Yena Lee

Inflammation as a neurobiological substrate of cognitive impairment in bipolar disorder: Evidence, pathophysiology and treatment implications.

BACKGROUND Bipolar disorder (BD) has been associated with cognitive impairment during depressed, manic and euthymic periods. Inflammation has been shown to be involved in the pathophysiology of BD and cognitive impairment. METHODS For this systematic review, the MEDLINE/PubMed, Embase, Google Scholar and ClinicalTrials.gov databases were searched for relevant articles assessing the association between cognitive function and inflammatory markers in BD subjects. A discussion of potential mechanisms and therapeutic implications is also included to provide further context to the subject matter. RESULTS Eight studies, including a total of 555 BD subjects, assessing the association between cognitive function and inflammatory markers were identified. Cognitive dysfunction was associated with elevated levels of pro-inflammatory markers YKL40, IL-6, sCD40L, IL-1Ra, hsCRP and TNF-α. Mechanistically, elevation in inflammatory cytokines alters monoamine levels leading to cognitive and affective dysfunction. Neuro-inflammation, manifesting as microglial activation, leads to increased oxidative stress, pathologic synaptic pruning and impaired neuroplasticity in key brain regions sub-serving mood and cognition. Immune dysfunction also activates the hypothalamic-pituitary-adrenal (HPA) axis leading to hypercortisolemia and metabolic dysfunction, further promoting neuronal dysfunction. Anti-inflammatory agents are therefore currently being investigated in the treatment of BD and appear to exert an antidepressant effect; however, cognitive outcomes have yet to be reported. CONCLUSION Several studies suggest that immune dysfunction is associated with cognitive impairment in BD. Several neurobiological pathways have been identified whereby immune dysfunction may promote cognitive impairment in BD. Future investigations of anti-inflammatory agents targeting cognitive function as a treatment outcome are merited.

Does Pharmacogenomic Testing Improve Clinical Outcomes for Major Depressive Disorder? A Systematic Review of Clinical Trials and Cost-Effectiveness Studies.

OBJECTIVE Pharmacogenomic testing has become scalable and available to the general public. Pharmacogenomics has shown promise for predicting antidepressant response and tolerability in the treatment of major depressive disorder (MDD). In theory, pharmacogenomics can improve clinical outcomes by guiding antidepressant selection and dosing. The current systematic review examines the extant literature to determine the impact of pharmacogenomic testing on clinical outcomes in MDD and assesses its cost-effectiveness. DATA SOURCES The MEDLINE/PubMed and Google Scholar databases were systematically searched for relevant articles published prior to October 2015. Search terms included various combinations of the following: major depressive disorder (MDD), depression, mental illness, mood disorder, antidepressant, response, remission, outcome, pharmacogenetic, pharmacogenomics, pharmacodynamics, pharmacokinetic, genetic testing, genome wide association study (GWAS), CYP450, personalized medicine, cost-effectiveness, and pharmacoeconomics. STUDY SELECTION Of the 66 records identified from the initial search, relevant clinical studies, written in English, assessing the cost-effectiveness and/or efficacy of pharmacogenomic testing for MDD were included. DATA EXTRACTION Each publication was critically examined for relevant data. RESULTS Two nonrandomized, open-label, 8-week, prospective studies reported overall greater improvement in depressive symptom severity in the group of MDD subjects receiving psychiatric care guided by results of combinatorial pharmacogenomic testing (GeneSight) when compared to the unguided group. One industry-sponsored, randomized, double-blind, 10-week prospective study reported a trend for improved outcomes for the GeneSight-guided group; however, the trend did not reach statistical significance. Another industry-sponsored, randomized, double-blind, 12-week prospective study reported a 2.5-fold increase in remission rates in the CNSDose-guided group (P < .0001). One naturalistic, unblinded, industry-sponsored study showed clinical improvement when pharmacogenomics testing guided prescribing; however, this study lacked a control group. A single cost-effectiveness study concluded that single gene testing was not cost-effective. Conversely, a separate study reported that combinatorial pharmacogenomic testing is cost-effective. CONCLUSIONS A limited number of studies have shown promise for the clinical utility of pharmacogenomic testing; however, cost-effectiveness of pharmacogenomics, as well as demonstration of improved health outcomes, is not yet supported with replicated evidence.

Cognition in major depressive disorder: a 'Systemically Important Functional Index' (SIFI).

Purpose of review Cognitive dysfunction in major depressive disorder (MDD) is common, pervasive across multiple subdomains of cognitive function, and is a principle determinant of health outcomes from patient, provider, and societal perspectives. The overarching aim herein is to provide rationale for the evaluation, measurement, and specific treatment of cognitive function in adults with MDD. Recent findings Evidence indicates that cognitive dysfunction in MDD is a critical mediator of workplace disability. Systematic evaluation and measurement of cognitive function is warranted. All individuals with MDD should be evaluated for both objective and subjective cognitive dysfunction. Although differences between antidepressants in overall antidepressant efficacy are not consistent, unequivocal differences in improving measures of cognitive function are noted with evidence indicating that vortioxetine has multidomain cognitive benefits, whereas duloxetine has replicated evidence of improving measures of acquisition and recall (i.e. memory). Summary The probability of functional recovery in MDD is likely to increase with interventions that specifically target and improve measures of cognitive function. Clinicians are encouraged to evaluate patients using a validated measure (e.g. the THINC-it tool); prevention of cognitive impairment in MDD is a critical therapeutic priority. Vortioxetine and duloxetine benefit measures of cognitive function in MDD. Preliminary evidence of beneficial effects on cognitive emotional processing are reported with ketamine.

