Renee-Marie Ragguett

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.

Assessing and measuring cognitive function in major depressive disorder

Cognitive dysfunction is a major component of major depressive disorder (MDD). No ‘gold-standard’ tool exists for the assessment of cognitive dysfunction for adults with MDD. The use of measurement-based care to improve treatment outcomes invites the need for a systematic screening, evaluation and measurement tool. The aim herein was to provide a succinct summary of literature documenting clinical implication of cognitive dysfunction in MDD, and a review of available screening, diagnostic and measurement tools for cognitive dysfunction in MDD is provided. We also take the opportunity to introduce a screening tool (ie, the THINC-it tool) targeted at addressing the unmet needs. We found that there are limitations to the current measurement scales; for example, many are not targeted for MDD and not all digitally available tests are free of charge. Furthermore, the spectrum of cognitive dysfunction in MDD is poorly represented by the existing tests and as such, there is a lack of sensitivity in the ability to screen a patient with MDD for a cognitive dysfunction. Recognising and addressing the limitations in the current screening techniques for cognitive dysfunction as well as being presented with the current tools available provides the ability to perform an educated cognitive screening for a patient with MDD.

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.

Air pollution, aeroallergens and suicidality: a review of the effects of air pollution and aeroallergens on suicidal behavior and an exploration of possible mechanisms

Abstract Objective: Risk factors for suicide can be broadly categorized as sociodemographic, clinical and treatment. There is interest in environmental risk and protection factors for suicide. Emerging evidence suggests a link between environmental factors in the form of air pollution and aeroallergens in relation to suicidality. Methods: Herein, we conducted a systematic review of 15 articles which have met inclusion criteria on the aforementioned effects. Results: The majority of the reviewed articles reported an increased suicide risk alongside increased air pollutants or aeroallergens (i.e. pollen) increase; however, not all environmental factors were explored equally. In specific, studies that were delimited to evaluating particulate matter (PM) reported a consistent association with suicidality. We also provide a brief description of putative mechanisms (e.g. inflammation and neurotransmitter dysregulation) that may mediate the association between air pollution, aeroallergens and suicidality. Conclusion: Available evidence suggests that exposure to harmful air quality may be associated with suicidality. There are significant public health implications which are amplified in regions and countries with greater levels of air pollution and aeroallergens. In addition, those with atopic sensitivity may represent a specific subgroup that is at risk.

Therapeutic potential of JAK/STAT pathway modulation in mood disorders

Abstract Convergent evidence demonstrates that immune dysfunction (e.g. chronic low-grade inflammatory activation) plays an important role in the development and progression of mood disorders. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway is a pleiotropic cellular cascade that transduces numerous signals, including signals from the release of cytokines and growth factors. The JAK/STAT signaling pathway is involved in mediating several functions of the central nervous system, including neurogenesis, synaptic plasticity, gliogenesis, and microglial activation, all of which have been implicated in the pathophysiology of mood disorders. In addition, the antidepressant actions of current treatments have been shown to be mediated by JAK/STAT-dependent mechanisms. To date, two JAK inhibitors (JAKinibs) have been approved by the U.S. Food and Drug Administration and are primarily indicated for the treatment of inflammatory conditions such as rheumatoid arthritis. Indirect evidence from studies in populations with inflammatory conditions indicates that JAKinibs significantly improve measures of mood and quality of life. There is also direct evidence from studies in populations with depressive disorders, suggesting that JAK/STAT pathways may be involved in the pathophysiology of depression and that the inhibition of specific JAK/STAT pathways (i.e. via JAKinibs) may be a promising novel treatment for depressive disorders.

Serum metabolic profiling using small molecular water-soluble metabolites in individuals with schizophrenia: A longitudinal study using a pre-post-treatment design: Metabolic profiling for schizophrenia

We sought to compare alterations in serum bioenergetic markers within a well‐characterized sample of adults with schizophrenia at baseline and after 8 weeks of pharmacological treatment with the hypothesis that treatment would be associated with significant changes in bioenergetic markers given the role of bioenergetic dysfunction in schizophrenia.

