Melanie M. Wall

Cannabis Use and Risk of Psychiatric Disorders: Prospective Evidence From a US National Longitudinal Study

IMPORTANCEnWith rising rates of marijuana use in the general population and an increasing number of states legalizing recreational marijuana use and authorizing medical marijuana programs, there are renewed clinical and policy concerns regarding the mental health effects of cannabis use.nnnOBJECTIVEnTo examine prospective associations between cannabis use and risk of mental health and substance use disorders in the general adult population.nnnDESIGN, SETTING, AND PARTICIPANTSnA nationally representative sample of US adults aged 18 years or older was interviewed 3 years apart in the National Epidemiologic Survey on Alcohol and Related Conditions (wave 1, 2001-2002; wave 2, 2004-2005). The primary analyses were limited to 34u202f653 respondents who were interviewed in both waves. Data analysis was conducted from March 15 to November 30, 2015.nnnMAIN OUTCOMES AND MEASURESnWe used multiple regression and propensity score matching to estimate the strength of independent associations between cannabis use at wave 1 and incident and prevalent psychiatric disorders at wave 2. Psychiatric disorders were measured with a structured interview (Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV). In both analyses, the same set of wave 1 confounders was used, including sociodemographic characteristics, family history of substance use disorder, disturbed family environment, childhood parental loss, low self-esteem, social deviance, education, recent trauma, past and present psychiatric disorders, and respondents history of divorce.nnnRESULTSnIn the multiple regression analysis of 34u202f653 respondents (14u202f564 male [47.9% weighted]; mean [SD] age, 45.1 [17.3] years), cannabis use in wave 1 (2001-2002), which was reported by 1279 respondents, was significantly associated with substance use disorders in wave 2 (2004-2005) (any substance use disorder: odds ratio [OR], 6.2; 95% CI, 4.1-9.4; any alcohol use disorder: OR, 2.7; 95% CI, 1.9-3.8; any cannabis use disorder: OR, 9.5; 95% CI, 6.4-14.1; any other drug use disorder: OR, 2.6; 95% CI, 1.6-4.4; and nicotine dependence: OR, 1.7; 95% CI, 1.2-2.4), but not any mood disorder (OR, 1.1; 95% CI, 0.8-1.4) or anxiety disorder (OR, 0.9; 95% CI, 0.7-1.1). The same general pattern of results was observed in the multiple regression analyses of wave 2 prevalent psychiatric disorders and in the propensity score-matched analysis of incident and prevalent psychiatric disorders.nnnCONCLUSIONS AND RELEVANCEnWithin the general population, cannabis use is associated with an increased risk for several substance use disorders. Physicians and policy makers should take these associations of cannabis use under careful consideration.

Mental disorders and risk of suicide attempt: a national prospective study

Most mental disorders, when examined independently, are associated with an elevated risk for suicide attempt. However, mental disorders often co-occur, and that co-occurrence is well explained by models where specific mental disorders are understood as manifestations of latent dimensions of psychopathology. To date, it remains unclear whether the risk of suicide attempt is due to specific mental disorders, to specific dimensions of psychopathology (that is, internalizing and externalizing dimensions), to a general psychopathology factor or to a combination of these explanations. In a large nationally representative prospective survey, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), we used structural equation modeling to examine the shared and specific effects of Axis I and Axis II disorders on the occurrence of suicide attempts in the general population and among individuals with a lifetime history of suicidal ideation. Effects of mental disorders on the risk of suicide attempt were exerted almost exclusively through a general psychopathology factor representing the shared effect across all mental disorders. Effects of remitted psychiatric disorders on the risk of suicide attempt were fully mediated by current mental disorders. Similar patterns of associations were found in individuals with suicidal ideation. These results held when using different approaches to modeling psychiatric comorbidity. Our findings underscore the importance of adopting dimensional approaches to comorbidity in the study of suicidal behavior. Because mental disorders increase the risk of suicide attempt through a general psychopathology liability, this dimension should be considered as an important therapeutic target to substantially advance suicide prevention.

