Dysregulation of mitochondrial dynamics, mitophagy and apoptosis in major depressive disorder: Does inflammation play a role?

Recent studies have suggested that mitochondrial dysfunction and dysregulated neuroinflammatory pathways are involved in the pathophysiology of major depressive disorder (MDD). Here, we aimed to assess the differences in markers of mitochondrial dynamics, mitophagy, general autophagy, and apoptosis in peripheral blood mononuclear cells (PBMCs) of MDD patients (n = 77) and healthy controls (HCs, n = 24). Moreover, we studied inflammation engagement as a moderator of mitochondria dysfunctions on the severity of depressive symptoms. We found increased levels of Mfn-2 (p < 0.001), short Opa-1 (S-Opa-1) (p < 0.001) and Fis-1 (p < 0.001) in MDD patients, suggesting an increase in the mitochondrial fragmentation. We also found that MDD patients had higher levels of Pink-1 (p < 0.001), p62/SQSTM1 (p < 0.001), LC3B (p = 0.002), and caspase-3 active (p = 0.001), and lower levels of parkin (p < 0.001) compared with HCs. Moreover, we showed that that MDD patients with higher CRP levels had higher levels of Mfn-2 (p = 0.001) and LC3B (p = 0.002) when compared with MDD patients with low CRP. Another notable finding was that the severity of depressive symptoms in MDD is associated with changes in protein levels in pathways related to mitochondrial dynamics and mitophagy, and can be dependent on the inflammatory status. Overall, our study demonstrated that a disruption in the mitochondrial dynamics network could initiate a cascade of abnormal changes relevant to the critical pathological changes during the course of MDD and lead to poor outcomes.

White matter predicts tDCS antidepressant effects in a sham-controlled clinical trial study.

Transcranial direct current stimulation (tDCS) has been used as treatment for depression, but its effects are heterogeneous. We investigated, in a subsample of the clinical trial Escitalopram versus Electrical Direct Current Therapy for Depression Study (ELECTTDCS), whether white matter areas associated with depression disorder were associated with tDCS response. Baseline diffusion tensor imaging data were analyzed from 49 patients (34 females, mean age 41.9) randomized to escitalopram 20 mg/day, tDCS (2 mA, 30 min, 22 sessions), or placebo. Antidepressant outcomes were assessed by Hamilton Depression Rating Scale-17 (HDRS) after 10-week treatment. We used whole-brain tractography for extracting white matter measures for anterior corpus callosum, and bilaterally for cingulum bundle, striato-frontal, inferior occipito-frontal fasciculus and uncinate. For the rostral body, tDCS group showed higher MD associated with antidepressant effects (estimate = -5.13 ± 1.64, p = 0.002), and tDCS significantly differed from the placebo and the escitalopram group. The left striato-frontal tract showed higher FA associated with antidepressant effects (estimate = -2.14 ± 0.72, p = 0.003), and tDCS differed only from the placebo group. For the right uncinate, the tDCS group lower AD values were associated with higher HDRS decrease (estimate = -1.45 ± 0.67, p = 0.031). Abnormalities in white matter MDD-related areas are associated with tDCS antidepressant effects. Suggested better white matter microstructure of the left prefrontal cortex was associated with tDCS antidepressant effects. Future studies should investigate whether these findings are driven by electric field diffusion and density in these areas.

The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a meta-analysis of 101 studies.

