Background/Objectives:Psychiatry lacks the objective clinical tests routinely used in other specializations. Novel computerized methods to characterize complex behaviors such as speech could be used to identify and predict psychiatric illness in individuals.AIMS:In this proof-of-principle study, our aim was to test automated speech analyses combined with Machine Learning to predict later psychosis onset in youths at clinical high-risk (CHR) for psychosis.Methods:Thirty-four CHR youths (11 females) had baseline interviews and were assessed quarterly for up to 2.5 years; five transitioned to psychosis. Using automated analysis, transcripts of interviews were evaluated for semantic and syntactic features predicting later psychosis onset. Speech features were fed into a convex hull classification algorithm with leave-one-subject-out cross-validation to assess their predictive value for psychosis outcome. The canonical correlation between the speech features and prodromal symptom ratings was computed.Results:Derived speech features included a Latent Semantic Analysis measure of semantic coherence and two syntactic markers of speech complexity: maximum phrase length and use of determiners (e.g., which). These speech features predicted later psychosis development with 100% accuracy, outperforming classification from clinical interviews. Speech features were significantly correlated with prodromal symptoms.Conclusions:Findings support the utility of automated speech analysis to measure subtle, clinically relevant mental state changes in emergent psychosis. Recent developments in computer science, including natural language processing, could provide the foundation for future development of objective clinical tests for psychiatry.

Language and speech are the primary source of data for psychiatrists to diagnose and treat mental disorders. In psychosis, the very structure of language can be disturbed, including semantic coherence (e.g., derailment and tangentiality) and syntactic complexity (e.g., concreteness). Subtle disturbances in language are evident in schizophrenia even prior to first psychosis onset, during prodromal stages. Using computer-based natural language processing analyses, we previously showed that, among English-speaking clinical (e.g., ultra) high-risk youths, baseline reduction in semantic coherence (the flow of meaning in speech) and in syntactic complexity could predict subsequent psychosis onset with high accuracy. Herein, we aimed to cross-validate these automated linguistic analytic methods in a second larger risk cohort, also English-speaking, and to discriminate speech in psychosis from normal speech. We identified an automated machine-learning speech classifier -comprising decreased semantic coherence, greater variance in that coherence, and reduced usage of possessive pronouns -that had an 83% accuracy in predicting psychosis onset (intra-protocol), a cross-validated accuracy of 79% of psychosis onset prediction in the original risk cohort (cross-protocol), and a 72% accuracy in discriminating the speech of recent-onset psychosis patients from that of healthy individuals. The classifier was highly correlated with previously identified manual linguistic predictors. Our findings support the utility and validity of automated natural language processing methods to characterize disturbances in semantics and syntax across stages of psychotic disorder. The next steps will be to apply these methods in larger risk cohorts to further test reproducibility, also in languages other than English, and identify sources of variability. This technology has the potential to improve prediction of psychosis outcome among at-risk youths and identify linguistic targets for remediation and preventive intervention. More broadly, automated linguistic analysis can be a powerful tool for diagnosis and treatment across neuropsychiatry.Key words: Automated language analysis, prediction of psychosis, semantic coherence, syntactic complexity, high-risk youths, machine learning (World Psychiatry 2018;17:67-75) Language offers a privileged view into the mind: it is the basis by which we infer others' thought processes, such that disorganized language is considered to reflect disorder in thought. Language disturbance is prevalent in schizophrenia and is related to functional disability, given that an individual needs to think and speak clearly in order to maintain friends and a job 1 . In schizophrenia, the speaker "violates the syntactical and semantic conventions which govern language usage", yielding reduction in syntactic complexity (concrete speech, poverty of content) and loss of semantic coherence, e.g. the disruption in flow of meaning in language (derailment, tangentiality) 2. This language disturbance is an early core feature of sch...

Background-MDMA (±3,4-methylenedioxymethamphetamine, 'ecstasy') users report that the drug produces unusual psychological effects, including increased empathy and prosocial feelings. These 'empathogenic' effects are cited as reasons for recreational ecstasy use, and also form the basis for the proposed use of MDMA in psychotherapy. However, they have yet to be characterized in controlled studies. Here, we investigate effects of MDMA on an important social cognitive capacity, the identification of emotional expression in others, and on socially-relevant mood states.

Cannabidiol (CBD), a constituent of cannabis with few psychoactive effects, has been reported in some studies to attenuate certain aspects of Δ 9 -tetrahydrocannabinol (THC) intoxication. However, most studies have tested only one dose of CBD in combination with one dose of oral THC, making it difficult to assess the nature of this interaction. Further, the effect of oral CBD on smoked cannabis administration is unknown. The objective of this multi-site, randomized, double-blind, within-subject laboratory study was to assess the influence of CBD (0, 200, 400, 800 mg, p.o.) pretreatment on the reinforcing, subjective, cognitive, and physiological effects of smoked cannabis (0.01 (inactive), 5.30-5.80% THC). Non-treatment-seeking, healthy cannabis smokers (n = 31; 17M, 14 F) completed eight outpatient sessions. CBD was administered 90 min prior to cannabis administration. The behavioral and cardiovascular effects of cannabis were measured at baseline and repeatedly throughout the session. A subset of participants (n = 8) completed an additional session to measure plasma CBD concentrations after administration of the highest CBD dose (800 mg). Under placebo CBD conditions, active cannabis (1) was self-administered by significantly more participants than placebo cannabis and (2) produced significant, time-dependent increases in ratings of 'High', 'Good Effect', ratings of the cannabis cigarette (eg, strength, liking), and heart rate relative to inactive cannabis. CBD, which alone produced no significant psychoactive or cardiovascular effects, did not significantly alter any of these outcomes. Cannabis self-administration, subjective effects, and cannabis ratings did not vary as a function of CBD dose relative to placebo capsules. These findings suggest that oral CBD does not reduce the reinforcing, physiological, or positive subjective effects of smoked cannabis.

