Exploring the association of interleukin polymorphisms with aggression and internalizing behaviors in children and adolescents.

BACKGROUND: There is growing evidence that inflammation influences mental health. Blood interleukin levels, which regulate inflammation, have been linked to aggression and internalizing behaviors. We performed a hypothesis-driven genetic study to (1) evaluate the association of IL1B, IL2, and IL6 gene variants with aggression and internalizing behaviors and (2) explore gene-environment interactions with childhood adversity in a deeply phenotyped childhood-onset aggression sample including 255 cases and 226 controls of European ancestry. METHODS: We evaluated the association of putative functional and tag SNPs within IL1B, IL2, and IL6 with aggression case status, parent-reported internalizing problems, self-reported anxiety symptoms, and self-reported depressive symptoms in our sample. We also performed exploratory GxE analyses within cases, testing for statistical interaction between interleukin SNP genotype and childhood adversity for depressive symptoms. RESULTS: No significant association was observed between any of the interleukin SNPs and childhood-onset aggression. We observed association of IL6 variant rs2069827 with depressive symptoms (p = 7.15×10-4 ), and trends for an interaction between severe childhood adversity and SNPs in IL1B and IL2 for depressive symptoms. CONCLUSIONS: Our findings provide preliminary evidence that common variation in IL6 may be associated with depressive symptoms in children and adolescents, and that common variation in interleukin genes may sensitize individuals to the depressogenic effects of traumatic life experiences. Replication in independent samples is needed.

Gene-drug pairings for antidepressants and antipsychotics: level of evidence and clinical application.

Substantial inter-individual discrepancies exist in both therapeutic effectiveness and adverse effects of antidepressant and antipsychotic medications, which can, in part, be explained by genetic variation. Here, we searched the Pharmacogenomics Knowledge Base for gene-antidepressant and gene-antipsychotic pairs with the highest level of evidence. We then extracted and compared the associated prescribing recommendations for these pairs developed by the Clinical Pharmacogenomics Implementation Consortium, the Dutch Pharmacogenetics Working Group or approved product labels in the US, Canada, Europe, and Asia. Finally, we highlight key economical, educational, regulatory, and ethical issues that, if not appropriately considered, can hinder the implementation of these recommendations in clinical practice. Our review indicates that evidence-based guidelines are available to assist with the implementation of pharmacogenetic-guided antidepressant and antipsychotic prescribing, although the maximum impact of these guidelines on patient care will not be realized until key barriers are minimized or eliminated.

Collaborating with individuals with lived experience to adapt CANMAT clinical depression guidelines into a patient treatment guide: The CHOICE-D co-design process.

Effective treatment of depression involves collaboration with informed patients and families and appropriate knowledge sharing. We describe here our experience, as a case example, of a collaboration to "translate" a clinical guideline designed for practitioners into an accessible, plainlanguage version that patients and families can use during the care process, both to provide basic educational information and to foster informed discussions with their treatment providers. Content experts in knowledge translation, patient advocacy, patient-oriented research, and psychiatry guided overall project design. Our first step was to identify lived experience writers to join in the codesign and co-writing of the "CHOICE-D Patient and Family Guide to Depression Treatment." A national call for writers attracted 62 applicants, from whom eight individuals with lived experience of depression and writing experience were selected. Individuals subsequently attended a welcoming teleconference, followed by a 1-day workshop designed to provide (a) a detailed overview of the clinician guideline, (b) an opportunity to select what should be included in the Guide, and (c) key principles of knowledge translation/lay writing. Both from the workshop and subsequently through the codesign process, lived experience writers recommended that the Guide address symptoms, effects of illness course on treatment, first-line treatments, safety/side effects, and treatment misconceptions. To promote patient autonomy, question scripts (how and what to ask your treatment provider), self-triaging resources, and treatment selection aids were suggested. Stylistic considerations included use of simple yet hopeful language, brevity, white space, key terms glossary, and graphics. Several strategies were particularly useful to optimize writer engagement in the codesign process: a pre-workshop conference call and circulation of project resources, an in-person workshop to increase content knowledge, structured discussion with co-writers and project leads to develop ideas, and practical training exercises with the provision of feedback. Both during and at the end of the project, writers provided additional recommendations for improving the process, including more in-person meetings, distribution of step-by-step instructions on the writing task, and a key terms glossary of technical terms to support their role. In conclusion, we describe a process with practical tips and reflective feedback on important considerations for engaging persons with lived experience as leaders in the codesign and writing process of lay treatment guidelines. These methods may serve as a model for similar projects in other areas of healthcare.