The importance of tryptophan as a precursor for neuroactive compounds has long been acknowledged. The metabolism of tryptophan along the kynurenine pathway and its involvement in mental disorders is an emerging area in psychiatry. We performed a meta-analysis to examine the differences in kynurenine metabolites in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ). Electronic databases were searched for studies that assessed metabolites involved in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, quinolinic acid, 3-hydroxykynurenine, and their associate ratios) in people with MDD, SZ, or BD, compared to controls. We computed the difference in metabolite concentrations between people with MDD, BD, or SZ, and controls, presented as Hedges' g with 95% confidence intervals. A total of 101 studies with 10,912 participants were included. Tryptophan and kynurenine are decreased across MDD, BD, and SZ; kynurenic acid and the kynurenic acid to quinolinic acid ratio are decreased in mood disorders (i.e., MDD and BD), whereas kynurenic acid is not altered in SZ; kynurenic acid to 3-hydroxykynurenine ratio is decreased in MDD but not SZ. Kynurenic acid to kynurenine ratio is decreased in MDD and SZ, and the kynurenine to tryptophan ratio is increased in MDD and SZ. Our results suggest that there is a shift in the tryptophan metabolism from serotonin to the kynurenine pathway, across these psychiatric disorders. In addition, a differential pattern exists between mood disorders and SZ, with a preferential metabolism of kynurenine to the potentially neurotoxic quinolinic acid instead of the neuroprotective kynurenic acid in mood disorders but not in SZ.

NLRP3 inflammasome-driven pathways in depression: Clinical and preclinical findings.

Over the past three decades, an intricate interaction between immune activation, release of pro-inflammatory cytokines and changes in brain circuits related to mood and behavior has been described. Despite extensive efforts, questions regarding when inflammation becomes detrimental or how we can target the immune system to develop new therapeutic strategies for the treatment of psychiatric disorders remain unresolved. In this context, novel aspects of the neuroinflammatory process activated in response to stressful challenges have recently been documented in major depressive disorder (MDD). The Nod-like receptor pyrin containing 3 inflammasome (NLRP3) is an intracellular multiprotein complex responsible for a number of innate immune processes associated with infection, inflammation and autoimmunity. Recent data have demonstrated that NLRP3 activation appears to bridge the gap between immune activation and metabolic danger signals or stress exposure, which are key factors in the pathogenesis of psychiatric disorders. In this review, we discuss both preclinical and clinical evidence that links the assembly of the NLRP3 complex and the subsequent proteolysis and release of the pro-inflammatory cytokines interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) in chronic stress models and patients with MDD. Importantly, we also focus on the therapeutic potential of targeting the NLRP3 inflammasome complex to improve stress resilience and depressive symptoms.

Treatment-resistant bipolar depression: concepts and challenges for novel interventions.

Treatment-resistant bipolar depression (TRBD) has been reported in about one-quarter of patients with bipolar disorders, and few interventions have shown clear and established effectiveness. We conducted a narrative review of the published medical literature to identify papers discussing treatment-resistant depression concepts and novel interventions for bipolar depression that focus on TRBD. We searched for potentially relevant English-language articles published in the last decade. Selected articles (based on the title and abstract) were retrieved for a more detailed evaluation. A number of promising new interventions, both pharmacological and non-pharmacological, are being investigated for TRBD treatment, including ketamine, lurasidone, D-cycloserine, pioglitazone, N-acetylcysteine, angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, cyclooxygenase 2 inhibitors, magnetic seizure therapy, intermittent theta-burst stimulation, deep transcranial magnetic stimulation, vagus nerve stimulation therapy, and deep brain stimulation. Although there is no consensus about the concept of TRBD, better clarification of the neurobiology associated with treatment non-response could help identify novel strategies. More research is warranted, mainly focusing on personalizing current treatments to optimize response and remission rates.

Social cognition and suicide-related behaviors in depression: a cross-sectional, exploratory study.

