Ketamine induces multiple individually distinct whole-brain functional connectivity signatures.

Background: Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine's molecular mechanisms connect to its neural and behavioral effects. Methods: We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition. 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr). We quantified resting-state functional connectivity via data-driven global brain connectivity and related it to individual ketamine-induced symptom variation and cortical gene expression targets. Results: We found that: (i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; (ii) ketamine's data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, while the mean effect did not; and (iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level. Conclusions: These results highlight the importance of considering individual behavioral and neural variation in response to ketamine. They also have implications for the development of individually precise pharmacological biomarkers for treatment selection in psychiatry. Funding: This study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1-190420) (FXV, KHP); Swiss Neuromatrix Foundation (Grant No. 2016-0111) (FXV, KHP); Swiss National Science Foundation under the framework of Neuron Cofund (Grant No. 01EW1908) (KHP); Usona Institute (2015 - 2056) (FXV). Clinical trial number: NCT03842800.

Ketamine is a widely used anesthetic as well as a popular illegal recreational drug. Recently, it has also gained attention as a potential treatment for depression, particularly in cases that don't respond to conventional therapies. However, individuals can vary in their response to ketamine. For example, the drug can alter some people's perception, such as seeing objects as larger or small than they are, while other individuals are unaffected. Although a single dose of ketamine was shown to improve depression symptoms in approximately 65% of patients, the treatment does not work for a significant portion of patients. Understanding why ketamine does not work for everyone could help to identify which patients would benefit most from the treatment. Previous studies investigating ketamine as a treatment for depression have typically included a group of individuals given ketamine and a group given a placebo drug. Assuming people respond similarly to ketamine, the responses in each group were averaged and compared to one another. However, this averaging of results may have masked any individual differences in response to ketamine. As a result, Moujaes et al. set out to investigate whether individuals show differences in brain activity and behavior in response to ketamine. Moujaes et al. monitored the brain activity and behavior of 40 healthy individuals that were first given a placebo drug and then ketamine. The results showed that brain activity and behavior varied significantly between individuals after ketamine administration. Genetic analysis revealed that different gene expression patterns paired with differences in ketamine response in individuals ­ an effect that was hidden when the results were averaged. Ketamine also caused greater differences in brain activity and behavior between individuals than other drugs, such as psychedelics, suggesting ketamine generates a particularly complex response in people. In the future, extending these findings in healthy individuals to those with depression will be crucial for determining whether differences in response to ketamine align with how effective ketamine treatment is for an individual.

Brain glutamate and sleep efficiency associations following a ketogenic diet intervention in individuals with Alcohol Use Disorder.

Background: We previously showed that ketogenic diet (KD) was effective in curbing alcohol withdrawal and craving in individuals with alcohol use disorder (AUD). We hypothesized that the clinical benefits were due to improvements in sleep. To test this, we performed a secondary analysis on the KD trial data to (1) examine the effects of KD on total sleep time (TST) and sleep quality and (2) investigate the association between KD-induced alterations in cingulate glutamate concentration and changes in TST and sleep quality. Methods: AUD individuals undergoing alcohol detoxification were randomized to receive KD (n=19) or standard American diet (SA; n=14) for three weeks. TST was measured weekly by self-report, GENEActive sleep accelerometer, and X4 Sleep Profiler ambulatory device. Sleep quality was assessed using subjectively ratings of sleep depth and restedness and Sleep Profiler (Sleep Efficiency [%]). Weekly 1H magnetic resonance spectroscopy scans measured cingulate glutamate levels. Results: TST was lower in KD than SA and increased with effect of time. Sleep depth, restedness, and Sleep Efficiency improved with time, but exhibited no effect of diet. In KD and SA combined, week 1 cingulate glutamate levels correlated positively with Sleep Efficiency, but not with TST. Conclusions: Although cingulate glutamate levels correlated positively with Sleep Efficiency in week 1, KD-induced glutamate elevation did not produce significant sleep improvements. Rather, KD was associated with lower TST than SA. Given the well-established associations between sleep and alcohol relapse, longer follow up assessment of KD's impact on sleep in AUD is warranted.

Naltrexone + Bupropion Combination for the Treatment of Binge-eating Disorder with Obesity: A Randomized, Controlled Pilot Study.

