Mehala Subramaniapillai

Liraglutide promotes improvements in objective measures of cognitive dysfunction in individuals with mood disorders: A pilot, open-label study.

BACKGROUND There is a paucity of treatments that are capable of reliably and robustly improving cognitive function in adults with mood disorders. Glucagon-like peptide-1 is synthesized centrally and its receptors are abundantly expressed in neural circuits subserving cognitive function. We aimed to determine the effects of liraglutide, a GLP-1 receptor (GLP-1R) agonist, on objective measures of cognition in adults with a depressive or bipolar disorder. METHODS In this 4-week, pilot, open-label, domain-based study (e.g. cognition), we recruited 19 individuals with major depressive disorder (MDD) or bipolar disorder (BD) and an impairment in executive function, defined as a below-average performance in the Trail Making Test-B (TMTB). Liraglutide 1.8mg/day was added as an adjunct to existing pharmacotherapy. RESULTS Participants had significant increases from baseline to week 4 in the TMTB standard score (age and education corrected) (Cohens d=0.64, p=0.009) and in a composite Z-score comprising multiple cognitive tests (i.e. Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, Stroop test) (Cohens d=0.77, p<0.001). Neither changes in mood rating scales nor metabolic parameters were associated with changes in cognitive performance (all p>0.05); however baseline insulin resistance (IR) and body mass index (BMI) moderated the changes in the composite Z-score (p=0.021 and p=0.046, respectively), indicating larger responses in individuals with higher IR and BMI at baseline. There was a significant increase in lipase (p<0.001), but individual values were above the upper limit of normality. LIMITATIONS Small sample size, open-label design, lack of a placebo group. CONCLUSIONS Liraglutide was safe and well tolerated by a sample of non-diabetic individuals with mood disorders and had beneficial effects on objective measures of cognitive function. Larger studies with controlled trial designs are necessary to confirm and expand the results described herein.

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.

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.

Cognitive impairment as measured by the THINC-integrated tool (THINC-it): Association with psychosocial function in major depressive disorder

BACKGROUND Psychosocial impairment represents an important treatment target in major depressive disorder (MDD). The majority of patients with MDD do not regain premorbid levels of psychosocial functioning despite the resolution of core depressive symptoms. This study aimed to investigate the respective effects of cognitive function and depression severity on impaired psychosocial function in MDD. METHODS Adults aged 18-65 with moderate-to-severe MDD (n = 100) and age-, sex-, and education-matched healthy controls participated in a cross-sectional study validating the THINC-integrated tool (THINC-it), a cognitive screening tool comprised of objective and subjective measures of cognitive function. Depression severity was assessed using the Montgomery-Åsberg Depression Rating Scale and psychosocial function was assessed using the Sheehan Disability Scale (SDS). RESULTS Subjects with MDD reported greater impairment in psychosocial function than healthy controls, with significant differences in SDS total and domain scores (ps < .01) after controlling for age, sex, and education. Generalized linear models indicated that subjective cognitive function was most strongly associated with SDS total score (RR = .14, p = .01) and SDS domains of work/school (RR = .15, p = .03), family and home responsibilities (RR = .15, p = .02), and economic days lost (RR = .18, p =.03). Depression severity was most strongly associated with SDS social life (RR = .08, p < .01) and economic days underproductive (RR = .07, p < .01). Objective cognitive function was not significantly associated with any SDS outcomes. LIMITATIONS The cross-sectional, observational study design limits temporal inferences. The self-report nature of measures included may have influenced associations observed. Potential medication effects are not noted. CONCLUSIONS Cognitive deficits, as measured by the THINC-it, are associated with significant psychosocial impairment in MDD. These results provide empirical support for the assessment of both subjective and objective measures of cognition, as they are not associated with each other and have differential effects on functional trajectory.