The utility of artificial intelligence in suicide risk prediction and the management of suicidal behaviors.

OBJECTIVE: Suicide is a growing public health concern with a global prevalence of approximately 800,000 deaths per year. The current process of evaluating suicide risk is highly subjective, which can limit the efficacy and accuracy of prediction efforts. Consequently, suicide detection strategies are shifting toward artificial intelligence platforms that can identify patterns within 'big data' to generate risk algorithms that can determine the effects of risk (and protective) factors on suicide outcomes, predict suicide outbreaks and identify at-risk individuals or populations. In this review, we summarize the role of artificial intelligence in optimizing suicide risk prediction and behavior management. METHODS: This paper provides a general review of the literature. A literature search was conducted in OVID Medline, EMBASE and PsycINFO databases with coverage from January 1990 to June 2019. Results were restricted to peer-reviewed, English-language articles. Conference and dissertation proceedings, case reports, protocol papers and opinion pieces were excluded. Reference lists were also examined for additional articles of relevance. RESULTS: At the individual level, prediction analytics help to identify individuals in crisis to intervene with emotional support, crisis and psychoeducational resources, and alerts for emergency assistance. At the population level, algorithms can identify at-risk groups or suicide hotspots, which help inform resource mobilization, policy reform and advocacy efforts. Artificial intelligence has also been used to support the clinical management of suicide across diagnostics and evaluation, medication management and behavioral therapy delivery. There could be several advantages of incorporating artificial intelligence into suicide care, which includes a time- and resource-effective alternative to clinician-based strategies, adaptability to various settings and demographics, and suitability for use in remote locations with limited access to mental healthcare supports. CONCLUSION: Based on the observed benefits to date, artificial intelligence has a demonstrated utility within suicide prediction and clinical management efforts and will continue to advance mental healthcare forward.

An examination of genes, stress and suicidal behavior in two First Nations communities: The role of the brain-derived neurotropic factor gene.

Suicide claims over 800,000 lives each year worldwide. Suicide rates in indigenous populations in Canada are about double that of the national average, making it a serious public health issue. Numerous factors are involved in suicide risk, including genetic factors, as well as various psychosocial stressors, such as historical experience with the Indian Residential School system for Indigenous populations, as well as protective variables such as social support. Here, we report the first genetic study of suicidal behaviors that includes multiple measures of stress and social supports. We investigated the role of the functional Val66Met marker (rs6265) in the Brain-Derived Neurotropic Factor (BDNF) gene in suicidal ideation and suicide attempt in a First Nations community sample (N = 278). We did not find a significant association between the BDNF rs6265 marker and suicidal behaviors. We found childhood adversities, recent life stress, chronic stress, perceived stress, difficulties, and hazardous alcohol use to be associated with both suicidal ideation and suicide attempt. Thus, while additional studies with larger samples are required to elucidate the genetic component of suicide, addressing environmental stressors may be important for suicide prevention.

Dimensional and Categorical Correlates of Substance Use Disorders among Canadian Adolescents with Bipolar Disorder.