PURPOSE: Binge-eating disorder (BED), the most prevalent eating disorder, is associated strongly with obesity and functional impairments. Few evidence-based treatments for BED exist; a pharmacotherapy effective in reducing both binge eating and weight needs to be identified. This placebo-controlled double-blind pilot RCT evaluated the acute effects of naltrexone + bupropion (NB) on BED with obesity and examined the longer-term effects through 6-month follow-up after the discontinuation of medication. METHODS: Twenty-two adult patients with BED were randomized to receive 12 weeks of double-blind treatment with fixed-dose NB (naltrexone + bupropion XL 50/300 mg) or placebo. Independent (blinded) researcher-clinicians evaluated patients at major outcome time points (baseline, posttreatment, and 6-month follow-up after the treatment period); patients were also evaluated for the tracking of course/tolerability throughout treatments and at 3-month follow-up. Primary outcomes were changes from baseline in binge-eating frequency and percentage weight. Secondary outcomes were changes in eating-disorder psychopathology and depression. FINDINGS: A total of 22 patients were enrolled (86.4% women; mean age, 50.4 years), with 77.3% of patients completing treatments; completion rates (NB, 83.3%; placebo, 70.0%) and adverse events did not differ significantly between NB and placebo. Analyses revealed significant reductions from baseline in binge-eating, eating-disorder psychopathology, depression, and weight during treatment, but these changes with NB did not differ significantly from those with placebo. The percentage of patients who attained 3% weight loss was significantly greater with NB than with placebo (45.5% vs 0%); weight-loss and binge-eating reductions were significantly correlated in the group that received NB. At 6-month follow-up, outcomes remained improved relative to baseline, with no significant differences between NB and placebo. IMPLICATIONS: The findings from this pilot RCT suggest that NB was well-tolerated in these patients with BED and comorbid obesity. Most outcomes were not statistically different between NB and placebo. A larger-scale, adequately powered RCT is needed for determining the efficacy of NB in the treatment of BED. ClinicalTrials.gov identifier: NCT02317744.

A robust and reproducible connectome fingerprint of ketamine is highly associated with the connectomic signature of antidepressants.

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 this longitudinal functional magnetic resonance imaging study of data from 265 participants, we used a validated predictive model approach that allows the full assessment of brain functional connectivity, without the need for seed selection or connectivity summaries. First, we identified a connectome fingerprint (CFP) in healthy participants (Cohort A, n = 25) during intravenous infusion of a subanesthetic dose of ketamine, compared to normal saline. We then demonstrated the robustness and reproducibility of the discovered ketamine CFP in two separate healthy samples (Cohort B, n = 22; Cohort C, n = 18). Finally, we investigated the ketamine CFP connectivity at 1-week post treatment in major depressive disorder patients randomized to 8 weeks of sertraline or placebo (Cohort D, n = 200). We found a significant, robust, and reproducible ketamine CFP, consistent with reduced connectivity within the primary cortices and within the executive network, but increased connectivity between the executive network and the rest of the brain. Compared to placebo, the ketamine CFP connectivity changes at 1 week predicted response to sertraline at 8 weeks. In each of Cohorts A-C, ketamine significantly increased connectivity in a previously identified antidepressant CFP. Investigating the brain connectivity networks, we successfully identified a robust and reproducible ketamine biomarker that is related to the mechanisms of antidepressants.

Randomized controlled trial testing the effectiveness of adaptive "SMART" stepped-care treatment for adults with binge-eating disorder comorbid with obesity.