OBJECTIVE: To explore the association between social cognition and previous suicide attempts and non-suicidal self-injurious behavior in adults with unipolar depressive disorders. METHODS: Seventy-two patients undergoing outpatient treatment for unipolar depression were enrolled in this cross-sectional study. Theory of mind was assessed using the Hinting Task and the Revised Reading the Mind in the Eyes Test. Empathy was evaluated using the Interpersonal Reactivity Index. Lifetime suicide attempts and non-suicidal self-injurious behavior were assessed using the Columbia Suicide Risk Rating Scale. Participants with and without these suicide-related outcomes were compared in terms of social cognition. RESULTS: Patients with previous suicide attempts performed worse on the Reading the Mind in the Eyes Test (p = 0.017). Patients with a history of non-suicidal self-injurious behavior were younger (p = 0.005), had a younger age at first depressive episode (p = 0.017), and scored higher on personal distress in the Interpersonal Reactivity Index (p = 0.027). Only personal distress remained independently associated with non-suicidal self-injurious behavior in multivariable analysis (p = 0.038). CONCLUSION: Among patients with depression, those with previous suicide attempts or non-suicidal self-injurious behavior showed worse social cognition. These results encourage future research on social cognition deficits as clinical markers of suicide-related behaviors and as targets for interventions.

Cross-cultural adaptation and psychometric evaluation of the Brazilian version of the Temporal Experience of Pleasure Scale (TEPS-Br).

INTRODUCTION: Anhedonia is a critical symptom of major depressive disorder that is defined as the reduced ability to experience pleasure. The Temporal Experience of Pleasure Scale (TEPS) is commonly used to measure anhedonia and has exhibited satisfactory reliability. OBJECTIVES: We aim to perform cross-cultural adaptation of a Brazilian version of the TEPS and evaluate its psychometric properties. METHOD: The cross-cultural adaptation was performed according to previously established protocols. Cronbach's alpha coefficient of internal consistency was used to establish the degree of interrelation and coherence of items. Also, we calculated the intraclass correlation coefficient to determine the stability of the scale after a proposed interval had elapsed and used exploratory factor analysis to evaluate the scale's factor structure and content validity. Principal component analysis was used to determine the factors to be retained in the factor model. RESULTS: The participants reported that the Brazilian version of the TEPS had good comprehensibility and applicability. The results revealed a statistically significant correlation between measures. The intraclass correlation coefficient calculated was significant. The Cronbach's alpha value calculated indicated that the scale's overall internal consistency was adequate. CONCLUSION: The Portuguese version of the TEPS scale proposed achieved good comprehensibility for the Brazilian population and its psychometric characteristics demonstrated good reliability and validity.

Emotional Stability and Anxiety Symptoms Differentiates People Leaving the Home Usually During the Covid-19 Pandemic.

Objective: The population's adhesion to measures to ensure social distancing represents a great management challenge in a pandemic context. Despite of evidence shown that social distancing is effective, lack of adherence still persists in many countries. Therefore, it is challenging to separate the effectiveness of government measures, from social distancing driven by personal initiatives. Theory: It is possible that the output of protective behaviors, such as adherence to protective measures and staying in social isolation, is influenced by individual characteristics, such as personality traits or symptoms of mental distress of anxiogenic nature. We hypothesized that individuals with more expressive symptoms of fear or anxiety would have a more protective behavioral tendency in terms of risk exposure, leaving less home during the pandemic. In contrast, individuals with greater emotional stability, as they feel more secure and with a lower perception of risk, could go out more often. Method: A total of 2709 individuals from all regions of Brazil participated in the study (mean age = 42 years; 2134 women). Correlation analysis was performed to investigate the relationships between personality traits according to the big five model and Psychopathological Symptoms (BSI). Then, correlation analysis was performed to investigate how people that go out often differ from people that stay at home, in both symptoms and personality traits. Finally, to investigate the predictors for going out usually, we use multiple regression analysis, using gender, marital status, level of education, and personality traits. Results: During the second wave of COVID-19 in Brazil, individuals with higher emotional stability tended to leave home more than those with more expressive levels of anxiogenic dysregulation. These results reinforce the role of both personality traits and psychopathological symptoms in prophylactic behavior during COVID-19 pandemics. Conclusions: Individuals with greater emotional stability were more likely to leave home during the second wave of COVID-19 than those with higher levels of anxiogenic dysregulation.

A narrative review on invasive brain stimulation for treatment-resistant depression.

