Mohini Ranganathan's research while affiliated with Yale University and other places

Publications (114)

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Importance: Serious mental illnesses, including schizophrenia, bipolar disorder, and depression, are heritable, highly multifactorial disorders and major causes of disability worldwide. Objective: To benchmark the penetrance of current neuropsychiatric polygenic risk scores (PRSs) in the Veterans Health Administration health care system and to e...
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Importance: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment. Objective: To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes....
Preprint
Background The prevalence of cannabis use and Cannabis Use Disorder (CUD) are highest amongst adolescents and young adults. A lack of brain tissues from patients with CUD limits the ability to examine the molecular basis of cannabis related neuropathology. Proteomic studies of neuron-derived extracellular vesicles (NDEs) isolated from the biofluids...
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There is considerable interest in the therapeutic potential of psychedelic drugs. Dimethyltryptamine (DMT) is a potent, rapid-onset, and short-acting psychedelic drug that has not yet been independently tested for the treatment of depression. The safety, tolerability, and efficacy of intravenous DMT were investigated in treatment-resistant individu...
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The phenotype of schizophrenia (SZ), regardless of etiology, represents the most studied psychotic disorder with respect to neurobiology and distinct phases of illness. The early phase of illness represents a unique opportunity to provide effective and individualized interventions that can alter illness trajectories. Developmental age and illness s...
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Background Cannabis is the most common illicit drug used in the USA and its use has been rising over the past decade, while the historical gap in rates of use between men and women has been decreasing. Sex differences in the effects of cannabinoids have been reported in animal models, but human studies are sparse and inconsistent. We investigated t...
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Objective: Cannabis use (CU) is common among persons with bipolar disorder (BD). Evidence suggests that CU is associated with poorer outcomes among persons with BD; however, these findings remain inconsistent. The present exploratory study aims to examine clinical, functional, and cognitive correlates of CU among persons with BD. Methods: U.S. vete...
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Objectives: The liberalisation of cannabis laws, the increasing availability and potency of cannabis has renewed concern about the risk of psychosis with cannabis. Methods: The objective of the WFSBP task force was to review the literature about this relationship. Results: Converging lines of evidence suggest that exposure to cannabis increase...
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Background: THC and CBD are the principal phyto-cannabinoids in the cannabis plant. The differential and possibly antagonistic effects of these compounds on specific brain and behavioral responses, and the mechanisms underlying their effects have generated extensive interest in pre-clinical and clinical neuroscience investigations. Methods: In this...
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Suicide is a public health crisis with limited treatment options. Ketamine has demonstrated rapid and robust improvements in suicidal ideation (SI). The parent study for the secondary pilot analyses presented here was a double-blind, cross-over trial that found pretreatment with the mechanistic target of rapamycin complex 1 (mTORC1) prolonged the a...
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This study tested the efficacy of repeated intravenous ketamine doses to reduce symptoms of posttraumatic stress disorder (PTSD). Veterans and service members with PTSD (n = 158) who failed previous antidepressant treatment were randomized to 8 infusions administered twice weekly of intravenous placebo (n = 54), low dose (0.2 mg/kg; n = 53) or stan...
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Decreased synaptic spine density has been the most consistently reported postmortem finding in schizophrenia (SCZ). A recently developed in vivo measure of synaptic vesicle density estimated using the novel positron emission tomography (PET) ligand [11C]UCB-J is a proxy measure of synaptic density. In this study we determined whether [11C]UCB-J bin...
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Decades of research have highlighted the importance of optimal stimulation of cortical dopaminergic receptors, particularly the D1R receptor (D1R), for prefrontal-mediated cognition. This mechanism is particularly relevant to the cognitive deficits in schizophrenia, given the abnormalities in cortical dopamine (DA) neurotransmission and in the expr...
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Cannabis is one of the most commonly and widely used psychoactive drugs. The rates of cannabis misuse have been increasing. Therefore, understanding the effects of cannabis use on the brain is important. Adolescent and adult rodents exposed to repeated administration of cannabinoids show persistent microstructural changes in the hippocampus both pr...