Characterizing exercise-induced feelings after one bout of exercise among adolescents with and without bipolar disorder

BACKGROUND Exercise may be a practical, non-pharmacological strategy for symptom and health management for adolescents with bipolar disorder (BD). The purpose of this study was to determine if adolescents with BD experience changes in exercise-induced feelings from one bout of exercise similar to their otherwise healthy peers. METHODS Thirty-two adolescents with BD (Age (SD)=16.91 (1.4)) and 31 healthy adolescents (Age (SD)=15.68 (1.76)) completed the Exercise-Induced Feeling Inventory (EFI) before and after a 20-min bout of moderate intensity exercise (heart rate goal of 60-80% of the age estimated maximum [220 - 0.7*age]) on a cycle ergometer. Repeated-Measures ANCOVA was conducted on the four EFI subscales, controlling for age and BMI. RESULTS There were no significant between-group differences on any subscales. An increase in Physical Exhaustion was of negligible effect size in both groups (BD: d=0.05; CONTROL d=0.16). There was an improvement in Revitalization (BD: d=0.49; CONTROL d=0.61) and a reduction in Tranquility (BD: d=-0.33; CONTROL d=-0.29) post-exercise of moderate and small effect size, respectively. The control group reported an increase in Positive Engagement that was of small-to-medium effect size, (d=0.41) with negligible change in the BD group (d=0.17). Healthy adolescents reported a significantly greater tolerance for high intensity exercise than adolescents with BD. LIMITATIONS Emotions were only assessed at two time points. CONCLUSIONS Adolescents with BD experience similar exercise-induced emotional benefits as their healthy peers. Experimental research is needed to examine the role of exercise as a strategy to regulate mood-related symptoms.

Treatment with a GLP−1R agonist over four weeks promotes weight loss-moderated changes in frontal-striatal brain structures in individuals with mood disorders

Cognitive deficits are a core feature across psychiatric disorders. Emerging evidence indicates that metabolic pathways are highly relevant for the substrates and phenomenology of the cognitive domain. Herein, we aimed to determine the effects of liraglutide, a GLP-1R agonist, on brain structural/volumetric parameters in adults with a mood disorder. This is the secondary analysis of a 4-week, pilot, proof-of-concept, open-label study. Participants (N=19) exhibiting impairments in executive function with either major depressive disorder (MDD) or bipolar disorder (BD) were recruited. Liraglutide 1.8mg/day was added as an adjunct to existing pharmacotherapy. Structural magnetic resonance imaging (MRI) scanning was obtained at baseline and endpoint. Results showed that at endpoint there was significant weight loss (mean: 3.15%; p<0.001). Changes in frontal and striatal volumes were significantly correlated with changes in body mass index (BMI), indicating the weight loss was associated with volume increase in most regions (e.g. r=-0.561, p=0.042 in the left superior frontal area). After adjusting for intracranial volume, age, gender, and BMI, we observed significant changes from baseline to endpoint in multiple regions (e.g. RR: 1.011, p=0.049 in the left rostral middle frontal area). Changes in regional volumes were associated with improvement in executive function (e.g. r=0.698, p=0.003 for the right superior frontal area). Adjunctive liraglutide results in clinically significant weight loss, with corresponding improvement in cognitive function; changes in cognitive function were partially moderated by changes in brain morphometry, underscoring the interrelationship between weight and brain structure/function.

Drug-drug interactions as a result of co-administering Δ9-THC and CBD with other psychotropic agents

ABSTRACT Introduction: To determine, via narrative, non-systematic review of pre-clinical and clinical studies, whether the effect of cannabis on hepatic biotransformation pathways would be predicted to result in clinically significant drug-drug interactions (DDIs) with commonly prescribed psychotropic agents. Areas covered: A non-systematic literature search was conducted using the following databases: PubMed, PsycInfo, and Scopus from inception to January 2017. The search term cannabis was cross-referenced with the terms drug interactions, cytochrome, cannabinoids, cannabidiol, and medical marijuana. Pharmacological, molecular, and physiologic studies evaluating the pharmacokinetics of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), both in vitro and in vivo, were included. Bibliographies were also manually searched for additional citations that were relevant to the overarching aim of this paper. Expert opinion: Δ9-Tetrahydrocannabinol and CBD are substrates and inhibitors of cytochrome P450 enzymatic pathways relevant to the biotransformation of commonly prescribed psychotropic agents. The high frequency and increasing use of cannabis invites the need for healthcare providers to familiarize themselves with potential DDIs in persons receiving select psychotropic agents, and additionally consuming medical marijuana and/or recreational marijuana.