While most patients with depression respond to pharmacotherapy and psychotherapy, about one-third will present treatment resistance to these interventions. For patients with treatment-resistant depression (TRD), invasive neurostimulation therapies such as vagus nerve stimulation, deep brain stimulation, and epidural cortical stimulation may be considered. We performed a narrative review of the published literature to identify papers discussing clinical studies with invasive neurostimulation therapies for TRD. After a database search and title and abstract screening, relevant English-language articles were analyzed. Vagus nerve stimulation, approved by the U.S. Food and Drug Administration as a TRD treatment, may take several months to show therapeutic benefits, and the average response rate varies from 15.2-83%. Deep brain stimulation studies have shown encouraging results, including rapid response rates (> 30%), despite conflicting findings from randomized controlled trials. Several brain regions, such as the subcallosal-cingulate gyrus, nucleus accumbens, ventral capsule/ventral striatum, anterior limb of the internal capsule, medial-forebrain bundle, lateral habenula, inferior-thalamic peduncle, and the bed-nucleus of the stria terminalis have been identified as key targets for TRD management. Epidural cortical stimulation, an invasive intervention with few reported cases, showed positive results (40-60% response), although more extensive trials are needed to confirm its potential in patients with TRD.

Brazilian Psychiatric Association guidelines for the management of suicidal behavior. Part 1. Risk factors, protective factors, and assessment.

Suicide is a global public health problem that causes the loss of more than 800,000 lives each year, principally among young people. In Brazil, the average mortality rate attributable to suicide is approximately 5.23 per 100,000 population. Although many guidelines have been published for the management of suicidal behavior, to date, there are no recent guidelines based on the principles of evidence-based medicine that apply to the reality of suicide in Brazil. The objective of this work is to provide key guidelines for managing patients with suicidal behavior in Brazil. This project involved 11 Brazilian psychiatry professionals selected by the Psychiatric Emergencies Committee (Comissão de Emergências Psiquiátricas) of the Brazilian Psychiatric Association for their experience and knowledge in psychiatry and psychiatric emergencies. For the development of these guidelines, 79 articles were reviewed (from 5,362 initially collected and 755 abstracts). In this review, we present definitions, risk and protective factors, assessments, and an introduction to the Safety Plan. Systematic review registry number: CRD42020206517.

Stigma toward individuals with mental disorders among Brazilian psychiatrists: a latent class analysis.

OBJECTIVE: The stigma toward individuals with mental disorders is highly prevalent, not only in the general population but among health care providers as well. The aim of this study was to identify subgroups based on stigmatizing beliefs related to psychiatric disorders among Brazilian psychiatrists, as well as to investigate their association with clinical and personality characteristics. METHODS: Latent cluster analysis was used to find subgroups of cases in multivariate data according to a psychotic (schizophrenia) and a nonpsychotic disorder (attention-deficit hyperactivity disorder). The clusters for each psychiatric disorder were compared according to sociodemographic, emotional traits, and personality characteristics. RESULTS: A total of 779 psychiatrists answered the questionnaire. Three different subgroups of stigma levels were identified regarding schizophrenia: the highest (n=202 [51.7%]), intermediate (108 [27.6%]), and the lowest (81 [20.7%]). Participants from the highest stigma group had a significantly longer time since graduation, higher anxiety-state scores, and lower positive affect. Two subgroups were identified with respect to attention-deficit hyperactivity disorder, although there were no differences between them in sociodemographic or clinical variables. CONCLUSION: There were more subgroups of stigmatizing beliefs regarding psychotic disorders. Individual characteristics, such as those related to trait anxiety and affect, can be associated with high stigma toward schizophrenia.

Neurobiology of COVID-19: how can the virus affect the brain?

Severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19), which has been declared a public health emergency of international interest, with confirmed cases in most countries. COVID-19 presents manifestations that can range from asymptomatic or mild infections up to severe manifestations that lead to hospitalization and death. A growing amount of evidence indicates that the virus may cause neuroinvasion. Postmortem brain study findings have included edema, hemorrhage, hydrocephalus, atrophy, encephalitis, infarcts, swollen axons, myelin loss, gliosis, neuronal satellitosis, hypoxic-ischemic damage, arteriolosclerosis, leptomeningeal inflammation, neuronal loss, and axon degeneration. In addition, the COVID-19 pandemic is causing dangerous effects on the mental health of the world population, some of which can be attributed to its social impact (social distancing, financial issues, and quarantine). There is also a concern that environmental stressors, enhanced by psychological factors, are contributing to the emergence of psychiatric outcomes during the pandemic. Although clinical studies and diagnosing SARS-CoV-2-related neurological disease can be challenging, they are necessary to help define the manifestations and burden of COVID-19 in neurological and psychiatric symptoms during and after the pandemic. This review aims to present the neurobiology of coronavirus and postmortem neuropathological hallmarks.

Brazilian Psychiatric Association guidelines for the management of suicidal behavior. Part 2. Screening, intervention, and prevention.

This article continues our presentation of the Brazilian Psychiatric Association guidelines for the management of patients with suicidal behavior, with a focus on screening, intervention, postvention, prevention, and promotion. For the development of these guidelines, we conducted a systematic review of the MEDLINE (via PubMed), Cochrane Database of Systematic Reviews, Web of Science, and SciELO databases for research published from 1997 to 2020. Systematic reviews, clinical trials, and cohort/observational studies on screening, intervention, and prevention in suicidal behavior were included. This project involved 14 Brazilian psychiatry professionals and 1 psychologist selected by the Psychiatric Emergencies Committee of the Brazilian Psychiatric Association for their experience and knowledge in psychiatry and psychiatric emergencies. Publications were evaluated according to the 2011 Oxford Center for Evidence-Based Medicine (OCEBM) Levels of Evidence Classification. Eighty-five articles were reviewed (of 5,362 initially collected and 755 abstracts on the drug approach). Forms of screening, intervention, and prevention are presented. The intervention section presents evidence for psychotherapeutic and drug interventions. For the latter, it is important to remember that each medication is effective only for specific groups and should not replace treatment protocols. We maintain our recommendation for the use of universal screening plus intervention. Although the various studies differ in terms of the populations evaluated and several proposals are presented, there is already significant evidence for certain interventions. Suicidal behavior can be analyzed by evidence-based medicine protocols. Currently, the best strategy is to combine several techniques through the Safety Plan. Nevertheless, further research on the topic is needed to elucidate some approaches with particular potential for intervention and prevention. Systematic review registry number: CRD42020206517.

Association Between Prematurity and Diagnosis of Neurodevelopment Disorder: A Case-Control Study.

The aim of this study is to investigate the association between prematurity and diagnosis of neurodevelopmental disorders (ND) (attention deficit/hyperactivity disorder [ADHD] or autism spectrum disorder [ASD]) in Brazilian children and adolescents. Case-control study based on medical records data from a specialized outpatient clinic. Prematurity was defined as gestational age less than 37 weeks. Prematurity was independently associated with diagnosis of a ND (adjusted odds ratio [AOR] 3.46, 95% CI 1.15 - 7.92), as well as with ADHD and ASD diagnosis after a multiple logistic regression analysis. These findings from Brazilian patients are related to what is found in the literature worldwide. Efforts to modify risk factors, such as prematurity, may impact incidence reduction of both ADHD and ASD.

Neurobiology of bipolar disorders: a review of genetic components, signaling pathways, biochemical changes, and neuroimaging findings.

