Carola Rong

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.

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.

The Efficacy of Psychostimulants in Major Depressive Episodes: A Systematic Review and Meta-Analysis.

Background Psychostimulants are frequently prescribed off-label for adults with major depressive disorder or bipolar disorder. The frequent and increasing usage of stimulants in mood disorders warrants a careful appraisal of the efficacy of this class of agents. Herein, we aim to estimate the efficacy of psychostimulants in adults with unipolar or bipolar depression. Methods The PubMed/Medline database was searched from inception to January 16, 2016 for randomized, placebo-controlled clinical trials investigating the antidepressant efficacy of psychostimulants in the treatment of adults with unipolar or bipolar depression. Results Psychostimulants were associated with statistically significant improvement in depressive symptoms in major depressive disorder (odds ratio [OR], 1.41; 95% confidence interval [CI], 1.13–1.78; P = 0.003) and bipolar disorder (OR, 1.42; 95% CI, 1.13–1.78; P = 0.003). Efficacy outcomes differed across the psychostimulants evaluated as a function of response rates: ar/modafinil (OR, 1.47; 95% CI, 1.20–1.81; P = 0.0002); dextroamphetamine (OR, 7.11; 95% CI, 1.09–46.44; P = 0.04); lisdexamfetamine dimesylate (OR, 1.21; 95% CI, 0.94–1.56; P = ns); methylphenidate (OR, 1.49; 95% CI, 0.88–2.54; P = ns). Efficacy outcomes also differed between agents used as adjunctive therapy (OR, 1.39; 95% CI, 1.19–1.64) or monotherapy (OR, 2.25; 95% CI, 0.67–7.52). Conclusions Psychostimulants are insufficiently studied as adjunctive or monotherapy in adults with mood disorders. Most published studies have significant methodological limitations (eg, heterogeneous samples, dependent measures, type/dose of agent). In addition to improvements in methodological factors, a testable hypothesis is that psychostimulants may be more appropriately tested in select domains of psychopathology (eg, cognitive emotional processing), rather than as “broad-spectrum” antidepressants.

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.

Pharmacodynamic and pharmacokinetic evaluation of buprenorphine + samidorphan for the treatment of major depressive disorder.

ABSTRACT Introduction: Treatment resistant depression (TRD) represents approximately 20% of all individuals receiving care for major depressive disorder. The opioidergic system is identified as a novel target which hitherto has not been sufficiently investigated in adults with TRD. The combination product buprenorphine + samidorphan is an opioid modulatory agent which has demonstrated replicated evidence of efficacy in TRD without abuse liability. Areas covered: Databases Pubmed, Google Scholar and clinicaltrials.gov were searched from inception through December 2017 for clinical trial information, pharmacokinetics, and pharmacodynamics of buprenorphine + samidorphan. Herein we provide a summary of the available information. Eight clinical trials were identified for inclusion, of the eight trials, five trials had available results and are included in detail in our review. Expert opinion: Buprenorphine + samidorphan has demonstrated efficacy in TRD. Extant evidence surrounding the safety and tolerability profile of buprenorphine + samidorphan does not identify any significant safety concerns. Additional studies are needed in order to assess the long-term safety and efficacy of this product.

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 neurogenic compound, NSI-189 phosphate: a novel multi-domain treatment capable of pro-cognitive and antidepressant effects

ABSTRACT Introduction: Alterations in neurogenic and neurotrophic processes as well as intracellular signalling cascades provides the basis for hypothesizing that neurogenic agents may be therapeutic across multiple RDoC-defined domains (e.g. positive valence systems, general cognitive processes). Moreover, using the DSM-5 taxonomy, neurogenic agents may mitigate symptoms in adults with depressive and bipolar disorders as well as individuals with cognitive disorders. Areas covered: NSI-189 is a benzylpiperizine-aminiopyridine, a novel chemical entity that stimulates neurogenesis of human hippocampus-derived neural stem cells in vitro and stimulates neurogenesis in murine hippocampus in vivo. Emerging evidence also indicates that NSI-189 phosphate has regionally specific effects insofar as neurogenesis is observed largely in the subventricular zone of the hippocampus. Results from a preliminary proof of concept study suggests that NSI-189 may be capable of mitigating depressive symptoms and improve cognitive function in adults with DSM-5-defined Major Depressive Disorder (MDD). Expert opinion: Preliminary proof-of-concept studies indicate both antidepressant and procognitive effects. Beneficial effects in cognitive-emotional processing as well as whether the procognitive effects are independent of antidepressant effects are vistas of future research. Taken together, NSI-189 is a multi-domain neurogenic compound with brain-therapeutic properties with potential therapeutic applications across disparate psychiatric disorders.

