Danielle S. Cha

COGNITIVE DEFICITS AND FUNCTIONAL OUTCOMES IN MAJOR DEPRESSIVE DISORDER: DETERMINANTS, SUBSTRATES, AND TREATMENT INTERVENTIONS

Few reports have aimed to describe the mediational effect of cognitive deficits on functional outcomes in major depressive disorder (MDD), and relatively few interventions are demonstrated to mitigate cognitive deficits in MDD.

Potential roles of zinc in the pathophysiology and treatment of major depressive disorder

Incomplete response to monoaminergic antidepressants in major depressive disorder (MDD), and the phenomenon of neuroprogression, suggests a need for additional pathophysiological markers and pharmacological targets. Neuronal zinc is concentrated exclusively within glutamatergic neurons, acting as an allosteric modulator of the N-methyl D-aspartate and other receptors that regulate excitatory neurotransmission and neuroplasticity. Zinc-containing neurons form extensive associational circuitry throughout the cortex, amygdala and hippocampus, which subserve mood regulation and cognitive functions. In animal models of depression, zinc is reduced in these circuits, zinc treatment has antidepressant-like effects and dietary zinc insufficiency induces depressive behaviors. Clinically, serum zinc is lower in MDD, which may constitute a state-marker of illness and a risk factor for treatment-resistance. Marginal zinc deficiency in MDD may relate to multiple putative mechanisms underlying core symptomatology and neuroprogression (e.g. immune dysfunction, monoamine metabolism, stress response dysregulation, oxidative/nitrosative stress, neurotrophic deficits, transcriptional/epigenetic regulation of neural networks). Initial randomized trials suggest a benefit of zinc supplementation. In summary, molecular and animal behavioral data support the clinical significance of zinc in the setting of MDD.

The impact of cognitive impairment on perceived workforce performance: Results from the International Mood Disorders Collaborative Project

BACKGROUND Cognitive dysfunction and depression severity are key mediators of workplace adjustment in adults with major depressive disorder (MDD). Herein, we sought to determine the extent to which measures of depression severity and cognitive dysfunction were associated with perceived global disability, workplace performance and quality of life. METHOD A post hoc analysis was conducted using data from 260 participants with a diagnosis of DSM-IV-TR-defined MDD who were enrolled in the International Mood Disorders Collaborative Project (IMDCP) between January 2008 and July 2013. Measures of workplace function, global disability, depression severity, cognitive function, and quality of life were employed. These data were analyzed using a multiple variable linear regression equations. RESULTS Perceived global disability was significantly predicted by clinical ratings of depression severity (β=0.54), and perceived inattention (β=0.24), accounting for 37% of the variance. In addition, perceived inattention (β=0.58) and clinical ratings of depression severity (β=0.18), were also significant predictors of perceived workplace productivity/performance, accounting for 38% of the variance. Finally, both clinical ratings of depression severity (β=-0.54), and perceived inattention (β=-0.18) were significant inverse predictors of perceived quality of life, accounting for 34% of the variance. CONCLUSION The overarching finding in the analysis herein is that workplace performance variability is explained by subjective measures of cognitive dysfunction to a greater extent than total depression symptom severity. Conversely, total depression symptom severity accounts for a greater degree of variability in global measures of disability relative to cognitive measures. Treatment strategies for adults with major depressive disorder should address issues of cognitive dysfunction to improve workforce participation and performance.

Treatment-emergent adverse events associated with atypical antipsychotics

Introduction: Atypical antipsychotics provide broad-spectrum effectiveness for the acute and/or preventative treatment of disparate psychiatric disorders. Atypical antipsychotics offer improved efficacy in some psychopathological domains when compared with typical antipsychotics. Notwithstanding, atypicals are not a catholicon and are associated with clinically significant and treatment-limiting side effects (e.g., extrapyramidal symptoms and weight gain). Areas covered: This article reviews commonly encountered adverse events attributable to the use of atypical antipsychotic agents. This review aims to provide a current overview of common adverse events associated with atypical agents with a particular emphasis on adverse events that frequently lead to treatment discontinuation (e.g., changes in weight, metabolism, extrapyramidal side effects, neuroendocrine changes, blood dyscrasias, and cardiovascular toxicity). Expert opinion: Atypicals are not a catholicon and are associated with clinically significant and treatment-limiting side effects (e.g., extrapyramidal symptoms and weight gain). Improving the utility of these agents requires a familiarity and understanding of the heterogeneous tolerability and safety profiles of atypical agents as well as the therapeutic evidence for their efficacy.