This randomized controlled trial (RCT) tested effectiveness of adaptive SMART stepped-care treatment to "standard" behavioral weight loss (BWL [standard]) for patients with binge-eating disorder (BED) and obesity. One hundred ninety-one patients were randomly assigned to 6 months of BWL (standard; n = 39) or stepped care (n = 152). Within stepped care, patients started with BWL for 1 month; treatment responders continued BWL, whereas nonresponders switched to cognitive-behavioral therapy (CBT), and patients receiving stepped care were additionally randomized to weight-loss medication or placebo (double-blind) for the remaining 5 months. Independent assessments were performed reliably at baseline, throughout treatment, and posttreatment. Intent-to-treat (ITT) analyses of remission rates (zero binges/month) revealed that BWL (standard) and stepped care did not differ (74.4% vs. 66.5%); within stepped care, remission rates ranged 40.0% to 83.3%, with medication significantly superior to placebo (overall) and among nonresponders switched to CBT. Mixed-models analyses of binge-eating frequency revealed significant time effects, but BWL (standard) and stepped care did not differ; within stepped care, medication was significantly superior to placebo and among nonresponders switched to CBT. Mixed models revealed significant weight loss, but BWL (standard; 5.1% weight-loss) and stepped care (5.8% weight-loss) did not differ; within stepped care (range = 0.4% to 8.8% weight-loss), medication was significantly superior to placebo and among both responders continued on BWL and nonresponders switched to CBT. In summary, BWL (standard) and adaptive stepped-care treatments produced robust improvements in binge eating and weight loss in patients with BED/obesity. Within adaptive stepped care, weight-loss medication enhanced outcomes for BED/obesity. Implications for clinical practice and future adaptive designs are offered. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Efficacy and safety of a fatty acid amide hydrolase inhibitor (PF-04457845) in the treatment of cannabis withdrawal and dependence in men: a double-blind, placebo-controlled, parallel group, phase 2a single-site randomised controlled trial.

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 acid amide hydrolase (FAAH), the enzyme that degrades the endocannabinoid anandamide. We aimed to test the efficacy and safety of the FAAH-inhibitor PF-04457845 in reduction of cannabis withdrawal and cannabis use in men who were daily cannabis users. METHODS: We did a double-blind, placebo-controlled, parallel group phase 2a trial at one site in men aged 18-55 years with cannabis dependence according to DSM-IV criteria (equivalent to cannabis use disorder in DSM-5). After baseline assessments, participants were randomly assigned (2:1) to receive PF-04457845 (4 mg per day) or placebo using a fixed block size of six participants, stratified by severity of cannabis use and desire to quit. Participants were admitted to hospital for 5 days (maximum 8 days) to achieve abstinence and precipitate cannabis withdrawal, after which they were discharged to continue the remaining 3 weeks of treatment as outpatients. The primary endpoints were treatment-related differences in cannabis withdrawal symptoms during hospital admission, and week 4 (end of treatment) self-reported cannabis use and urine THC-COOH concentrations in the intention-to-treat population. The study is registered at ClinicalTrials.gov, number NCT01618656. FINDINGS: Between Sept 12, 2012, and Jan 18, 2016, 46 men were randomly assigned to PF-04457845 and 24 to placebo. Adherence to study medication was 88%, as confirmed by video-calling and pill count, and corroborated by corresponding drug and anandamide concentrations in blood. Relative to placebo, treatment with PF-04457845 was associated with reduced symptoms of cannabis withdrawal (first day of treatment mean symptom score 11·00 [95% CI 7·78-15·57] vs 6·04 [4·43-8·24]; difference 4·96 [0·71-9·21]; padj=0·048; second day of treatment 11·74 [8·28-16·66] vs 6·02 [4·28-8·47]; difference 5·73 [1·13-10·32]; padj=0·035) and related mood symptoms during the inpatient phase. Additionally, treatment with PF-04457845 was associated with lower self-reported cannabis use at 4 weeks (mean 1·27 joints per day [95% CI 0·82-1·97] vs 0·40 [0·25-0·62]; difference 0·88 [0·29-1·46]; p=0·0003) and lower urinary THC-COOH concentrations (mean 657·92 ng/mL [95% CI 381·60-1134·30] vs 265·55 [175·60-401·57]; difference 392·37 [17·55-767·18)]; p=0·009). Eight (17%) patients in the PF-04457845 group and four (17%) in the placebo group discontinued during the treatment period. During the 4-week treatment phase, 20 (43%) of 46 participants in the PF-04457845 group and 11 (46%) of 24 participants in the placebo group had an adverse event. There were no serious adverse events. INTERPRETATION: PF-04457845, a novel FAAH inhibitor, reduced cannabis withdrawal symptoms and cannabis use in men, and might represent an effective and safe approach for the treatment of cannabis use disorder. FUNDING: United States National Institute of Drug Abuse (NIDA).

The Barriers and Benefits to Developing Forensic Rotations for Psychiatry Residents.

