-Spectrum Quotient test (AQ-test), the Hamilton depression scales for depression and anxiety, the Young Mania Rating Scale (YMRS), the Hypomania-Checklist-32 (HCL-32), second revision (for subthreshold bipolarity), the Brown Assessment and Beliefs Scale (BABS), the Yale-Brown-Cornell Eating Disorders Scale (YBC-EDS), and the Eating Disorder Examination Questionnaire (EDE-Q). Cases were split into two groups depending on body mass index (BMI): severe AN (AN+) if BMI < 16, not severe (AN-) if BMI ≥ 16. RESULTS: The "subthreshold bipolarity with prominent autistic traits" pattern correctly classified 83.6% of AN patients (AN+ = 78.1%; AN- = 91.3%, Exp(B) = 1.391). AN+ cases showed higher rates of positive scores for YMRS items 2 (increased motor activity-energy) and 5 (irritability) compared to AN- cases. CONCLUSIONS: In our sample, depressed patients with severe AN had more pronounced autistic traits and subtly mixed bipolarity. Further studies with larger samples and prospective follow-up of treatment outcomes are warranted to replicate these findings.

Adjunctive vortioxetine for SSRI-resistant major depressive disorder: a "real-world" chart review study.

OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) are the cornerstone of treatment of major depressive disorder (MDD). However, non-response is common, often necessitating combination strategies. The present study assessed the efficacy of vortioxetine as an add-on therapy in patients with SSRI-resistant MDD. METHODS: The charts of 36 adult outpatients with DSM-IV-TR MDD who had not achieved a response after at least 8 weeks of treatment with an SSRI were reviewed retrospectively. Subjects were treated with vortioxetine (5-20 mg/day) for 8 weeks added to the current SSRI. The main outcome measures were change from baseline in total Hamilton Scale for Depression (HAM-D) score and the rate of response (a 50% or greater reduction in HAM-D score and a Clinical Global Impression - Improvement module [CGI-I] score of 1 or 2 at endpoint). HAM-D scores ≤ 7 were considered as remission. Additional outcome measures included the Snaith-Hamilton Pleasure Scale (SHAPS) and the Scale for Suicide Ideation (SSI). RESULTS: 32 patients completed the 8 weeks of treatment. At 8 weeks, a significant reduction in HAM-D score was observed (p ≤ 0.001), with response obtained by 41.7% and remission by 33.3% of patients. Significant reductions in SHAPS and SSI were also observed (p ≤ 0.001 for both scales). CONCLUSIONS: Adjunctive vortioxetine may be useful and well-tolerated in stage I treatment-resistant depression. However, the limitations of this study (such as small sample size, absence of randomization and control group, retrospective design, etc.) must be considered.

Lithium Exposure During Pregnancy and the Postpartum Period: A Systematic Review and Meta-Analysis of Safety and Efficacy Outcomes.