OBJECTIVES: Despite increasing evidence of excessive substance use disorder (SUD) prevalence among adolescents with bipolar disorder (BP), little is known about this topic among Canadian adolescents with BP. We therefore sought to examine the clinical characteristics and dimensional measures of psychopathology associated with comorbid SUD among Canadian BP adolescents. METHOD: Participants were 100 adolescents, ages 13-19 years, with BP I, II, or not otherwise specified (NOS). Diagnoses (current and lifetime) were determined via the Schedule for Affective Disorders and Schizophrenia for School-Aged Children, Present and Lifetime version (KSADS-PL). Participants were considered to have lifetime SUD if they met DSM-IV criteria for abuse of or dependence on alcohol or any drug other than nicotine. Chi-square analyses and independent samples t-tests were followed by logistic regression analyses. RESULTS: The lifetime prevalence of SUD was 33% (primarily alcohol and cannabis use disorders). In univariate analyses, SUD was associated with greater lifetime prevalence of conduct disorder, oppositional defiant disorder, panic disorder, assault of others, and a greater number of stressful life events. SUD was significantly associated with greater self-reported impulsivity and parent-report of anger/depression in the adolescent. In multivariable analyses, SUD was associated with panic disorder and oppositional defiant disorder. CONCLUSION: SUD is highly prevalent among Canadian adolescents with BP and is associated with anxiety disorders, behavioural disorders, and trait impulsivity. Targeting these clinical characteristics may help guide preventative and treatment strategies for this population.

OBJECTIFS: Malgré des preuves croissantes de la prévalence excessive du trouble d'utilisation de substances (TUS) chez des adolescents souffrant de trouble bipolaire (TB), ce sujet est très peu connu des adolescents canadiens souffrant de TB. Nous avons donc cherché à examiner les caractéristiques cliniques et les mesures dimensionnelles de la psychopathologie associée au TUS comorbide chez les adolescents canadiens souffrant de TB. MÉTHODE: Les participants étaient 100 adolescents de 13 à 19 ans souffrant de TB I, II, ou non spécifié ailleurs (NSA). Les diagnostics (actuels et de durée de vie) ont été déterminés par le tableau des troubles affectifs et de la schizophrénie pour les enfants d'âge scolaire, version actuelle et de durée de vie (KSADS-PL). Les participants étaient évalués avoir un TUS de durée de vie s'ils satisfaisaient aux critères du DSM-IV en matière d'abus ou de dépendance à l'alcool ou à toute autre drogue que la nicotine. Les analyses chi-carré et les tests t d'échantillons indépendants ont été suivis d'analyses de régression logistique. RÉSULTATS: La prévalence de durée de vie du TUS était de 33 % (principalement des troubles d'utilisation d'alcool et de cannabis). Dans les analyses univariées, le TUS était associé à une prévalence de durée de vie plus marquée du trouble des conduites, du trouble oppositionnel avec provocation, du trouble panique, d'agression physique et d'un plus grand nombre d'événements de la vie stressants. Le TUS était significativement associé à une plus grande impulsivité auto-déclarée et à des rapports des parents sur la colère/dépression de l'adolescent. Dans les analyses multivariées, le TUS était associé au trouble panique et au du trouble oppositionnel avec provocation. CONCLUSION: Le TUS est hautement prévalent chez les adolescents canadiens souffrant de TB et est associé aux troubles anxieux, aux troubles du comportement, et à l'impulsivité. Cibler ces caractéristiques cliniques peut aider à guider l'élaboration de stratégies préventives et de traitement pour cette population.

Neuroimaging biomarkers as predictors of treatment outcome in Major Depressive Disorder.