The use of brexpiprazole amongst individuals with insufficient outcomes with aripiprazole or bupropion: A case series

PURPOSE We sought to characterize the clinical experience of outpatients treated with brexpiprazole after achieving suboptimal outcomes with aripiprazole or bupropion as determined by the treating psychiatric provider. DESIGN AND METHODS Case series; inefficacy, intolerability, or other unsatisfactory outcome to previous trial with aripiprazole or bupropion. FINDINGS The majority of individuals in our sample exhibited tolerability of brexpiprazole. In addition, reduction in mean PHQ-9 scores was observed with brexpiprazole treatment. IMPLICATIONS The results of our preliminary analysis suggest that a subpopulation of adults who have insufficient outcomes on aripiprazole or bupropion due to intolerability, inefficacy or other unsatisfactory outcome may benefit by switching to brexpiprazole treatment. Larger randomized controlled trials are needed, as well as sophisticated network analysis to further understand efficacy and tolerability differences between atypical antipsychotics.

Predictors of Response to Ketamine in Treatment Resistant Major Depressive Disorder and Bipolar Disorder

Objectives: Extant evidence indicates that ketamine exerts rapid antidepressant effects in treatment-resistant depressive (TRD) symptoms as a part of major depressive disorder (MDD) and bipolar disorder (BD). The identification of depressed sub-populations that are more likely to benefit from ketamine treatment remains a priority. In keeping with this view, the present narrative review aims to identify the pretreatment predictors of response to ketamine in TRD as part of MDD and BD. Method: Electronic search engines PubMed/MEDLINE, ClinicalTrials.gov, and Scopus were searched for relevant articles from inception to January 2018. The search term ketamine was cross-referenced with the terms depression, major depressive disorder, bipolar disorder, predictors, and response and/or remission. Results: Multiple baseline pretreatment predictors of response were identified, including clinical (i.e., Body Mass Index (BMI), history of suicide, family history of alcohol use disorder), peripheral biochemistry (i.e., adiponectin levels, vitamin B12 levels), polysomnography (abnormalities in delta sleep ratio), neurochemistry (i.e., glutamine/glutamate ratio), neuroimaging (i.e., anterior cingulate cortex activity), genetic variation (i.e., Val66Met BDNF allele), and cognitive functioning (i.e., processing speed). High BMI and a positive family history of alcohol use disorder were the most replicated predictors. Conclusions: A pheno-biotype of depression more, or less likely, to benefit with ketamine treatment is far from complete. Notwithstanding, metabolic-inflammatory alterations are emerging as possible pretreatment response predictors of depressive symptom improvement, most notably being cognitive impairment. Sophisticated data-driven computational methods that are iterative and agnostic are more likely to provide actionable baseline pretreatment predictive information.

Pain and major depressive disorder: Associations with cognitive impairment as measured by the THINC-integrated tool (THINC-it)

Abstract Objectives To examine the role of pain on cognitive function in adults with major depressive disorder (MDD). Methods Adults (18–65) with a Diagnostic and Statistical Manual – Fifth Edition (DSM-5)-defined diagnosis of MDD experiencing a current major depressive episode (MDE) were enrolled (nMDD = 100). All subjects with MDD were matched in age, sex, and years of education to healthy controls (HC) (nHC = 100) for comparison. Cognitive function was assessed using the recently validated THINC-integrated tool (THINC-it), which comprises variants of the choice reaction time (i.e., THINC-it: Spotter), One-Back (i.e., THINC-it: Symbol Check), Digit Symbol Substitution Test (i.e., THINC-it: Codebreaker), Trail Making Test – Part B (i.e., THINC-it: Trails), as well as the Perceived Deficits Questionnaire for Depression – 5-item (i.e., THINC-it: PDQ-5-D). A global index of objective cognitive function was computed using objective measures from the THINC-it, while self-rated cognitive deficits were measured using the PDQ-5-D. Pain was measured using a Visual Analogue Scale (VAS). Regression analyses evaluated the role of pain in predicting objective and subjective cognitive function. Results A significant between-group differences on the VAS was observed (p < 0.001), with individuals with MDD reporting higher pain severity as evidenced by higher scores on the VAS than HC. Significant interaction effects were observed between self -rated cognitive deficits and pain ratings (p < 0.001) on objective cognitive performance (after adjusting for MADRS total score), suggesting that pain moderates the association between self-rated and objective cognitive function. Conclusions Results indicated that pain is associated with increased self-rated and objective cognitive deficits in adults with MDD. Implications The study herein provides preliminary evidence demonstrating that adults with MDD reporting pain symptomatology and poorer subjective cognitive function is predictive of poorer objective cognitive performance. THINC-it is capable of detecting cognitive dysfunction amongst adults with MDD and pain.