OBJECTIVE: Uncertainty surrounds the risks of lithium use during pregnancy in women with bipolar disorder. The authors sought to provide a critical appraisal of the evidence related to the efficacy and safety of lithium treatment during the peripartum period, focusing on women with bipolar disorder and their offspring. METHODS: The authors conducted a systematic review and random-effects meta-analysis assessing case-control, cohort, and interventional studies reporting on the safety (primary outcome, any congenital anomaly) or efficacy (primary outcome, mood relapse prevention) of lithium treatment during pregnancy and the postpartum period. The Newcastle-Ottawa Scale and the Cochrane risk of bias tools were used to assess the quality of available PubMed and Scopus records through October 2018. RESULTS: Twenty-nine studies were included in the analyses (20 studies were of good quality, and six were of poor quality; one study had an unclear risk of bias, and two had a high risk of bias). Thirteen of the 29 studies could be included in the quantitative analysis. Lithium prescribed during pregnancy was associated with higher odds of any congenital anomaly (N=23,300, k=11; prevalence=4.1%, k=11; odds ratio=1.81, 95% CI=1.35-2.41; number needed to harm (NNH)=33, 95% CI=22-77) and of cardiac anomalies (N=1,348,475, k=12; prevalence=1.2%, k=9; odds ratio=1.86, 95% CI=1.16-2.96; NNH=71, 95% CI=48-167). Lithium exposure during the first trimester was associated with higher odds of spontaneous abortion (N=1,289, k=3, prevalence=8.1%; odds ratio=3.77, 95% CI=1.15-12.39; NNH=15, 95% CI=8-111). Comparing lithium-exposed with unexposed pregnancies, significance remained for any malformation (exposure during any pregnancy period or the first trimester) and cardiac malformations (exposure during the first trimester), but not for spontaneous abortion (exposure during the first trimester) and cardiac malformations (exposure during any pregnancy period). Lithium was more effective than no lithium in preventing postpartum relapse (N=48, k=2; odds ratio=0.16, 95% CI=0.03-0.89; number needed to treat=3, 95% CI=1-12). The qualitative synthesis showed that mothers with serum lithium levels <0.64 mEq/L and dosages <600 mg/day had more reactive newborns without an increased risk of cardiac malformations. CONCLUSIONS: The risk associated with lithium exposure at any time during pregnancy is low, and the risk is higher for first-trimester or higher-dosage exposure. Ideally, pregnancy should be planned during remission from bipolar disorder and lithium prescribed within the lowest therapeutic range throughout pregnancy, particularly during the first trimester and the days immediately preceding delivery, balancing the safety and efficacy profile for the individual patient.

Brexpiprazole for treatment-resistant major depressive disorder.

Introduction:Treatment-resistant depression (TRD), seldom interchangeably referred to as 'depression inadequately responding to the standard antidepressant drug,' carries a significant burden. The atypical antipsychotics represent a popular augmentation strategy for antidepressant-resistant depression, although their efficacy/safety profiles vary across different agents and presentations of depression. Areas covered: This review appraises the evidence supporting the use of brexpiprazole augmentation for major depressive disorder (MDD) adults showing an inadequate response to standard antidepressants, covering the related regulatory affairs, and essential pharmacology. Expert opinion: Brexpiprazole is a 'third-generation' antipsychotic featuring dopaminergic D2 and serotonergic 5-HT1A partial agonism approved by the U.S. Food and Drug Administration for the treatment of MDD, besides schizophrenia in adults. The clinical trials leading to the extended approval of brexpiprazole rely on the definition of 'inadequate response' to antidepressants, which seems to poorly represent the most severe cases of TRD seen in clinical practice. TRD definitions appraised in the literature are likewise inconsistent and questionable from a clinical-standpoint. Compared to aripiprazole, brexpiprazole has lower D2 intrinsic activity, although the latter features a more potent serotonergic 5-HT2A antagonism. The actual propensity of brexpiprazole to induce akathisia and tardive dyskinesia warrants assessment by ad-hoc designed long-term, controlled trials.

The FDA "Black Box" Warning on Antidepressant Suicide Risk in Young Adults: More Harm Than Benefits?

The decision made in the year 2004 by the U.S. Food and Drug Administration (FDA) to require a boxed warning on antidepressants regarding the risk of suicidality in young adults still represents a matter of controversy. The FDA warning was grounded on industry-sponsored trials carried one decade ago or earlier. However, within the past decade, an increasing number of reports have questioned the actual validity of the FDA warning, especially considering a decline in the prescription of the antidepressant drugs associated with an increase in the rate of suicidal events among people with severe depression. The present report provides an overview of the FDA black box warning, also documenting two Major Depressive Disorder patients whose refusal to undergo a pharmacological antidepressant treatment possibly led to an increased risk for suicidal behaviors. The concerns raised by the FDA black box warning need to be considered in real-world clinical practice, stating the associated clinical and public health implications.