Advancing biomarker research: utilizing ‘Big Data’ approaches for the characterization and prevention of bipolar disorder

To provide a strategic framework for the prevention of bipolar disorder (BD) that incorporates a ‘Big Data’ approach to risk assessment for BD.

The prevalence and illness characteristics of DSM-5-defined “mixed feature specifier” in adults with major depressive disorder and bipolar disorder: Results from the International Mood Disorders Collaborative Project

BACKGROUND A substantial proportion of individuals with mood disorders present with sub-syndromal hypo/manic features. The objective of this analysis was to evaluate the prevalence and illness characteristics of the Diagnostic and Statistical Manual Version-5 (DSM-5) - defined mixed features specifier (MFS) in adults with major depressive disorder (MDD) and bipolar disorder (BD). METHOD Data from participants who met criteria for a current mood episode as part of MDD (n=506) or BD (BD-I: n=216, BD-II: n=130) were included in this post-hoc analysis. All participants were enrolled in the International Mood Disorders Collaborative Project (IMDCP): a collaborative research platform at the Mood Disorders Psychopharmacology Unit, University of Toronto and the Cleveland Clinic, Cleveland, Ohio. Mixed features specifier was operationalized as a score ≥ 1 on 3 or more select items on the Young Mania Rating Scale (YMRS) or ≥ 1 on 3 select items of the Montgomery Åsberg Depression Rating Scale (MADRS) or Hamilton Depression Rating Scale (HAMD-17) during an index major depressive episode (MDE) or hypo/manic episode, respectively. RESULTS A total of 26.0% (n=149), 34.0% (n=65), and 33.8% (n=49) of individuals met criteria for MFS during an index MDE as part of MDD, BD-I and BD-II, respectively. Mixed features specifier during a hypo/manic episode was identified in 20.4% (n=52) and 5.1% (n=8) in BD-I and BD-II participants, respectively. Individuals with MDE-MFS as part of BD or MDD exhibited a more severe depressive phenotype (p=0.0002 and p<0.0002, respectively) and reported a higher rate of alcohol/substance use disorder in the context of BD but not MDD (p=0.002). Individuals with MFS were more likely to have co-existing heart disease suggestive of a distinct pattern of comorbidity and neurobiology. LIMITATIONS Data were post-hoc and obtained from individuals utilizing a university-based mood disorder centre which may affect generalizability. CONCLUSIONS Diagnostic and Statistical Manual Version-5-defined MFS is common during an MDE as part of MDD and BD. The presence of MFS identifies a subgroup of individuals with greater illness complexity and possibly a higher rate of cardiovascular comorbidity. The results herein underscore the common occurrence of MFS in adults with either BD or MDD. Moreover, the results of our analysis indicate that adults with mood disorders and MFS have distinct clinical characteristics and comorbidity patterns.

Crosstalk between metabolic and neuropsychiatric disorders

Evidence supporting the concurrence of metabolic disturbances (e.g. insulin resistance, diabetes and obesity) and neuropsychiatric disorders has been demonstrated in both human and animal studies, suggesting the possibility that they have shared pathophysiological mechanisms. During the past decade, our understanding for the role of insulin in both normal and abnormal central nervous system (CNS) processes has become increasingly refined. Evidence indicates that insulin is a pleiotropic peptide, critical to neurotrophism, neuroplasticity, and neuromodulation. Moreover, the role of insulin underscores its importance in the development of several neuropsychiatric disorders, including, but not limited to, mechanisms involved in the pathogenesis and progression towards diabetes, obesity, and neurodegenerative disorders, such as Alzheimers disease. This review focuses on the insulin-mediated effects on normal and abnormal brain function and discusses why targeting insulin-related pathways in the brain may emerge as a new approach for refining treatment of neurological and psychiatric disorders.

The Prevalence, Measurement, and Treatment of the Cognitive Dimension/Domain in Major Depressive Disorder