Pharmacological Treatment of Cognitive Symptoms in Major Depressive Disorder

BACKGROUND Cognitive dysfunction is a core transdiagnostic domain of Major Depressive Disorder (MDD) and is a principal determinant of functional recovery. However, it has been insufficiently targeted within the current therapeutic framework for MDD. OBJECTIVE To highlight these unmet cognitive needs in MDD. METHOD An article search was conducted using PubMed from inception to November 2016: Major Depressive Disorder (and/or variant) was cross-referenced with the following terms: antidepressants, augmentation, cognition, cognitive deficits, cognitive dysfunction, functional outcomes, mechanism of action, and treatment. Articles informed by observational studies, clinical trials, and review articles relevant to the discussion of cognition and cognitive impairment in MDD were included for review. Additional terms and citations previously not identified in the initial search were obtained from a manual review of article reference lists. RESULTS Cognitive deficits in MDD are replicable, non-specific, and clinically significant. Abnormalities in the domains of learning/memory, executive function, attention, concentration, and processing speed are consistently reported. Only two antidepressants (i.e., duloxetine and vortioxetine) have established procognitive effects utilizing rigorous methodology in MDD. Most antidepressants improve cognitive function(s), but the extent to which they directly exert pro-cognitive effects is not yet understood. CONCLUSION Cognitive dysfunction in MDD is a principal determinant of patient-reported outcomes (e.g., psychosocial function). Healthcare providers are encouraged to screen for cognitive dysfunction in MDD and familiarize themselves with the efficacy profiles of antidepressants on disparate cognitive domains.

The effect of an acute bout of exercise on executive function among individuals with schizophrenia

Cognitive impairment represents a significant source of disability among individuals with schizophrenia. Therefore, the aim of this study was to investigate, at a proof-of-concept level, whether one single bout of exercise can improve executive function among these individuals. In this within-participant, counterbalanced experiment, participants with schizophrenia (n=36) completed two sessions (cycling at moderate-intensity and passively sitting) for 20min, with a one-week washout period between the two sessions. Participants completed the Wisconsin Card Sorting Test (WCST) before and after each session to measure changes in executive function. The inclusion of both sessions completed by each participant in the analyses revealed a significant carryover effect. Consequently, only the WCST scores from the first session completed by each participant was analyzed. There was a significant time by session interaction effect for non-perseverative errors. Post-hoc Tukeys HSD contrasts revealed a significant reduction in non-perseverative errors in the exercise group that was of moderate-to-large effect. Furthermore, there was also a moderate between-group difference at post-testing. Therefore, an acute bout of exercise can improve performance on an executive function task in individuals with schizophrenia. Specifically, the reduction in non-perseverative errors on the WCST may reflect improved attention, inhibition and overall working memory.

Evidence supporting a mechanistic role of sirtuins in mood and metabolic disorders

Sirtuins are NAD+-dependent histone deacetylases that play essential roles in cell survival, energy metabolism, inflammation, and aging; therefore, sirtuins are potential therapeutic targets in the treatment of type 2 diabetes, cancer, inflammatory and metabolic disorders, and neurodegenerative diseases. Available evidence provides the basis for hypothesizing that sirtuins 1, 2, and 3 (SIRT1, SIRT2, and SIRT3) may have a mechanistic role subserving mood disorders (i.e. downregulation) and associated co-morbidity (e.g. metabolic disorders). Specifically, the domains of general cognitive processes, as well as cognitive emotional processing may be particularly relevant to sirtuin physiology. Given the role of sirtuins in the perpetuation of circadian rhythmicity, and evidence of dysfunctional circadian cycling in mood disorders, sirtuins may be an underlying etiological factor that links circadian rhythm functionality with mood disorders. Caloric restriction, and caloric restriction mimetics (e.g. resveratrol) are all capable of upregulating sirtuin isoforms implicated in stress response syndromes. Repurposing existing treatments and/or discovery of novel agents capable of modulating sirtuin physiology may represent genuinely novel approaches for trans-diagnostic domains affected in mood disorders and other brain-based illnesses.