Psychiatry residents' experiences in forensic psychiatry vary greatly across the country, and many psychiatry programs meet the Accreditation Council for Graduate Medical Education requirements for a forensic experience through general psychiatry rotations (e.g., on a consult-liaison service) or classroom-based activities. Forensic clinical experiences during psychiatry residency are important for preparing future general psychiatrists for practice with justice-involved patients, generating interest in forensic psychiatry, and easing the transition from "healer to evaluator" for future fellows. Unfortunately, residency programs interested in expanding their forensic training may face many challenges because of current regulatory frameworks, the nature of forensic practice, and competing demands within residency training programs. This article describes these challenges, and the experience of the authors at one institution with developing a novel forensic experience in a criminal justice diversion setting. The authors conclude with some practical considerations for educators interested in developing forensic experiences at their institutions.

Sleep Perception and Misperception in Chronic Cocaine Users During Abstinence.

Study Objectives: During abstinence, chronic cocaine users experience an objective worsening of sleep that is perceived as qualitatively improving. This phenomenon has been termed "occult insomnia." The objective of this study was to determine whether chronic cocaine users experience positive sleep state misperception during abstinence. Methods: Forty-three cocaine-dependent persons were admitted to an inpatient research facility for 12 days and 11 nights to participate in a treatment study of modafinil. Polysomnographic sleep recordings were performed on study nights 3, 4, 10, and 11, when participants were on average 1 and 2 weeks abstinent from cocaine. Participants also completed sleep diary questionnaires every evening before bed and every morning upon awakening. Polysomnographic and sleep diary measurements of total sleep time, sleep latency, time awake after sleep onset, and time in bed after final awakening were compared. Results: Chronic cocaine users accurately reported total sleep time after 1 week of abstinence but overreported total sleep time by an average of 40 min after 2 weeks of abstinence. Underestimating sleep latency and time spent awake after sleep onset were responsible for this difference. Conclusions: Positive sleep state misperception is revealed in chronic cocaine users after 2 weeks of abstinence and is consistent with the previously identified "occult insomnia" in this population.

Schizophrenia is associated with a pattern of spatial working memory deficits consistent with cortical disinhibition.

Schizophrenia is associated with severe cognitive deficits, including impaired working memory (WM). A neural mechanism that may contribute to WM impairment is the disruption in excitation-inhibition (E/I) balance in cortical microcircuits. It remains unknown, however, how these alterations map onto quantifiable behavioral deficits in patients. Based on predictions from a validated microcircuit model of spatial WM, we hypothesized two key behavioral consequences: i) increased variability of WM traces over time, reducing performance precision; and ii) decreased ability to filter out distractors that overlap with WM representations. To test model predictions, we studied N=27 schizophrenia patients and N=28 matched healthy comparison subjects (HCS) who performed a spatial WM task designed to test the computational model. Specifically, we manipulated delay duration and distractor distance presented during the delay. Subjects used a high-sensitivity joystick to indicate the remembered location, yielding a continuous response measure. Results largely followed model predictions, whereby patients exhibited increased variance and less WM precision as the delay period increased relative to HCS. Schizophrenia patients also exhibited increased WM distractibility, with reports biased toward distractors at specific spatial locations, as predicted by the model. Finally, the magnitude of the WM drift and distractibility were significantly correlated, indicating a possibly shared underlying mechanism. Effects are consistent with elevated E/I ratio in schizophrenia, establishing a framework for translating neural circuit computational model of cognition to human experiments, explicitly testing mechanistic behavioral hypotheses of cellular-level neural deficits in patients.

Computerized Cognitive Behavioral Therapy for Insomnia in a Community Health Setting.