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Aims To conduct a meta-analysis of the effect of ketamine on psychopathology in healthy volunteers and patients with schizophrenia, and the experimental factors affecting this. Background Ketamine is increasingly used to treat depression and other psychiatric disorders but can induce schizophrenia-like symptoms. Despite this, the consistency and m...
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Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the principal phyto-cannabinoids in the cannabis plant. The differential and possibly antagonistic effects of these compounds on specific brain and behavioral responses, and the mechanisms underlying their effects have generated extensive interest in pre-clinical and clinical neuroscience...
Preprint
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Background: This study tested the efficacy of repeated intravenous ketamine doses to reduce antidepressant-resistant symptoms of posttraumatic stress disorder (PTSD). Methods: Veterans and service members with PTSD (n=158) who failed previous antidepressant treatment were randomized to 8 infusions administered twice weekly of intravenous placebo (n...
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Objectives Extracellular vesicles, including exosomes, cross the blood brain barrier with their contents intact and can be assayed peripherally. Circulating exosomes have been studied in other neurodegenerative disorders, but there is scarce data in schizophrenia. This study aimed to examine neuropathology-relevant protein biomarkers in circulating...
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RationaleAnimal studies and anecdotal human reports suggest that cannabinoids have antinociceptive effects. Controlled human studies have produced mixed results.Objectives We sought to reduce existing variability by investigating the effects of intravenous delta-9-tetrahydrocannabinol (THC) in several pain paradigms within the same human subjects,...
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Over the past decade, various N-methyl-D-aspartate modulators have failed in clinical trials, underscoring the challenges of developing novel rapid-acting antidepressants based solely on the receptor or regional targets of ketamine. Thus, identifying the effect of ketamine on the brain circuitry and networks is becoming increasingly critical. In th...
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Importance Ketamine hydrochloride is increasingly used to treat depression and other psychiatric disorders but can induce schizophrenia-like or psychotomimetic symptoms. Despite this risk, the consistency and magnitude of symptoms induced by ketamine or what factors are associated with these symptoms remain unknown. Objective To conduct a meta-ana...
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Introduction: There is increasing interest in the relationship between cannabinoids and psychosis. While individual human laboratory studies have been critical in demonstrating that cannabinoids (e.g., delta-9-tetrahydrocannabinol [THC]) can induce acute transient psychosis-like effects in healthy human volunteers, combining data from multiple stu...
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Over the past decade, various N-Methyl-D-Aspartate modulators have failed in clinical trials, underscoring the challenges of developing novel rapid-acting antidepressants based solely on the receptor or regional targets of ketamine. Thus, identifying the effect of ketamine on the brain circuitry and networks is becoming increasingly critical. In th...
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Delta-9-tetrahydrocannabinol (THC) is known to modulate immune response in peripheral blood cells. The mechanisms of THC’s effects on gene expression in human immune cells remains poorly understood. Combining a within-subject design with single cell transcriptome mapping, we report that THC acutely alters gene expression in 15,973 blood cells. We i...
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Twenty-four hours after administration, ketamine exerts rapid and robust antidepressant effects that are thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine. Twenty patients sufferi...
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Background There is considerable interest in identifying peripheral biomarkers that reflect neuropathological changes in schizophrenia. Extracellular vesicles, including exosomes can cross the blood brain barrier with their contents intact and their cargo, including lipids, proteins and genetic materials can be assayed peripherally. Circulating exo...
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Rationale Δ-9-Tetrahydrocannabinol (Δ-9-THC) produces psychotomimetic effects in humans. However, the role of dopamine signaling in producing such effects is unclear. We hypothesized that dopaminergic antagonism would reduce the psychotomimetic effect of Δ-9-THC. Objective The objective of this study was to evaluate whether pre-treatment with halo...
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Rationale The catechol-O-methyl transferase (COMT) enzyme has been implicated in determining dopaminergic tone and the effects of delta-9-tetrahydrocannabinol (THC) in the human brain. Objective This study was designed to evaluate the effect of (1) a functional polymorphism and (2) acute pharmacological inhibition of COMT on the acute response to...