BACKGROUND: Current practice for selecting pharmacological and non-pharmacological antidepressant treatments has yielded low response and remission rates in Major Depressive Disorder (MDD). Neuroimaging biomarkers of brain structure and function may be useful in guiding treatment selection by predicting response vs. non-response outcomes. METHODS: In this review, we summarize data from studies examining predictors of treatment response using structural and functional neuroimaging modalities, as they pertain to pharmacotherapy, psychotherapy, and stimulation treatment strategies. A literature search was conducted in OVID Medline, EMBASE, and PsycINFO databases with coverage from January 1990 to January 2017. RESULTS: Several imaging biomarkers of therapeutic response in MDD emerged: frontolimbic regions, including the prefrontal cortex, anterior cingulate cortex, hippocampus, amygdala, and insula were regions of interest. Since these sub-regions are implicated in the etiology of MDD, their association with response outcomes may be the result of treatments having a normalizing effect on structural or activation abnormalities. LIMITATIONS: The direction of findings is inconsistent in studies examining these biomarkers, and variation across 'biotypes' within MDD may account for this. Limitations in sample size and differences in methodology likely also contribute. CONCLUSIONS: The identification of accurate, reliable neuroimaging biomarkers of treatment response holds promise toward improving treatment outcomes and reducing burden of illness for patients with MDD. However, before these biomarkers can be translated into clinical practice, they will need to be replicated and validated in large, independent samples, and integrated with data from other biological systems.

Sirukumab: A Potential Treatment for Mood Disorders?

Convergent evidence indicates that abnormalities in the innate immune system may be pertinent to the pathogenesis, phenomenology, and possible treatment of several mental disorders. In keeping with this view, the targeting of interleukin-6 with the human monoclonal antibody sirukumab may represent a possible treatment and disease modification approach, for adults with brain-based disorders (e.g., major depressive disorder). A PubMed/Medline database search was performed using the following search terms: sirukumab; anti-IL-6; IL-6; major depressive disorder; inflammation. A systematic review was conducted of both preclinical and clinical trials reporting on the pharmacology of sirukumab or investigating the efficacy of targeting IL-6 signaling. Overall, sirukumab has been reported to be a safe and well-tolerated agent, capable of modulating the immune response in healthy populations as well as in subjects with inflammatory disorders (e.g., rheumatoid arthritis). Sirukumab's effects on cytokine networks as part of the innate immune system provide a coherent rationale for possible application in neuropsychiatric disorders with possible benefits across several domains of the biobehavioral Research Domain Criteria matrix (e.g., general cognitive processes, positive valence systems). Amongst individuals with complex brain-based disorders (e.g., mood disorders), the dimensions/domains most likely to benefit with sirukumab are negative valence disturbances (e.g., anxiety, depression, rumination), positive valence disturbances (e.g., anhedonia) as well as general cognitive processes. We suggest that sirukumab represents a prototype and possibly a proof-of-concept that agents that engage IL-6 targets have salutary effects in psychiatry.

Inflammatory Cytokines and Antipsychotic-Induced Weight Gain: Review and Clinical Implications.

Antipsychotic medications (APs), particularly second-generation APs, are associated with significant weight gain in schizophrenia patients. Recent evidence suggests that the immune system may contribute to antipsychotic-induced weight gain (AIWG) via AP-mediated alterations of cytokine levels. Antipsychotics with a high propensity for weight gain, such as clozapine and olanzapine, influence the expression of immune genes, and induce changes in serum cytokine levels to ultimately down-regulate neuroinflammation. Since inflammatory cytokines are normally involved in anorexigenic responses, reduced inflammation has been independently shown to mediate changes in feeding behaviours and other metabolic parameters, resulting in obesity. Genetic variation in pro-inflammatory cytokines is also associated with both general obesity and weight change during AP treatment, and thus, may be implicated in the pharmacogenetics of AIWG. At this time, preliminary data support a cytokine-mediated model of AIWG which may have clinical utility in developing more effective metabolic monitoring guidelines and prevention measures. However, further research is still needed to clearly elucidate the validity of this immune model. This article reviews the evidence implicating inflammatory cytokines in AIWG and its potential clinical relevance.

Zebrafish models of major depressive disorders.