STUDY OBJECTIVES: Insomnia, though quite common in the general population, is especially prevalent among individuals with co-occurring mental illnesses, patients whose condition can be further exacerbated by insomnia and vice versa. For individuals taking one or more psychotropic medications, cognitive behavioral therapy for insomnia (CBT-I), the gold standard in insomnia treatment, is a particularly favorable option (vis-à-vis pharmacotherapy). However, CBT-I can be inaccessible for persons with low socioeconomic status, a group that includes many with psychiatric diagnoses. Computer-based delivery of CBT-I (cb-CBT-I) has the potential to be a cost-effective tool that could greatly improve accessibility for this at-risk demographic. METHODS: Thirty-four participants with insomnia who were currently engaged in mental health care treatment were randomized to an active control group (sleep diary group; n = 16) or cb-CBT-I (n = 18) during weekly outpatient sessions over the course of 6 w. All participants completed sleep and activity logs at each appointment, whereas those in the cb-CBT-I group also completed one session of the cb-CBT-I program each week. RESULTS: cb-CBT-I treatment was associated with lower scores (improved sleep) on the Pittsburgh Sleep Quality Index (PSQI). Post hoc tests demonstrated a between groups difference at week 6 (p = 0.02), with a statistically significant decrease in PSQI scores in the cb-CBT-I group (p = 0.0006) but not in the sleep diary group (p = 0.35). CONCLUSIONS: cb-CBT-I improves sleep in individuals with insomnia and co-occurring mental illness. The significant improvements on the PSQI suggest that implementing a cb-CBT-I treatment in a community mental health center would be a simple and effective treatment for improving sleep over a short period of time. COMMENTARY: A commentary on this article appears in this issue on page 161.

Sleep abnormalities associated with alcohol, cannabis, cocaine, and opiate use: a comprehensive review.

Sleep abnormalities are associated with acute and chronic use of addictive substances. Although sleep complaints associated with use and abstinence from addictive substances are widely recognized, familiarity with the underlying sleep abnormalities is often lacking, despite evidence that these sleep abnormalities may be recalcitrant and impede good outcomes. Substantial research has now characterized the abnormalities associated with acute and chronic use of alcohol, cannabis, cocaine, and opiates. This review summarizes this research and discusses the clinical implications of sleep abnormalities in the treatment of substance use disorders.

Modafinil and sleep architecture in an inpatient-outpatient treatment study of cocaine dependence.

OBJECTIVE: To determine whether the increase in slow-wave sleep associated with modafinil treatment in chronic cocaine users mediates improved clinical outcomes. METHOD: 57 cocaine dependent participants were randomized to receive modafinil 400mg or placebo daily during a period of inpatient treatment followed by six weeks of outpatient treatment. Participants underwent polysomnographic sleep recording during inpatient treatment prior to and after starting modafinil. Outpatient treatment consisted of weekly cognitive behavioral therapy. Contingency management was used to promote participation in treatment and research demands, including thrice weekly visits during the outpatient phase for urine toxicology screens and other assessments. The primary clinical outcome was the percent of urine toxicology screens that were negative for cocaine. RESULTS: Modafinil treatment was associated with a higher mean percentage (52% vs. 26%) of cocaine-free urine screens (p=0.02) and an increase in N3 sleep time (p=0.002). The change in N3 sleep time mediated the higher rate of cocaine-free urine screens. Modafinil treatment was also associated with more consecutive days abstinent during outpatient treatment, greater survival of abstinence, higher daily rates of abstinence, and less sleep degradation typically associated with abstinence from chronic cocaine use. CONCLUSIONS: Morning-dosed modafinil improves slow-wave sleep in abstinent cocaine users in the inpatient setting, and this effect is a statistical mediator of improved clinical outcomes associated with continued modafinil treatment. The high rates of abstinence achieved in this trial suggest that promoting healthy sleep physiology in an inpatient setting may be important in the effective treatment of cocaine dependence.

Association of Cigarette Smoking With Interpersonal and Self-Directed Violence in a Large Community-Based Sample.

INTRODUCTION: Substance use is a major risk factor for various forms of violence, yet how cigarette smoking influences violence outcomes is incompletely understood. We investigated associations between cigarette smoking and three types of violence in a large, nationally representative, community-based sample. METHODS: Adult subjects participating in both Wave 1 (2001-2002; N = 43 093) and Wave 2 (2004-2005; N = 34 653) of the National Epidemiological Survey on Alcohol and Related Conditions (NESARC) were stratified by daily cigarette smoking status at Wave 1, and individuals with unchanged smoking status between waves were analyzed (nonsmokers [consisting of never and former daily smokers]: N = 22 529; daily smokers: N = 7442). We created composites of other- and self-directed violence and victimization occurring between Waves 1 and 2, and performed logistic regression models, controlling for psychiatric diagnoses, alcohol and substance use, and relevant demographic covariates. RESULTS: Daily smokers at Wave 1 were 2.1 (95% CI: 1.5-3.0), 2.5 (2.1-2.9), and 1.7 (1.5-2.1) times more likely than nonsmokers to report self-directed violence, other-directed violence, or victimization between Waves 1 and 2, respectively. Former daily smokers were significantly less likely to report other-directed violence than individuals who were never daily smokers. CONCLUSIONS: Daily cigarette smoking is temporally associated with multiple forms of violence compared to never and former cigarette smokers, even when common covariates associated with violence are controlled. Smoking status should be carefully controlled for in studies designed to identify risk factors for violence, and may be a useful component of violence risk assessment. IMPLICATIONS: The findings suggest that cigarette smoking status should be carefully and systematically controlled for in studies of violence risk factors. The findings also support further investigation of the utility of cigarette smoking status for violence risk assessment, and whether smoking cessation strategies mitigate violence risk.