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Delta 9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, is also known to modulate immune response in peripheral cells. The mechanisms of THC's effects on gene expression in human immune cells remains poorly understood. Combining a within-subject design with single cell transcriptome mapping, we report that administra...
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Background Decreased synaptic spine density has been the most consistently reported neuropathological finding in postmortem studies of schizophrenia (SCZ). This has, however, not been verified in-vivo in humans to-date. The purpose of the study was to determine, for the first time, whether in-vivo measure of synaptic vesicle density estimated using...
Preprint
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BACKGROUND: Ketamine exerts rapid and robust antidepressant effects thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine. METHODS: Twenty-three patients suffering a major depressive...
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Purpose of Review To summarize the current literature on the effects of cannabinoids in humans and to discuss the existing literature on the sex- and gender-related differences in the effects of cannabinoids. Recent Findings Cannabis and its constituent cannabinoids are associated with risk of addiction, cognitive deficits, and mood/psychotic diso...
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Background Cannabis is one of the most widely used drugs worldwide. Cannabis use disorder is characterised by recurrent use of cannabis that causes significant clinical and functional impairment. There are no approved pharmacological treatments for cannabis use disorder. One approach is to potentiate endocannabinoid signalling by inhibiting fatty a...
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Background: Binding studies have demonstrated that levels of the cannabinoid receptor type-1 are highest in the basal ganglia and cerebellum, two areas critical for motor control. However, no studies have systematically examined the dose-related effects of intravenous delta-9-tetrahydrocannabinol, the primary cannabinoid receptor type-1 partial ag...
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We assessed the acceptability of nurse-delivered mobile phone-based counseling to support adherence to antiretroviral treatment (ART) and self-care behaviors among HIV-positive women in India. We conducted open-ended, in-depth interviews with 27 HIV-positive women and 19 key informants at a government ART center in Karnataka, India. Data were analy...
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Rationale: Preliminary evidence suggests that cannabidiol (CBD) may be effective in the treatment of neurodegenerative disorders; however, CBD has never been evaluated for the treatment of cognitive impairments associated with schizophrenia (CIAS). Objective: This study compared the cognitive, symptomatic, and side effects of CBD versus placebo...
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Background Cannabidiol is a component of herbal cannabis, studied for a number of potential pharmaceutical indications, more recently, its potential anti-psychotic effects with an extremely favorable side effect profile. Cannabidiol content of cannabis may also attenuate the psychotic and cognitive effects associated with cannabis use. Early psycho...
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With rising rates of cannabis use in the general population and an increasing number of US states legalizing both recreational and medical cannabis use, it is important to be informed about the adverse consequences of cannabinoids. This Commentary provides an overview of the psychiatric effects of plant-based and synthetic cannabinoids, differentia...
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Cannabis use has been associated with altered sensory gating and neural oscillations. However, it is unclear which constituent in cannabis is responsible for these effects, or whether these are cannabinoid receptor 1 (CB1R) mediated. Therefore, the present study in humans and rats examined whether cannabinoid administration would disrupt sensory ga...
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Background: Glycine transporter-1 (GlyT1) inhibitors may ameliorate cognitive impairments associated with schizophrenia. The dose-related occupancy and target engagement of the GlyT1 inhibitor PF-03463275 were studied to inform optimal dose selection for a clinical trial for cognitive impairments associated with schizophrenia. Methods: In substu...
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Preclinical and clinical data suggest that the cannabinoid and glutamatergic systems are implicated in the pathophysiology of schizophrenia (SZ), the prototypical psychotic disorder. This has led to distinct “cannabis” and “ketamine” models of SZ, respectively. However, these two models need not be mutually exclusive. Indeed, in several brain regio...
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The plant Cannabis sativa, commonly called cannabis or marijuana, has been used for its psychotropic and mind-altering side effects for millennia. There has been growing attention in recent years on its potential therapeutic efficacy as municipalities and legislative bodies in the United States, Canada, and other countries grapple with enacting pol...