Applications of machine learning algorithms to predict therapeutic outcomes in depression: A meta-analysis and systematic review

BACKGROUND No previous study has comprehensively reviewed the application of machine learning algorithms in mood disorders populations. Herein, we qualitatively and quantitatively evaluate previous studies of machine learning-devised models that predict therapeutic outcomes in mood disorders populations. METHODS We searched Ovid MEDLINE/PubMed from inception to February 8, 2018 for relevant studies that included adults with bipolar or unipolar depression; assessed therapeutic outcomes with a pharmacological, neuromodulatory, or manual-based psychotherapeutic intervention for depression; applied a machine learning algorithm; and reported predictors of therapeutic response. A random-effects meta-analysis of proportions and meta-regression analyses were conducted. RESULTS We identified 639 records: 75 full-text publications were assessed for eligibility; 26 studies (n=17,499) and 20 studies (n=6325) were included in qualitative and quantitative review, respectively. Classification algorithms were able to predict therapeutic outcomes with an overall accuracy of 0.82 (95% confidence interval [CI] of [0.77, 0.87]). Pooled estimates of classification accuracy were significantly greater (p < 0.01) in models informed by multiple data types (e.g., composite of phenomenological patient features and neuroimaging or peripheral gene expression data; pooled proportion [95% CI] = 0.93[0.86, 0.97]) when compared to models with lower-dimension data types (pooledproportion=0.68[0.62,0.74]to0.85[0.81,0.88]). LIMITATIONS Most studies were retrospective; differences in machine learning algorithms and their implementation (e.g., cross-validation, hyperparameter tuning); cannot infer importance of individual variables fed into learning algorithm. CONCLUSIONS Machine learning algorithms provide a powerful conceptual and analytic framework capable of integrating multiple data types and sources. An integrative approach may more effectively model neurobiological components as functional modules of pathophysiology embedded within the complex, social dynamics that influence the phenomenology of mental disorders.

Probiotics for the treatment of depressive symptoms: An anti-inflammatory mechanism?

During the past decade, there has been renewed interest in the relationship between brain-based disorders, the gut microbiota, and the possible beneficial effects of probiotics. Emerging evidence suggests that modifying the composition of the gut microbiota via probiotic supplementation may be a viable adjuvant treatment option for individuals with major depressive disorder (MDD). Convergent evidence indicates that persistent low-grade inflammatory activation is associated with the diagnosis of MDD as well as the severity of depressive symptoms and probability of treatment response. The objectives of this review are to (1) evaluate the evidence supporting an anti-inflammatory effect of probiotics and (2) describe immune system modulation as a potential mechanism for the therapeutic effects of probiotics in populations with MDD. A narrative review of studies investigating the effects of probiotics on systemic inflammation was conducted. Studies were identified using PubMed/Medline, Google Scholar, and clinicaltrials.gov (from inception to November 2017) using the following search terms (and/or variants): probiotic, inflammation, gut microbiota, and depression. The available evidence suggests that probiotics should be considered a promising adjuvant treatment to reduce the inflammatory activation commonly found in MDD. Several controversial points remain to be addressed including the role of leaky gut, the role of stress exposure, and the role of blood-brain-barrier permeability. Taken together, the results of this review suggest that probiotics may be a potentially beneficial, but insufficiently studied, antidepressant treatment intervention.

Efficacy of levomilnacipran extended release in treating major depressive disorder

ABSTRACT Introduction: Major depressive disorder (MDD) is the leading cause of disability worldwide with a heterogeneous symptom profile. Levomilnacipran extended release (ER) (Fetzima), a SNRI, has been approved by the Food and Drug Administration for treatment of MDD. While categorized as a SNRI, in contradistinction to other approved SNRIs, levomilnacipran exhibits differential affinity for the norepinephrine reuptake transporter when compared to the serotonin reuptake transporter. Areas covered: Completed clinical trials which focused on levomilnacipran ER administered in those with MDD were included in this drug evaluation. Expert opinion: Levomilnacipran ER, like all other first-line antidepressants exhibits significant efficacy in reducing total symptom severity. Levomilnacipran ER is particularly effective at improving measures of motivation, energy, and interest. Head to head comparative trials are not available with other antidepressants, and consequently, there are no claims of superior efficacy when compared to alternative antidepressants. Notwithstanding, it would be a viable and testable hypothesis that differential efficacy in favor of levomilnacipran may be obtained across select dimensions of depressive symptoms (e.g., fatigue and lack of motivation). Unfortunately, rigorous studies evaluating levomilnacipran for cognitive function in MDD have not been conducted. Levomilnacipran ER is generally well tolerated with minimal propensity for metabolic and weight disturbance.