Ketamine-Induced Hallucinations.

BACKGROUND: Ketamine, the NMDA glutamate receptor antagonist drug, is increasingly employed as an experimental model of psychosis in healthy volunteers. At subanesthetic doses, it safely and reversibly causes delusion-like ideas, amotivation and perceptual disruptions reminiscent of the aberrant salience experiences that characterize first-episode psychosis. However, auditory verbal hallucinations, a hallmark symptom of schizophrenia, have not been reported consistently in healthy volunteers even at high doses of ketamine. SAMPLING AND METHODS: Here we present data from a set of healthy participants who received moderately dosed, placebo-controlled ketamine infusions in the reduced stimulation environment of the magnetic resonance imaging (MRI) scanner. We highlight the phenomenological experiences of 3 participants who experienced particularly vivid hallucinations. RESULTS: Participants in this series reported auditory verbal and musical hallucinations at a ketamine dose that does not induce auditory hallucination outside of the scanner. CONCLUSIONS: We interpret the observation of ketamine-induced auditory verbal hallucinations in the context of the reduced perceptual environment of the MRI scanner and offer an explanation grounded in predictive coding models of perception and psychosis - the brain fills in expected perceptual inputs, and it does so more in situations of altered perceptual input. The altered perceptual input of the MRI scanner creates a mismatch between top-down perceptual expectations and the heightened bottom-up signals induced by ketamine. Such circumstances induce aberrant percepts, including musical and auditory verbal hallucinations. We suggest that these circumstances might represent a useful experimental model of auditory verbal hallucinations and highlight the impact of ambient sensory stimuli on psychopathology.

N-methyl-D-aspartate receptor antagonist effects on prefrontal cortical connectivity better model early than chronic schizophrenia.

BACKGROUND: Prefrontal cortex (PFC) function contributes to schizophrenia onset and progression. However, little is known about neural mechanisms behind PFC functional alterations along illness stages. Recent pharmacologic studies indicate that glutamate dysfunction may produce increased functional connectivity. However, pharmacologic models of schizophrenia overlook effects of illness progression on PFC function. This study compared N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist effects in healthy volunteers with stages of schizophrenia with respect to PFC functional connectivity. METHODS: First, we tested ketamine effects on PFC functional connectivity in healthy volunteers in a data-driven way (n = 19). Next, we compared healthy subjects (n = 96) with three clinical groups: individuals at high risk for schizophrenia (n = 21), people early in their course of schizophrenia (EC-SCZ) (n = 28), and patients with chronic illness (n = 20). Across independent analyses, we used data-driven global brain connectivity techniques restricted to PFC to identify functional dysconnectivity. RESULTS: Results revealed robust PFC hyperconnectivity in healthy volunteers administered ketamine (Cohen's d = 1.46), resembling individuals at high risk for schizophrenia and EC-SCZ. Hyperconnectivity was not found in patients with chronic illness relative to EC-SCZ patients. Results provide the first evidence that ketamine effects on PFC functional connectivity resemble early course but not chronic schizophrenia. CONCLUSIONS: Results suggest an illness phase-specific relevance of NMDAR antagonist administration for prefrontal dysconnectivity associated with schizophrenia. This finding has implications for the neurobiology of illness progression and for the widespread use of NMDAR antagonists in the development of therapeutics for schizophrenia.

Effects of endogenous and exogenous progesterone on emotional intelligence in cocaine-dependent men and women who also abuse alcohol.