Insufficient outcomes amongst adults with major depressive disorder (MDD) provide the impetus to identify and refine therapeutic targets that are most critical to outcome from patient, provider, and societal perspectives. Towards this aim, a pivotal shift towards the transnosological domain, cognition, is occurring in the study of MDD and other brain disorders. This paper aims to provide a framework for conceptualizing and prioritizing cognitive function amongst adults with MDD with a particular view to provide a conceptual framework for research and clinical priorities. We also summarize extant data pertaining to psychotropic effects, notably antidepressants, on the cognitive dimension/domain. This narrative review was based on articles identified through a PubMed/MEDLINE search of all English-language articles published between January 1966 and October 2014. The search words were major depressive disorder, depression, unipolar depression, cognition, cognitive dysfunction, cognitive deficit, and cognitive function. The search was supplemented with a manual review of relevant references. The selection of articles for inclusion in this review was based on overall methodological quality as well as on their pertinence to informing the framework described herein. Cognitive dysfunction in MDD is a discrete domain subserved by discrete yet overlapping substrates. There is a need to provide a glossary of terms commonly employed in the cognition literature for consensus as to the appropriate screening, measurement, and monitoring tools. The guiding principle of measurement-based care should include systematic assessment and measurement of cognition in subpopulations with MDD, as a tactic to improve outcome. Relatively few treatment strategies have demonstrated efficacy specifically for the cognitive domain in MDD. The antidepressant vortioxetine has replicated evidence of specific pro-cognitive effects in adults with MDD across multiple subdomains of cognitive function. Vortioxetine is a novel antidepressant that is hypothesized to act through a combination of direct effects on receptor activity and serotonin receptor inhibition, as well as other systems. Pro-cognitive effects for other US FDA-approved agents are suggested, but pseudospecificity has not been excluded as a possible explanation of their beneficial effects on cognitive function. A disparate assortment of other agents are currently under investigation for possible benefit in mitigating cognitive deficits and improving cognitive performance (e.g., intranasal insulin, erythropoietin, anti-inflammatory agents). Non-pharmacological approaches including, but not limited to, cognitive remediation (CR), aerobic exercise, and neuromodulation are promising.

The Association between Childhood Adversity and Components of Metabolic Syndrome in Adults with Mood Disorders: Results from the International Mood Disorders Collaborative Project

Objective: We sought to determine whether a reported history of childhood adversity is associated with components of the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP-III)-defined metabolic syndrome in adults with mood disorders. Method: This was a cross-sectional analysis of adult outpatients (n = 373; n = 230 female, n = 143 male; mean age [SD]=42.86 [14.43]) from the International Mood Disorders Collaborative Project (University of Toronto and Cleveland Clinic) with DSM-IV-defined major depressive disorder and bipolar I/II disorder. Childhood adversity was measured with the Klein Trauma & Abuse-Neglect self-report scale. The groups with and without childhood adversity were compared to determine possible differences in the rates of metabolic syndrome and its components. Logistic and linear regressions adjusted for age, sex, education, employment status, and smoking were used to evaluate the association between childhood adversity and components of metabolic syndrome. Results: For the full sample, 83 subjects (22.25%) met criteria for metabolic syndrome. Individuals reporting a history of any childhood adversity had higher systolic and diastolic blood pressure (systolic: p = 0.040; diastolic: p = 0.038). Among subjects with a history of sexual abuse, a significant proportion met criteria for obesity (45.28% vs. 32.88%; p = 0.010); a trend toward overweight was found for subjects with a history of physical abuse (76.32% vs. 63.33%; p = 0.074), although this relationship did not remain significant after adjusting for potential confounders. There was no statistically significant difference in the overall rate of dyslipidemia and/or metabolic syndrome between subjects with and without childhood adversity. Conclusion: The results herein provide preliminary evidence suggesting that childhood adversity is associated with metabolic syndrome components in individuals with mood disorders.

Gut emotions - mechanisms of action of probiotics as novel therapeutic targets for depression and anxiety disorders.

A priority clinical and research agenda in mood and anxiety disorders is to identify determinants that influence illness trajectory and outcome. Over the past decade, studies have demonstrated a bidirectional relationship between the gut microbiome and brain function (i.e., the microbiota-gut-brain axis). Probiotic treatments and developmental analysis of the microbiome may provide potential treatments and preventative measures for depressive and anxiety disorders. This systematic literature review aims to identify original studies linking the gut microbiota to major depressive disorder and anxiety disorders. Furthermore, this review searched for original reports focusing on possible therapeutic and preventative effects of probiotics for these debilitating conditions. Accumulating data indicate that the gut microbiota communicates with the CNS through neural, endocrine and immune pathways. Studies in germ-free animals indicate that the microbiota is involved in the regulation of the stress response (e.g., hypothalamic-pituitary-adrenal axis) and in CNS development at critical stages. Probiotics attenuate anxiety and depressive-like behaviors in experimental animal models. Notwithstanding some inconsistencies and methodological limitations across trials, clinical studies suggest that probiotics may mitigate anxiety symptoms. However, future studies should investigate the anxiolytic and antidepressant effects of probiotics in more phenotypically homogeneous populations. In conclusion, the emerging concept of a gut microbiota-brain axis suggests that the modulation of the gut microbiota may provide a novel therapeutic target for the treatment and/or prevention of mood and anxiety disorders.