Bipolar disorder (BD) is a chronic mental illness characterized by changes in mood that alternate between mania and hypomania or between depression and mixed states, often associated with functional impairment. Although effective pharmacological and non-pharmacological treatments are available, several patients with BD remain symptomatic. The advance in the understanding of the neurobiology underlying BD could help in the identification of new therapeutic targets as well as biomarkers for early detection, prognosis, and response to treatment in BD. In this review, we discuss genetic, epigenetic, molecular, physiological and neuroimaging findings associated with the neurobiology of BD. Despite the advances in the pathophysiological knowledge of BD, the diagnosis and management of the disease are still essentially clinical. Given the complexity of the brain and the close relationship between environmental exposure and brain function, initiatives that incorporate genetic, epigenetic, molecular, physiological, clinical, environmental data, and brain imaging are necessary to produce information that can be translated into prevention and better outcomes for patients with BD.

At-risk drinking and current cannabis use among medical students: a multivariable analysis of the role of personality traits.

OBJECTIVE: To explore the role of personality traits in at-risk drinking and current cannabis use among medical students. METHODS: This cross-sectional study evaluated 707 medical students from two universities. Multiple logistic regression models for at-risk drinking and current cannabis use were constructed including sociodemographic, psychiatric, and personality variables. RESULTS: At-risk drinking and current cannabis use were reported by 19.3% and 14.9% of participants, respectively. Models including Big Five measures showed associations of at-risk drinking with higher extraversion (p < 0.00001, adjusted odds ratio [AOR] = 1.9) and lower conscientiousness (p = 0.00001, AOR = 0.5); cannabis use was also associated with lower conscientiousness (p = 0.003, AOR = 0.6), besides higher openness to experience (p = 0.002, AOR = 1.9). Models including measures of the Behavioral Inhibition and Activation Systems scales (BIS/BAS) showed associations of at-risk drinking with lower BIS (p = 0.002, AOR = 0.9) and higher BAS fun-seeking (p = 0.0005, AOR = 1.2); cannabis use was also associated with higher BAS fun-seeking (p = 0.008, AOR = 1.2). Personality variables had modest effects on model fit. CONCLUSION: Specific personality traits were independently associated with at-risk drinking and current cannabis use, albeit with modest effect sizes.

Difficulties in activities of daily living are associated with stigma in patients with Parkinson's disease who are candidates for deep brain stimulation.

OBJECTIVE: Parkinson's disease (PD) is often accompanied by stigma, which could contribute to a worse prognosis. The objective of this study is to identify the variables associated with stigma in PD patients who are candidates for deep brain stimulation (DBS). METHODS: We investigated sociodemographic and clinical variables associated with stigma in a sample of 54 PD patients indicated for DBS. The independent variables were motor symptoms assessed by the Movement Disorder Society-sponsored revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS III), depressive symptoms measured by the Hospital Anxiety and Depression Scale, age, disease duration and the presence of a general medical condition. The Mobility, Activities of daily living and Emotional well-being domains of the 39-item Parkinson's Disease Questionnaire (PDQ-39) were also investigated as independent variables, and the Stigma domain of the PDQ-39 scale was considered the outcome variable. RESULTS: After multiple linear regression analysis, activities of daily living remained associated with the Stigma domain (B = 0.42 [95%CI 0.003-0.83], p = 0.048). The full model accounted for 15% of the variance in the Stigma domain (p = 0.03). CONCLUSIONS: Although causal assumptions are not appropriate for cross-sectional studies, the results suggest that ADL difficulties could contribute to greater stigma in PD patients with refractory motor symptoms who are candidates for DBS.

Brazilian guidelines for the management of psychomotor agitation. Part 2. Pharmacological approach.

OBJECTIVE: To present the essential guidelines for pharmacological management of patients with psychomotor agitation in Brazil. METHODS: This is a systematic review of articles retrieved from the MEDLINE (PubMed), Cochrane Database of Systematic Reviews, and SciELO databases published from 1997 to 2017. Other relevant articles in the literature were also used to develop these guidelines. The search strategy used structured questions formulated using the PICO model, as recommended by the Guidelines Project of the Brazilian Medical Association. Recommendations were summarized according to their level of evidence, which was determined using the Oxford Centre for Evidence-based Medicine system and critical appraisal tools. RESULTS: Of 5,362 articles retrieved, 1,731 abstracts were selected for further reading. The final sample included 74 articles that met all inclusion criteria. The evidence shows that pharmacologic treatment is indicated only after non-pharmacologic approaches have failed. The cause of the agitation, side effects of the medications, and contraindications must guide the medication choice. The oral route should be preferred for drug administration; IV administration must be avoided. All subjects must be monitored before and after medication administration. CONCLUSION: If non-pharmacological strategies fail, medications are needed to control agitation and violent behavior. Once medicated, the patient should be monitored until a tranquil state is possible without excessive sedation. SYSTEMATIC REVIEW REGISTRY NUMBER: CRD42017054440.