Aripiprazole-induced atrial fibrillation in a patient with concomitant risk factors.

Aripiprazole is an atypical antipsychotic drug with a polypharmacological mechanism of action and a favorable tolerability profile. Its major indications are schizophrenia and mania in adults and adolescents. Here we present the case of a 43-year-old Caucasian man with schizophrenia who developed atrial fibrillation (AF) after starting aripiprazole treatment. Prior to this treatment, he had never received any antipsychotic drugs. On admission to our inpatient unit, he showed severe psychotic symptoms and was started on aripiprazole with a rapid titration regimen (15 mg on the first day and then 15 mg twice daily thereafter) in combination with lorazepam (2.5 mg thrice a day). On the third day, the patient exhibited vomiting and an irregular pulse. An electrocardiogram (ECG) revealed new-onset AF with rapid ventricular response. Aripiprazole was discontinued and cardioversion was obtained with intravenous amiodarone. A different antipsychotic treatment was thus started (perphenazine 12 mg/d), which led to symptom remission without any relevant adverse effects. During the 2-year follow-up observation, neither psychotic symptoms nor ECG abnormalities were detected. Besides aripiprazole, other co-occurring factors might have contributed to the onset of AF in our patient, namely hypertension, low-grade diastolic dysfunction, chronic inflammatory disease, CYP2D6 polymorphism, corticosteroid and antiulcer treatment, and a family loading for myocardial infarction. In conclusion, our case study suggests that although aripiprazole has fewer cardiovascular effects than other antipsychotic drugs, in the presence of concomitant risk factors, high dose, and rapid titration regimen, regular monitoring of clinical parameters and ECG is highly recommended. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Pharmacological management of depression in patients with multiple sclerosis.

INTRODUCTION: The pharmacotherapeutic management of depression in patients with multiple sclerosis (MS) is a matter of debate that cannot be decided from the evidence available in the current literature. Therefore, its management essentially relies on the clinical experience of the prescribing clinician rather than on evidence-based approaches. AREAS COVERED: This review provides a clinically oriented critical perspective on the connection between MS and major depressive disorder (MDD) or depression associated with bipolar disorder (BD), focusing on its optimal pharmacotherapy. Both clinical and pharmacological considerations are accounted in order to promote rational pharmacotherapy, both in terms of efficacy and tolerability. EXPERT OPINION: Despite its clinical burden and relatively frequent occurrence, the interplay of MS and depression still requires further controlled trials to better clarify the appropriate pharmacotherapy across varying 'diseases categories' of MS itself, as well as discriminating between depressive symptoms that do not necessarily reach the threshold of either MDD or BD. Additional insight into new mood-tolerated neurological pharmacotherapy for MS is likewise warranted toward a more effective, immune- and patient-tailored pharmacotherapy, while promoting innovation in drug design, with the ultimate goal of enhancing the overall quality life of the affected individual, his/her caregivers, and to reduce the associated economic and social burden.

Progress in bipolar disorder drug design toward the development of novel therapeutic targets: a clinician's perspective.

INTRODUCTION: Bipolar disorder (BD) is a considerable burden to the affected individual. The need for novel drug targets and improved drug design (DD) in BD is therefore clear. Areas covered: The following article provides a brief, narrative, clinician-oriented overview of the most promising novel pharmacological targets for BD along with a concise overview regarding the general DD process and the unmet needs relevant to BD. Expert opinion: A number of novel potential drug targets have been investigated. With the notable exception of the kynurenine pathway, available evidence is too scarce to highlight a definitive roadmap for forthcoming DD in BD. BD itself may present with different facets, as it is a polymorphic clinical spectrum. Therefore, promoting clinical-case stratification should be based on precision medicine, rather than on novel biological targets. Furthermore, the full release of raw study data to the scientific community and the development of uniform clinical trial standards (including more realistic outcomes) should be promoted to facilitate the DD process in BD.