The role of polyunsaturated fatty acids in the neurobiology of major depressive disorder and suicide risk.

Long-chain polyunsaturated fatty acids (LC-PUFAs) are obtained from diet or derived from essential shorter-chain fatty acids, and are crucial for brain development and functioning. Fundamentally, LC-PUFAs' neurobiological effects derive from their physicochemical characteristics, including length and double bond configuration, which differentiate LC-PUFA species and give rise to functional differences between n(omega)-3 and n-6 LC-PUFAs. LC-PUFA imbalances are implicated in psychiatric disorders, including major depression and suicide risk. Dietary intake and genetic variants in enzymes involved in biosynthesis of LC-PUFAs from shorter chain fatty acids influence LC-PUFA status. Domains impacted by LC-PUFAs include 1) cell signaling, 2) inflammation, and 3) bioenergetics. 1) As major constituents of lipid bilayers, LC-PUFAs are determinants of cell membrane properties of viscosity and order, affecting lipid rafts, which play a role in regulation of membrane-bound proteins involved in cell-cell signaling, including monoaminergic receptors and transporters. 2) The n-3:n-6 LC-PUFA balance profoundly influences inflammation. Generally, metabolic products of n-6 LC-PUFAs (eicosanoids) are pro-inflammatory, while those of n-3 LC-PUFAs (docosanoids) participate in the resolution of inflammation. Additionally, n-3 LC-PUFAs suppress microglial activation and the ensuing proinflammatory cascade. 3) N-3 LC-PUFAs in the inner mitochondrial membrane affect oxidative stress, suppressing production of and scavenging reactive oxygen species (ROS), with neuroprotective benefits. Until now, this wealth of knowledge about LC-PUFA biomechanisms has not been adequately tapped to develop translational studies of LC-PUFA clinical effects in humans. Future studies integrating neurobiological mechanisms with clinical outcomes may suggest ways to identify depressed individuals most likely to respond to n-3 LC-PUFA supplementation, and mechanistic research may generate new treatment strategies.

Nutritional counselling in adults promoting adherence to the Mediterranean diet as adjuvant in the treatment of major depressive disorder (INDEPT): a randomized open controlled trial study protocol.

BACKGROUND: Major Depressive Disorder (MDD) is a leading cause of disability worldwide. Approximately one-third of patients with MDD do not respond to treatment, and often exhibit elevated inflammation biomarkers, which are associated with worse prognosis. Previous research has linked healthier dietary patterns, such as the Mediterranean Diet (MedDiet), with a lower risk of MDD and symptoms of depression, potentially due to their anti-inflammatory properties. The aim of this study is to evaluate the effectiveness of a nutritional counselling intervention promoting MedDiet to alleviate symptoms of depression in adults recently diagnosed with MDD and presenting with elevated inflammation biomarkers. METHODS: This study is a randomized controlled trial (RCT) that will recruit adults from outpatient clinics, between the ages of 18 and 70 years who have been diagnosed with MDD and are currently receiving treatment with the first prescribed antidepressant, and who exhibit elevated inflammation biomarkers (interleukin-6 and/or C-reactive protein). The control group will receive treatment-as-usual (TAU) only. The primary outcome of the study will be the change in symptoms of depression, as measured by the Beck Depression Inventory 2 (BDI-II), after 12 weeks of intervention. Data analysis will follow an intention-to-treat approach. Secondary outcomes will include changes in inflammation biomarkers, quality of life, adherence to the MedDiet, and cost-effectiveness of nutritional counselling. All outcomes will be assessed at baseline, after the 12-week intervention, and at 6- and 12-months post-baseline. DISCUSSION: This study will be the first RCT to evaluate the effect of a nutritional intervention with anti-inflammatory properties, as an adjuvant in the treatment of MDD, in individuals diagnosed with MDD and elevated inflammation biomarkers. The results of this study may contribute to the development of more effective and personalized interventions for MDD patients with elevated inflammation biomarkers.

Communication skills in psychiatry for undergraduate students: A scoping review.

Communication skills are paramount in all areas of medicine but particularly in psychiatry due to the challenges posed by mental health patients and the essential role of communication from diagnosis to treatment. Despite the prevalence of psychiatric disorders in different medical specialties, particularly in primary care settings, communication skills in psychiatry and their training are not well studied and are often not included in the undergraduate medical curriculum. Our paper explores the relevance of teaching communication competencies in psychiatry for undergraduate medical students. Our work focused on reviewing the methods for teaching communication skills to undergraduate students in Psychiatry. Eleven studies were selected to be included in this review. We found considerable heterogeneity among methods for teaching communication skills but also some common elements such as the use of simulated patients and providing feedback. This review has identified two models: the Calgary-Cambridge interview model and the Kolb cycle-based model. However, most studies still lack a theoretical background model. We believe that the inclusion of communication skills training in medical curricula is fundamental to teaching medical students general communication skills but also specific training on establishing adequate communication with psychiatric patients. However, more research is needed to determine the best method for training but also regarding its translation to patient care and cost-effectiveness.

Suicide Attempt in a Patient with Sibutramine Associated Psychosis.