Treating to target in major depressive disorder: response to remission to functional recovery.

Treating to target in chronic diseases [e.g. Major Depressive Disorder (MDD)] fosters precision, consistency, and appropriateness of treatment selection and sequencing. Therapeutic target definitions/endpoints in MDD should satisfy patient-, provider-, and societal expectations. Functional recovery in depression and return to both physical and mental health are the overarching therapeutic objectives. Treating to target in MDD implies multidimensional symptomatic remission, with a particular emphasis on cognitive function and aspects of positive mental health. Several atypical antipsychotic agents (i.e. brexpiprazole, aripiprazole, quetiapine) are FDA-approved as augmentation agents in MDD. Vortioxetine, duloxetine, and psychostimulants have evidence of independent, direct, and robust effects on cognitive function in MDD. Vortioxetine is the only agent that demonstrates efficacy across multiple cognitive domains in MDD associated with functional recovery. Measurement-based care, health information technology/systems, and integrated care models (e.g. medical homes) provide requisite tools and health environments for optimal health outcomes in MDD. Achieving remission in MDD does not equate to health. Return to positive mental health as well as full functioning provide the impetus to pivot away from traditional provider-defined outcomes toward an inclusive perspective involving patient- and society-defined outcomes (i.e. optimization of human capital). As in other chronic diseases, treating to target (e.g. cognitive function) further increases the probability of achieving optimal health outcomes.

Assessment of abnormal brain structures and networks in major depressive disorder using morphometric and connectome analyses

BACKGROUND It is hypothesized that the phenomenology of major depressive disorder (MDD) is subserved by disturbances in the structure and function of brain circuits; however, findings of structural abnormalities using MRI have been inconsistent. Generalized q-sampling imaging (GQI) methodology provides an opportunity to assess the functional integrity of white matter tracts in implicated circuits. METHODS The study population was comprised of 16 outpatients with MDD (mean age 44.81±2.2 years) and 30 age- and gender-matched healthy controls (mean age 45.03±1.88 years). We excluded participants with any other primary mental disorder, substance use disorder, or any neurological illnesses. We used T1-weighted 3D MRI with voxel-based morphometry (VBM) and vertex-wise shape analysis, and GQI with voxel-based statistical analysis (VBA), graph theoretical analysis (GTA) and network-based statistical (NBS) analysis to evaluate brain structure and connectivity abnormalities in MDD compared to healthy controls correlates with clinical measures of depressive symptom severity, Hamilton Depression Rating Scale 17-item (HAMD) and Hospital Anxiety and Depression Scale (HADS). RESULTS Using VBM and vertex-wise shape analyses, we found significant volumetric decreases in the hippocampus and amygdala among subjects with MDD (p<0.001). Using GQI, we found decreases in diffusion anisotropy in the superior longitudinal fasciculus and increases in diffusion probability distribution in the frontal lobe among subjects with MDD (p<0.01). In GTA and NBS analyses, we found several disruptions in connectivity among subjects with MDD, particularly in the frontal lobes (p<0.05). In addition, structural alterations were correlated with depressive symptom severity (p<0.01). LIMITATIONS Small sample size; the cross-sectional design did not allow us to observe treatment effects in the MDD participants. CONCLUSIONS Our results provide further evidence indicating that MDD may be conceptualized as a brain disorder with abnormal circuit structure and connectivity.

The THINC-integrated tool (THINC-it) screening assessment for cognitive dysfunction: Validation in patients with major depressive disorder

OBJECTIVE To validate the THINC-integrated tool (THINC-it)-a freely available, patient-administered, computerized screening tool integrating subjective and objective measures of cognitive function in adults with major depressive disorder (MDD). METHODS Subjects aged 18 to 65 years (n = 100) with recurrent MDD experiencing a major depressive episode of at least moderate severity were evaluated and compared to age-, sex-, and education-matched healthy controls (n = 100). Between January and June 2016, subjects completed the THINC-it, which includes variants of the Choice Reaction Time Identification Task (IDN), One-Back Test, Digit Symbol Substitution Test, Trail Making Test-Part B, and the Perceived Deficits Questionnaire for Depression-5-item (PDQ-5-D). RESULTS The THINC-it required approximately 10 to 15 minutes for administration and was capable of detecting cognitive deficits in adults with MDD. A total of 44.4% of adults with MDD exhibited cognitive performance at ≥ 1.0 SD below that of healthy controls on standardized mean scores of the THINC-it. Concurrent validity of the overall tool, based on a calculated composite score, was acceptable (r = 0.539, P < .001). Concurrent validity of the component tests ranged from -0.083 (IDN) to 0.929 (PDQ-5-D). Qualitative survey results indicated that there was a high level of satisfaction and perceived value in administering the THINC-it regarding its impact on the appropriateness and quality of care being received. CONCLUSIONS The THINC-it is a valid and sensitive tool for detecting cognitive dysfunction in adults with MDD that is free, easy to use, and rapidly administered. The THINC-it should be incorporated into the assessment and measurement of all patients with MDD, particularly among those with enduring functional impairment. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02508493.