The zebrafish (Danio rerio) has emerged as a model species for translational research in various neuroscience areas, including depressive disorders. Because of their physiological (neuroanatomical, neuroendocrine, neurochemical) and genetic homology to mammals, robust phenotypes, and value in high-throughput genetic and chemical genetic screens, zebrafish are ideal for developing valid experimental models of major depression and discovering novel therapeutics. Behavioral testing approaches, such as approach-avoidance, cognitive, and social paradigms, are available in zebrafish and have utility in identifying depression-like indices in zebrafish in response to physiological, genetic, environmental, and/or psychopharmacological alterations. In addition, the high sensitivity of zebrafish to commonly prescribed psychotropic drugs supports the use of this model as an invaluable tool for pharmacological research and drug screening. This Review outlines the benefits of using the zebrafish model for depression studies and summarizes the current research in this field.

Genetic variation in IL-1ß, IL-2, IL-6, TSPO and BDNF and response to duloxetine or placebo treatment in major depressive disorder.

AIM: This study investigated polymorphisms of five inflammatory-related genes for association with duloxetine and placebo response in patients with major depression. PATIENTS & METHODS: Twenty SNPs in IL-1ß, IL-2, IL-6, TSPO and BDNF were genotyped in major depressive disorder patients treated with either duloxetine (n = 215) or placebo (n = 235) for up to 8 weeks. Treatment response was measured with the Montgomery-Åsberg Depression Rating Scale. RESULTS: IL-6 variants rs2066992 and rs10242595 were nominally associated with response to duloxetine (p = 0.047 and p = 0.028, respectively). Notably, the variant rs2066992 was also associated with placebo response (p = 0.026). However, none of our results remained significant after correction for multiple testing. CONCLUSION: Our findings tentatively suggest that IL-6 variants play a role in duloxetine and placebo response, which warrants further investigation.

Novel investigational drugs targeting IL-6 signaling for the treatment of depression.

INTRODUCTION: Elevated levels of IL-6 have been implicated in the pathophysiology and treatment of major depressive disorder (MDD). Convergent evidence suggests that IL-6 primarily mediates proinflammatory functions via the soluble IL-6 receptor/trans-signaling, and anti-inflammatory functions via a transmembrane receptor (IL-6R). A targeted approach to selectively inhibit IL-6 trans-signaling may offer putative antidepressant effects. AREAS COVERED: This review addresses three primary domains. The first focuses on the biological role of IL-6 within inflammation and its signal transduction pathways. The second addresses the potential contributions of IL-6 to the pathophysiology of MDD, and the mechanisms that may mediate these effects. Finally, the article outlines the therapeutic benefits of incorporating anti-inflammatory properties into the pharmacological treatment of MDD, and proposes inhibition of IL-6 signaling as a viable treatment strategy. EXPERT OPINION: To improve drug development for the treatment of MDD, there is a critical need to identify promising targets. Target identification will require guidance from a strategic framework such as The Research Domain Criteria, and convincing evidence relating known targets to brain function under both physiological and pathological conditions. Although current evidence provides rationale for administering anti-IL-6 treatments in MDD, further studies confirming safety, target affinity and therapeutic benefits are warranted.

The role of genetic variation across IL-1ß, IL-2, IL-6, and BDNF in antipsychotic-induced weight gain.

OBJECTIVES: Antipsychotics with high weight gain-inducing propensities influence the expression of immune and neurotrophin genes, which have been independently related to obesity indices. Thus, we investigated whether variants in the genes encoding interleukin (IL)-1ß, IL-2, and IL-6 and brain-derived neurotrophic factor (BDNF) Val66Met are associated with antipsychotic-induced weight gain (AIWG). METHODS: Nineteen polymorphisms were genotyped using Taqman(®) assays in 188 schizophrenia patients on antipsychotic treatment for up to 14 weeks. Mean weight change (%) from baseline was compared across genotypic groups using analysis of covariance (ANCOVA). Epistatic effects between cytokine polymorphisms and BDNF Val66Met were tested using Model-Based Multifactor Dimensionality Reduction. RESULTS: In European patients, IL-1ß rs16944*GA (P = 0.013, Pcorrected = 0.182), IL-1ß rs1143634*G (P = 0.001, Pcorrected = 0.014), and BDNF Val66Met (Val/Val, P = 0.004, Pcorrected = 0.056) were associated with greater AIWG, as were IL-1ß rs4849127*A (P = 0.049, Pcorrected = 0.784), and IL-1ß rs16944*GA (P = 0.012, Pcorrected = 0.192) in African Americans. BDNF Val66Met interacted with both IL-1ß rs13032029 (Val/Met+ TT, PPerm = 0.029), and IL-6 rs2069837 (Val/Val+ AA, PPerm = 0.021) in Europeans, in addition to IL-1ß rs16944 (Val/Val+ GA, PPerm = 0.006) in African Americans. CONCLUSIONS: SNPs across IL-1ß and BDNF Val66Met may influence AIWG. Replication of these findings in larger, independent samples is warranted.