Sibutramine is a serotonin-norepinephrine-dopamine reuptake inhibitor, initially developed as a potential antidepressant and later approved for the management of obesity. Sibutramine use is also associated with psychiatric symptoms, namely mania, panic attacks, and, less frequently, psychosis. We report the case of a 32-year-old man, admitted to our hospital due to a suicide attempt in the context of sibutramine-associated psychosis. The symptoms remitted completely after discontinuation of sibutramine and a brief period of antipsychotic medication. The aim of this manuscript is to highlight the importance of the recognition of sibutramine-associated psychosis, to discuss the possible pathophysiology and the proper clinical and therapeutic management.

A sibutramina é um inibidor não seletivo da recaptação de serotonina-noradrenalina-dopamina, inicialmente desenvolvido como potencial antidepressivo e posteriormente aprovado para o tratamento da obesidade. O uso de sibutramina está também associado ao aparecimento de sintomas psiquiátricos como mania, ataques de pânico e, com menor frequência, psicose. Relatamos um caso de um homem de 32 anos, internado no nosso hospital devido a uma tentativa de suicídio no contexto de uma psicose associada à sibutramina. Os sintomas remitiram completamente após a descontinuação da sibutramina e um breve período de terapêutica antipsicótica. O objetivo deste artigo é destacar a importância do reconhecimento da psicose associada à sibutramina, discutir a sua possível fisiopatologia e o seu apropriado manejo clínico e terapêutico.

Relationships between inflammatory markers and suicide risk status in major depression.

Pro-inflammatory status has been implicated in depression and suicidal behaviors. Polyunsaturated fatty acids (PUFAs) and cytokines, two types of inflammatory biomarkers, have been associated with suicide, independent of depression severity. How these biomarkers relate to each other is less clear. We measured plasma phospholipid levels of arachidonic acid (AA%), docosahexaenoic acid (DHA%), and eicosapentaenoic acid (EPA%) as a percentage of total phospholipids, as well as serum interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and tumor necrosis factor α (TNF-α), in 80 patients with major depressive disorder (MDD) and 24 healthy controls (HC). Individual PUFA and cytokine species were compared using ANOVA across four suicide risk-stratified groups: 1) highest-risk, recent (within 5 years) suicide attempters (n = 20); 2) high-risk, severe current suicidal ideators (having intent or plan) with no recent attempt history (n = 22); 3) low-risk, current non-ideators who were also lifetime non-attempters (n = 38); and 4) HC (n = 24). None of the participants were enrolled following an acute suicide attempt. Of biomarkers studied, only DHA% (p = 0.012) and IL-1ß (p = 0.002) differed between groups. In post-hoc testing, DHA% was lower in attempters than ideators (p = 0.018) or MDD non-ideators (trend level, p = 0.073). IL-1ß was lowest in attempters, differentiating them from ideators (p = 0.009) and HC (p = 0.004). Recent suicide attempt, one of the most powerful predictors of suicide risk, was also most closely tied to inflammatory indices in this study. Low DHA% as an indicator of suicide risk is consistent with previous reports; however, lower IL-1ß was unexpected and may relate to acuity/chronicity of inflammation. There is a need for prospective studies of immune status with respect to suicidal behaviors.

Lipid correlates of antidepressant response to omega-3 polyunsaturated fatty acid supplementation: A pilot study.

Low omega-3 polyunsaturated fatty acid (PUFA) levels are seen in major depression. We examined effects of six weeks of fish oil supplementation on clinical characteristics in 16 patients with symptomatic major depressive disorder, and tested plasma phospholipid levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) as correlates of clinical response. Depression symptoms improved after supplementation (p=0.007). The reduction in depression severity was not predicted by baseline PUFA levels but did exhibit a relationship with endpoint PUFAs, correlating negatively with DHA as a percentage of plasma phospholipids (DHA%; R2=0.60, p=0.004), adjusting for endpoint EPA%; and correlating positively with endpoint EPA% (R2=0.58, p=0.007), adjusting for endpoint DHA%. Thus, the higher the proportion of DHA to EPA, the greater the reduction in depression severity (r=-0.43, p=0.097). Five patients showed a decrease of >50% on the 17-item Hamilton Depression Rating Scale and a final score <7 and were thus not only responders but met standard criteria for remission, and were distinguished from non-responders by higher levels of DHA% (p=0.03). This pilot study suggests that post-supplementation DHA% levels may be a necessary target for antidepressant response to fish oil, and that this may depend to some extent on the efficacy of EPA conversion to DHA.

Lisdexamfetamine in the treatment of moderate-to-severe binge eating disorder in adults: systematic review and exploratory meta-analysis of publicly available placebo-controlled, randomized clinical trials.