Cannabidiol in medical marijuana: Research vistas and potential opportunities

ABSTRACT The high and increasing prevalence of medical marijuana consumption in the general population invites the need for quality evidence regarding its safety and efficacy. Herein, we synthesize extant literature pertaining to the phytocannabinoid cannabidiol (CBD) and its brain effects. The principle phytocannabinoid &Dgr;9‐tetrahydrocannabinol (&Dgr;9‐THC) and CBD are the major pharmacologically active cannabinoids. The effect of CBD on brain systems as well as on phenomenological measures (e.g. cognitive function) are distinct and in many cases opposite to that of &Dgr;9‐THC. Cannabidiol is without euphoriant properties, and exerts antipsychotic, anxiolytic, anti‐seizure, as well as anti‐inflammatory properties. It is essential to parcellate phytocannabinoids into their constituent moieties as the most abundant cannabinoid have differential effects on physiologic systems in psychopathology measures. Disparate findings and reports related to effects of cannabis consumption reflect differential relative concentration of &Dgr;9‐THC and CBD. Existing literature, notwithstanding its deficiencies, provides empirical support for the hypothesis that CBD may exert beneficial effects on brain effector systems/substrates subserving domain‐based phenomenology. Interventional studies with purified CBD are warranted with a call to target‐engagement proof‐of‐principle studies using the research domain criteria (RDoC) framework.

A new perspective on the anti-suicide effects with ketamine treatment: a procognitive effect

Abstract Available evidence indicates that a single, low-dose administration of ketamine is a robust, rapid-onset intervention capable of mitigating depressive symptoms in adults with treatment-resistant mood disorders. Additional evidence also suggests that ketamine may offer antisuicide effects. Herein, we propose that the antidepressant effects reported with ketamine administration are mediated, in part, by targeting neural circuits that subserve cognitive processing relevant to executive function and cognitive emotional processing. Empirical support for the conceptual framework of the cognitive domain as a critical target of ketamines action is the additional observation that pretreatment cognitive function predicts treatment outcomes with ketamine administration. The proposal that beneficial effects on cognitive function may be, in some individuals, the proximate mechanism mitigating symptom relief in mood disorders exists alongside the well-established deleterious effect of ketamine on cognitive function. During the past 5 years, there have been several reviews and meta-analyses concluding that ketamine has possible clinical benefits in refractory mood disorders. We introduce the conceptual framework that ketamines salutary effects, notably in suicidality, may in part be via procognitive mechanisms.

Adverse effects of obesity on cognitive functions in individuals at ultra high risk for bipolar disorder: Results from the global mood and brain science initiative

The burden of illness associated with bipolar disorder (BD) warrants early pre‐emption/prevention. Prediction models limited to psychiatric phenomenology have insufficient predictive power. Herein, we aimed to evaluate whether the presence of overweight/obesity is associated with greater cognitive decline in individuals at high risk (HR) or ultra high risk (UHR) for BD.

Efficacy of antidepressants on measures of workplace functioning in major depressive disorder: a systematic review

INTRODUCTION Work-related disability and productivity loss in Major Depressive Disorder (MDD) are critical determinants of patient quality of life and contribute significantly to the human and economic costs of MDD. Notwithstanding the return to work and pre-morbid levels of functioning as a critical therapeutic objective among individuals with MDD, it is unclear whether antidepressant treatment significantly and reliably improves measures of workplace functioning. Herein, we investigate to what extent antidepressant treatment improves workplace functioning among adults with MDD. METHODS We conducted a systematic review of randomized, double-blind, placebo-controlled or active comparator clinical trials primarily or secondarily investigating the efficacy of antidepressant agents on subjective ratings of workplace functioning and/or measures of work absence. RESULTS Thirteen placebo-controlled and four active comparator clinical trials reported on the efficacy of agomelatine, bupropion, desvenlafaxine, duloxetine, fluoxetine, levomilnacipran, paroxetine, sertraline, venlafaxine, or vortioxetine on subjective measures of workplace impairment. Overall, antidepressant treatment improved standardized measures of workplace functioning (e.g., Sheehan Disability Scale-work item). One placebo-controlled trial of agomelatine and one clinical trial comparing the efficacy of vortioxetine to that of venlafaxine had mixed results on measures of work absence. LIMITATIONS Included interventional trials evaluated work-related disability as a secondary outcome using subjective rating scales. CONCLUSION Extant data suggest that antidepressant treatment improves workplace outcomes in MDD. The capability of antidepressants in improving measures of workplace functioning should be considered in cost-benefit analyses to better inform cost-modelling studies pertaining to antidepressant therapy.