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N-methyl-d-aspartate glutamate receptor (NMDAR) hypofunction has been implicated in the pathophysiology of schizophrenia, including auditory processing abnormalities reflected by the mismatch negativity (MMN) event-related potential component. Evidence suggesting cognitive benefits from nicotine administration, together with the high rate of cigare...
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One prominent, long-standing view is that individuals with schizophrenia smoke cigarettes more than the general population to "self-medicate" cognitive deficits and other symptoms. This study tested the self-medication hypothesis by examining the effects of smoking abstinence and resumption on cognition in patients with schizophrenia. Nicotine-depe...
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There is a need to develop treatments for cognitive impairment associated with schizophrenia (CIAS). The significant role played by N-methyl-d-aspartate receptors (NMDARs) in both the pathophysiology of schizophrenia and in neuronal plasticity suggests that facilitation of NMDAR function might ameliorate CIAS. One strategy to correct NMDAR hypofunc...
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Cannabis is being increasingly used as a medical treatment for a variety of illnesses. However, the cannabis plant has more than 70 different phytocannabinoids with potential pharmacologic activity. Two of the most researched phytocannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Evidence suggests CBD can decrease some of t...
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There is growing interest in the relationship between cannabis and psychosis. The link between cannabis use and psychosis comprises three distinct relationships: acute psychosis associated with cannabis intoxication, acute psychosis that lasts beyond the period of acute intoxication, and persistent psychosis not time-locked to exposure. Experimenta...
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Background Women living with HIV are vulnerable to a variety of psychosocial barriers that limit access and adherence to treatment. There is little evidence supporting interventions for improving access and treatment adherence among vulnerable groups of women in low- and middle-income countries. The Mobile Phone-BasedApproach forHealthImprovement,L...
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Objective: Medication nonadherence is a serious issue in clinical trials, especially in studies of substance abuse disorders. Measuring and confirming adherence is critical to ensuring that collected data is accurate and interpretable. This study evaluated the feasibility and success of a smartphone-based approach (Cellphone Assisted Remote Observ...
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Some of the most compelling evidence supporting an association between cannabinoid agonists and psychosis comes from controlled laboratory studies in humans. Randomized, double-blinded, placebo-controlled, crossover laboratory studies demonstrate that cannabinoid agonists including phyto-cannabinoids and synthetic cannabinoids produce a wide range...
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Psychotic disorders including schizophrenia are amongst the most debilitating psychiatric disorders. There is an urgent need to develop methods to identify individuals at risk with greater precision and as early as possible. At present, a prerequisite for a diagnosis of schizophrenia is the occurrence of a psychotic episode. Therefore, attempting t...
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The kappa opioid receptor (KOR) is thought to play an important therapeutic role in a wide range of neuropsychiatric and substance abuse disorders, including alcohol dependence. LY2456302 is a recently-developed KOR antagonist with high affinity and selectivity, and showed efficacy in suppression of ethanol consumption in rats. This study investiga...
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Background: Several lines of evidence suggest the presence of abnormalities in the endocannabinoid (eCB) system in schizophrenia (SCZ). However, there are limited in vivo measures of the eCB system in SCZ. Methods: Twenty five male SCZ subjects (SCZs) (18 antipsychotic treated and 7 antipsychotic free) were compared with 18 age-matched male heal...
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Background: The widespread use of cannabis, the increasing legalization of "medical" cannabis, the increasing potency of cannabis and the growing recreational use of synthetic cannabinoid 1 receptor (CB1R) full agonists underscores the importance of elucidating the effects of cannabinoids on the CB1R system. Exposure to cannabinoids is known to re...
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This Editorial discusses some of the medical and legal considerations surrounding use of medical marijuana and cannabinoid drugs. There is a pressing need to develop new medications for many debilitating conditions. Novel approaches based on marijuana or its constituent cannabinoids, if proven, could be added to the armamentarium of available trea...