RATIONALE ±3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) reportedly produces unique subjective effects, including increased sociability, feelings of closeness with others, and reduced interpersonal defensiveness. Despite their apparent importance in recreational and potential psychotherapeutic use of MDMA, the defining characteristics and neurobiological mechanisms of these interpersonal effects are poorly understood. MATERIALS AND METHODS We investigated acute effects of MDMA on self-reported sociability, and neuronal activation in response to socially threatening (angry and fearful faces) and socially rewarding (happy faces) stimuli. Assessment of social threat response focused on amygdala activation, whereas assessment of social reward focused on ventral striatum activation. Healthy volunteers (N=9) reporting past ecstasy use completed three experimental sessions, receiving MDMA (0.75mg/kg, and 1.5mg/kg), and placebo (PBO) under double-blind conditions. During peak drug effects, participants underwent functional magnetic resonance imaging while viewing standardized images depicting emotional facial expressions including angry, fearful, happy and neutral expressions. They also completed standardized self-report measures of sociability. RESULTS MDMA (1.5mg/kg) increased self-reported sociability compared to MDMA (0.75mg/kg) and PBO. MDMA (1.5mg/kg) attenuated left amygdala response to angry facial expressions compared to PBO, but MDMA did not affect amygdala reactivity to fearful expressions. MDMA (0.75mg/kg) enhanced ventral striatum response to happy expressions relative to PBO. CONCLUSIONS These data present the first evidence that MDMA may increase sociability in humans both by diminishing responses to threatening stimuli and enhancing responses to rewarding social signals.

Background Abstinent drug users remain at risk for relapse long after withdrawal subsides. Animal studies indicate that responses to drug-related cues not only persist, but increase, with abstinence, a phenomenon termed “incubation of drug craving”. It is unknown if cue-induced craving increases, decreases, or remains constant with abstinence in humans. We investigated effects of abstinence on cue-induced craving in cigarette smokers. Methods Eighty-six non-treatment-seeking, adult smokers (≥ 10 cigarettes daily) were paid to abstain for 7 (Group 1), 14 (Group 2), or 35 (Groups 3, 4) days. Abstinence was verified daily. Groups 1, 2, and 3 underwent a single cue session on the final abstinence day (7, 14, or 35). Group 4 viewed cues on days 7, 14, and 35. Results Between and within groups, smoking-cue-induced craving increased with abstinence on some measures. Cue-induced craving was greater in Group 3 (35-day) compared to Group 1 (7-day). Within Group 4, cue-induced craving was greater at 35 than 14 days. Cue-induced craving did not decrease with abstinence on any measure. Conclusions We present initial evidence of incubation of cue-induced craving in humans. The observation that cue-induced craving increases with abstinence, even as “background” craving and withdrawal symptoms subside, may have treatment implications.

Users of ±3,4-Methylenedioxymethamphetamine (MDMA; ‘ecstasy’) report prosocial effects such as sociability and empathy. Supporting these apparently unique social effects, data from controlled laboratory studies indicate that MDMA alters social feelings, information processing, and behavior in humans, and social behavior in rodents. Here, we review this growing body of evidence. In rodents, MDMA increases passive prosocial behavior (adjacent lying) and social reward while decreasing aggression, effects that may involve serotonin 1A receptor mediated oxytocin release interacting with vasopressin receptor 1A. In humans, MDMA increases plasma oxytocin and produces feelings of social affiliation. It decreases identification of negative facial expressions (cognitive empathy) and blunts responses to social rejection, while enhancing responses to others’ positive emotions (emotional empathy) and increasing social approach. Thus, consistent with drug folklore, laboratory administration of MDMA robustly alters social processing in humans and increases social approach in humans and animals. Effects are consistent with increased sociability, with mixed evidence about enhanced empathy. These neurobiologically-complex prosocial effects likely motivate recreational ecstasy use.

Few individuals seeking treatment for marijuana use achieve sustained abstinence. The cannabinoid receptor agonist, Δ(9)-tetrahydrocannabinol (THC; dronabinol), decreases marijuana withdrawal symptoms, yet does not decrease marijuana use in the laboratory or clinic. Dronabinol has poor bioavailability, which may contribute to its poor efficacy. The FDA-approved synthetic analog of THC, nabilone, has higher bioavailability and clearer dose-linearity than dronabinol. This study tested whether nabilone administration would decrease marijuana withdrawal symptoms and a laboratory measure of marijuana relapse relative to placebo. Daily, nontreatment-seeking marijuana smokers (8 men and 3 women), who reported smoking 8.3±3.1 marijuana cigarettes/day completed this within-subject study comprising three, 8-day inpatient phases; each phase tested a different nabilone dose (0, 6, 8 mg/day, administered in counter-balanced order on days 2-8). On the first inpatient day, participants took placebo capsules and smoked active marijuana (5.6% THC) at six timepoints. For the next 3 days, they had the opportunity to self-administer placebo marijuana (0.0% THC; withdrawal), followed by 4 days in which active marijuana was available for self-administration (5.6% THC; relapse). Both nabilone dose conditions decreased marijuana relapse and reversed withdrawal-related irritability and disruptions in sleep and food intake (p<0.05). Nabilone (8 mg/day) modestly worsened psychomotor task performance. Neither dose condition increased ratings of capsule 'liking' or desire to take the capsules relative to placebo. Thus, nabilone maintenance produced a robust attenuation of marijuana withdrawal symptoms and a laboratory measure of relapse even with once per day dosing. These data support testing of nabilone for patients seeking marijuana treatment.