Significance of borderline personality-spectrum symptoms among adolescents with bipolar disorder.

BACKGROUND: Little is known regarding correlates of borderline personality-spectrum symptoms (BPSS) among adolescents with bipolar disorder (BP). METHODS: Participants were 90 adolescents, 13-19 years of age, who fulfilled DSM-IV-TR criteria for BP using semi-structured diagnostic interviews. BPSS status was ascertained using the Life Problems Inventory which assessed identity confusion, interpersonal problems, impulsivity, and emotional lability. Analyses compared adolescents with "high" versus "low" BPSS based on a median split. RESULTS: Participants with high, relative to low, BPSS were younger, and had greater current and past depressive episode severity, greater current hypo/manic episode severity, younger age of depression onset, and reduced global functioning. High BPSS participants were more likely to have BP-II, and had higher rates of social phobia, generalized anxiety disorder, conduct disorder, oppositional defiant disorder, homicidal ideation, assault of others, non-suicidal self-injury, suicidal ideation, and physical abuse. Despite greater illness burden, high BPSS participants reported lower rates of lithium use. The most robust independent predictors of high BPSS, identified in multivariate analyses, included lifetime social phobia, non-suicidal self-injury, reduced global functioning, and conduct and/or oppositional defiant disorder. LIMITATIONS: The study design is cross-sectional and cannot determine causality. CONCLUSIONS: High BPSS were associated with greater mood symptom burden and functional impairment. Presence of high BPSS among BP adolescents may suggest the need to modify clinical monitoring and treatment practices. Future prospective studies are needed to examine the direction of observed associations, the effect of treatment on BPSS, and the effect of BPSS as a moderator or predictor of treatment response.

Second generation antipsychotic-induced obsessive-compulsive symptoms in schizophrenia: a review of the experimental literature.

Second generation antipsychotics (SGAs) have been implicated in the de novo emergence and exacerbation of obsessive-compulsive symptoms (OCS) in patients with schizophrenia. Among SGAs, clozapine, olanzapine, and risperidone are the most prominent agents associated with these sequelae, according to case reports. Comorbid OCS can impede recovery by compromising treatment benefits, medication compliance, and clinical prognoses. Previous reviews of SGA-induced OCS have predominantly focused on descriptive case reports, with limited attention paid toward experimental findings. To address this paucity of data, we sought to review the effects of SGAs on OCS in schizophrenia in the experimental literature, while addressing the role of different treatment (duration, dose, serum levels) and pharmacogenetic factors. Our findings suggest that clozapine confers the greatest risk of OCS in schizophrenia, with 20 to 28% of clozapine-treated patients experiencing de novo OCS, in addition to 10 to 18% incurring an exacerbation of pre-existing OCS. Clozapine can also yield full threshold obsessive-compulsive disorder (OCD), in some cases. Olanzapine is another high risk drug for secondary OCS which occurs in 11 to 20% of schizophrenic patients receiving olanzapine therapy. At this time, there is insufficient experimental evidence to characterize the effects of other SGAs on OCS. Despite some experimental support for the involvement of longer treatment duration and genetic factors in mediating drug-induced OCS, more research is needed to clearly elucidate these associations. Based on these results, schizophrenic patients should be routinely monitored for OCS throughout the course of SGA treatment, particularly when clozapine or olanzapine is administered.