OBJECTIVE: As sex differences in substance dependence may impinge upon the perception and regulation of emotion, we assess emotional intelligence (EI) as a function of gender, menstrual cycle (MC) phase and hormonal changes in early abstinent cocaine-dependent individuals who abuse alcohol (CDA). METHODS: Study 1: The Mayer, Salovey, and Caruso Emotional Intelligence Test (MSCEIT) was administered to 98 CDA (55 M/43 F) and 56 healthy (28 M/28 F) individuals. Performance in women was also assessed by MC phase. Study 2: The MSCEIT was administered to 28 CDA (19 M/9 F) who received exogenous progesterone (400 mg/day) versus placebo for 7 days (study 2). RESULTS: Study 1: Healthy females were better than healthy males at facilitating thought and managing emotions. This gender discrepancy was not observed in the CDA group. Additionally, all women in the high compared with the low progesterone phase of their MC were better at managing their emotions. Study 2: Exogenous progesterone improved ability to facilitate thought in both males and females. CONCLUSIONS: CDA women may be vulnerable to difficulties managing and regulating emotions. Gonadal hormones may contribute to this gender effect, as increases in both endogenous and exogenous progesterone improved selective aspects of EI.

Correlates of polysomnographic sleep changes in cocaine dependence: self-administration and clinical outcomes.

BACKGROUND: Abstinence from chronic cocaine use is associated with abnormal sleep architecture. As sleep abnormalities are associated with clinical outcome in alcohol dependence, we hypothesized a similar relationship in cocaine dependence. METHODS: We report data from a cocaine self-administration study (N=12) and the placebo arm of a randomized clinical trial (N=20). Self-administration participants underwent three cocaine self-administration sessions during a three-week inpatient stay. Treatment participants underwent two weeks of inpatient followed by six weeks of outpatient treatment including once-weekly cognitive behavioral therapy. Measurements included polysomnography from early and late in abstinence during the inpatient stays. Clinical outcomes included amount of cocaine self-administered, urine tests, and self-reported use and withdrawal symptoms. RESULTS: Change in slow-wave sleep from early to late abstinence (ΔSWS; p=0.05), late abstinence rapid eye movement sleep (REM; p=0.002), and late abstinence total sleep time (p=0.02) were negatively correlated with the amount of cocaine self-administered. Early abstinence REM was positively correlated with withdrawal symptoms (p=0.02). Late abstinence REM was positively correlated with percent negative urines and maximum consecutive number of days abstinent (both p<0.001). ΔSWS was positively correlated with percent negative urines (p=0.03) and participants with increased SWS had greater percent negative urines (p=0.008) and maximum consecutive number of days abstinent (p=0.009). CONCLUSIONS: Correlations between sleep deficits and amount of cocaine self-administered, clinical outcomes, and severity of withdrawal symptoms underscore the relevance of sleep in clinical outcomes in the treatment of cocaine dependence.

Preliminary evidence for normalization of risk taking by modafinil in chronic cocaine users.

Modafinil, a wake-promoting agent used to treat sleep disorders, is thought to enhance cognition. Although modafinil has shown promise as a pharmacotherapy for the treatment of cocaine dependence, it is unknown to what extent cognitive effects may play a role in such treatment. We examined the effect of modafinil on the Balloon Analogue Risk Task (BART), a behavioral measure in which higher scores are purported to reflect a greater propensity for risk-taking. Thirty cocaine dependent individuals, enrolled in a randomized clinical trial of modafinil 400mg (n=12) versus placebo (n=18), were administered the BART during the second week of inpatient treatment for cocaine dependence. A comparison cohort of healthy participants (n=19) performed the BART under similar conditions. Modafinil treatment was associated with significantly higher BART scores (p=0.01), which were comparable to scores in healthy persons. BART scores in placebo treated participants were much lower than previously reported in healthy participants, and lower than those observed in the comparison cohort. As propensity toward risk taking is typically associated with higher BART scores as well as increased risk for substance use, our findings may reflect a novel aspect of cognitive impairment related to chronic cocaine use. Notably, the low BART scores reflect highly suboptimal performance on the task, and the observed effect of modafinil may indicate a normalization of this impairment and have implications for treatment outcome.