Brazilian guidelines for the management of psychomotor agitation. Part 1. Non-pharmacological approach.

OBJECTIVE: To present the essential guidelines for non-pharmacological management of patients with psychomotor agitation in Brazil. METHODS: These guidelines were developed based on a systematic review of articles published from 1997 to 2017, retrieved from MEDLINE (PubMed), Cochrane Database of Systematic Review, and SciELO. Other relevant articles identified by searching the reference lists of included studies were also used to develop these guidelines. The search strategy used structured questions formulated using the PICO model, as recommended by the Guidelines Project of the Brazilian Medical Association. Recommendations were summarized according to their level of evidence, which was determined using the Oxford Centre for Evidence-based Medicine system and critical appraisal tools. RESULTS: We initially selected 1,731 abstracts among 5,362 articles. The final sample included 104 articles that fulfilled all the inclusion criteria. The management of agitated patients should always start with the least coercive approach. The initial non-pharmacological measures include a verbal strategy and referral of the patient to the appropriate setting, preferably a facility designed for the care of psychiatric patients with controlled noise, lighting, and safety aspects. Verbal de-escalation techniques have been shown to decrease agitation and reduce the potential for associated violence in the emergency setting. The possibility of underlying medical etiologies must be considered first and foremost. Particular attention should be paid to the patient's appearance and behavior, physical signs, and mental state. If agitation is severe, rapid tranquilization with medications is recommended. Finally, if verbal measures fail to contain the patient, physical restraint should be performed as the ultimate measure for patient protection, and always be accompanied by rapid tranquilization. Healthcare teams must be thoroughly trained to use these techniques and overcome difficulties if the verbal approach fails. It is important that healthcare professionals be trained in non-pharmacological management of patients with psychomotor agitation as part of the requirements for a degree and graduate degree. CONCLUSION: The non-pharmacological management of agitated patients should follow the hierarchy of less invasive to more invasive and coercive measures, starting with referral of the patient to an appropriate environment, management by a trained team, use of verbal techniques, performance of physical and mental assessment, use of medications, and, if unavoidable, use of the mechanical restraint. SYSTEMATIC REVIEW REGISTRY NUMBER: CRD42017054440.

Treatment-resistant bipolar depression: concepts and challenges for novel interventions

Treatment-resistant bipolar depression (TRBD) has been reported in about one-quarter of patients with bipolar disorders, and few interventions have shown clear and established effectiveness. We conducted a narrative review of the published medical literature to identify papers discussing treatment-resistant depression concepts and novel interventions for bipolar depression that focus on TRBD. We searched for potentially relevant English-language articles published in the last decade. Selected articles (based on the title and abstract) were retrieved for a more detailed evaluation. A number of promising new interventions, both pharmacological and non-pharmacological, are being investigated for TRBD treatment, including ketamine, lurasidone, D-cycloserine, pioglitazone, N-acetylcysteine, angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, cyclooxygenase 2 inhibitors, magnetic seizure therapy, intermittent theta-burst stimulation, deep transcranial magnetic stimulation, vagus nerve stimulation therapy, and deep brain stimulation. Although there is no consensus about the concept of TRBD, better clarification of the neurobiology associated with treatment non-response could help identify novel strategies. More research is warranted, mainly focusing on personalizing current treatments to optimize response and remission rates.