BACKGROUND: Preliminary placebo-controlled evidence paved the ground to the US Food and Drug Administration approval extension of lisdexamfetamine for the treatment of moderate-to-severe binge eating disorder (BED) in adults. OBJECTIVES: To provide a preliminary qualitative and quantitative synthesis of the placebo-controlled, randomized clinical trials (RCTs) considering the efficacy and tolerability of lisdexamfetamine in the acute and/or maintenance treatment of moderate-to-severe BED in adults. METHODS: A preliminary, yet comprehensive, systematic review was performed by accessing a broad range of resources providing publicly available data about lisdexamfetamine at the time of inquiry (March 2016). Study eligibility criteria, participants, and interventions were considered focusing on major clinical and functional outcomes of either efficacy or tolerability of lisdexamfetamine in the treatment of moderate-to-severe BED in adults. RESULTS: Meta-analysis of data pooled from three acute RCTs significantly favored lisdexamfetamine over placebo in the reduction of binge eating days/week, Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating total score, weight, response, and remission rates (all, P≤0.01). In contrast, discontinuation rates due to treatment-emergent adverse events were significantly higher among patients in receipt of lisdexamfetamine (relative risk 2.19, P=0.04) versus placebo. LIMITATIONS: Publication, selection, performance, attrition, reporting, sponsorship, and "diagnostic shift" biases. Lack of inclusion of adverse event effects other than those requiring discontinuation of the trial(s), as well as lack of information about clinically relevant psychiatric or other medical comorbidities, limits the overall generalizability of pooled results. CONCLUSION: Across the included acute phase RCTs, lisdexamfetamine (at 30, 50, or 70 mg/day) led to significant reduction in a number of clinically relevant outcomes compared to placebo. Moreover, safety concerns related to adverse events, high discontinuation rates, and the need for additional long-term maintenance of RCTs solicit careful monitoring of the drug in terms of overall safety and tolerability by further RCTs.

Atypical Antipsychotics in the Treatment of Acute Bipolar Depression with Mixed Features: A Systematic Review and Exploratory Meta-Analysis of Placebo-Controlled Clinical Trials.

Evidence supporting the use of second generation antipsychotics (SGAs) in the treatment of acute depression with mixed features (MFs) associated with bipolar disorder (BD) is scarce and equivocal. Therefore, we conducted a systematic review and preliminary meta-analysis investigating SGAs in the treatment of acute BD depression with MFs. Two authors independently searched major electronic databases from 1990 until September 2015 for randomized (placebo-) controlled trials (RCTs) or open-label clinical trials investigating the efficacy of SGAs in the treatment of acute bipolar depression with MFs. A random-effect meta-analysis calculating the standardized mean difference (SMD) between SGA and placebo for the mean baseline to endpoint change in depression as well as manic symptoms score was computed based on 95% confidence intervals (CI). Six RCTs and one open-label placebo-controlled studies (including post-hoc reports) representing 1023 patients were included. Participants received either ziprasidone, olanzapine, lurasidone, quetiapine or asenapine for an average of 6.5 weeks across the included studies. Meta-analysis with Duval and Tweedie adjustment for publication bias demonstrated that SGA resulted in significant improvements of (hypo-)manic symptoms of bipolar mixed depression as assessed by the means of the total scores of the Young Mania Rating Scale (YMRS) (SMD -0.74, 95% CI -1.20 to -0.28, n SGA = 907, control = 652). Meta-analysis demonstrated that participants in receipt of SGA (n = 979) experienced a large improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) scores (SMD -1.08, 95% CI -1.35 to -0.81, p < 0.001) vs. placebo (n = 678). Publication and measurement biases and relative paucity of studies. Overall, SGAs appear to offer favorable improvements in MADRS and YMRS scores vs. placebo. Nevertheless, given the preliminary nature of the present report, additional original studies are required to allow more reliable and clinically definitive conclusions.

The role of cytokines in the pathophysiology of suicidal behavior.

OBJECTIVE: Immune dysregulation has been implicated in depression and other psychiatric disorders. What is less clear is how immune dysregulation can affect risk of suicidal behavior. We reviewed the scientific literature concerning cytokines related to suicidal ideation, suicidal behavior and suicide, and surveyed clinical and neurobiological factors associated with cytokine levels that may modulate effects of inflammation on suicide risk. METHODS: We searched PubMed, Embase, Scopus and PsycINFO for relevant studies published from 1980 through February, 2015. Papers were included if they were written in English and focused on cytokine measurements in patients with suicidal behaviors. RESULTS: The literature search yielded 22 studies concerning cytokines and suicidal ideation, suicide attempts or suicide completion. The most consistent finding was elevated interleukin (IL)-6, found in 8 out of 14 studies, in CSF, blood, and postmortem brain. In one study, IL-6 in CSF was also found to be higher in violent than nonviolent attempters and to correlate with future suicide completion. Low plasma IL-2 was observed in 2 studies of suicide attempters, while divergent results were seen for tumor necrosis factor (TNF)-α, interferon (IFN)-γ, transforming growth factor (TGF)-ß, IL-4, and soluble Il-2 receptors. CONCLUSIONS: Given the complexity suggested by the heterogenous cytokine findings, putative mediators and moderators of inflammation on suicidal behavior merit further study. Elevated IL-6 was the most robust cytokine finding, associated with suicidal ideation and both nonfatal suicide attempts and suicides. Future studies should evaluate the predictive value of high IL-6, consider how this may alter brain function to impact suicidal behavior, and explore the potential beneficial effects of reducing IL-6 on suicide risk.