Modeling and treating internalizing psychopathology in a clinical trial: a latent variable structural equation modeling approach

BACKGROUNDnClinical trials are typically designed to test the effect of a specific treatment on a single diagnostic entity. However, because common internalizing disorders are highly correlated (co-morbid), we sought to establish a practical and parsimonious method to characterize and quantify changes in a broad spectrum of internalizing psychopathology targeted for treatment in a clinical trial contrasting two transdiagnostic psychosocial interventions.nnnMETHODnAlcohol dependence treatment patients who had any of several common internalizing disorders were randomized to a six-session cognitive-behavioral therapy (CBT) experimental treatment condition or a progressive muscle relaxation training (PMRT) comparison treatment condition. Internalizing psychopathology was characterized at baseline and 4 months following treatment in terms of the latent structure of six distinct internalizing symptom domain surveys.nnnRESULTSnExploratory structural equation modeling (ESEM) identified a two-factor solution at both baseline and the 4-month follow-up: Distress (measures of depression, trait anxiety and worry) and Fear (measures of panic anxiety, social anxiety and agoraphobia). Although confirmatory factor analysis (CFA) demonstrated measurement invariance between the time-points, structural models showed that the latent means of Fear and Distress decreased substantially from baseline to follow-up for both groups, with a small but statistically significant advantage for the CBT group in terms of Distress (but not Fear) reduction.nnnCONCLUSIONSnThe approach demonstrated in this study provides a practical solution to modeling co-morbidity in a clinical trial and is consistent with converging evidence pointing to the dimensional structure of internalizing psychopathology.

Utility of Imaging-Based Biomarkers for Glutamate-Targeted Drug Development in Psychotic Disorders: A Randomized Clinical Trial

Importance Despite strong theoretical rationale and preclinical evidence, several glutamate-targeted treatments for schizophrenia have failed in recent pivotal trials, prompting questions as to target validity, compound inadequacy, or lack of target engagement. A key limitation for glutamate-based treatment development is the lack of functional target-engagement biomarkers for translation between preclinical and early-stage clinical studies. We evaluated the utility of 3 potential biomarkers—ketamine-evoked changes in the functional magnetic imaging (fMRI) blood oxygen level–dependent response (pharmacoBOLD), glutamate proton magnetic resonance spectroscopy (1H MRS), and task-based fMRI—for detecting ketamine-related alterations in brain glutamate. Objective To identify measures with sufficient effect size and cross-site reliability to serve as glutamatergic target engagement biomarkers within early-phase clinical studies. Design, Setting, and Participants This randomized clinical trial was conducted at an academic research institution between May 2014 and October 2015 as part of the National Institute of Mental Health–funded Fast-Fail Trial for Psychotic Spectrum Disorders project. All raters were blinded to study group. Healthy volunteers aged 18 to 55 years of either sex and free of significant medical or psychiatric history were recruited from 3 sites. Data were analyzed between November 2015 and December 2016. Interventions Volunteers received either sequential ketamine (0.23 mg/kg infusion over 1 minute followed by 0.58 mg/kg/h infusion over 30 minutes and then 0.29 mg/kg/h infusion over 29 minutes) or placebo infusions. Main Outcomes and Measures Ketamine-induced changes in pharmacoBOLD, 1H MRS, and task-based fMRI measures, along with symptom ratings. Measures were prespecified prior to data collection. Results Of the 65 volunteers, 41 (63%) were male, and the mean (SD) age was 31.1 (9.6) years; 59 (91%) had at least 1 valid scan. A total of 53 volunteers (82%) completed both ketamine infusions. In pharmacoBOLD, a highly robust increase (Cohen du2009=u20095.4; Pu2009<u2009.001) in fMRI response was observed, with a consistent response across sites. A smaller but significant signal (Cohen du2009=u20090.64; Pu2009=u2009.04) was also observed in 1H MRS–determined levels of glutamate+glutamine immediately following ketamine infusion. By contrast, no significant differences in task-activated fMRI responses were found between groups. Conclusions and Relevance These findings demonstrate robust effects of ketamine on pharmacoBOLD across sites, supporting its utility for definitive assessment of functional target engagement. Other measures, while sensitive to ketamine effects, were not sufficiently robust for use as cross-site target engagement measures. Trial Registration clinicaltrials.gov Identifier: NCT02134951

Temporal discounting across three psychiatric disorders: Anorexia nervosa, obsessive compulsive disorder, and social anxiety disorder

Temporal discounting refers to the tendency for rewards to lose value as the expected delay to receipt increases. Individuals with anorexia nervosa (AN) have been found to show reduced temporal discounting rates, indicating a greater preference for delayed rewards compared to healthy peers. Obsessive–compulsive disorder (OCD) and social anxiety disorder (SAD) commonly co‐occur with AN, and anxiety has been related to development and prognosis of AN. We examined whether reduced temporal discounting is present across these potentially related disorders, and explored the relationship between temporal discounting and anxiety transdiagnostically.

Attention bias in adults with anorexia nervosa, obsessive-compulsive disorder, and social anxiety disorder

BACKGROUNDnAttention bias to threat (selective attention toward threatening stimuli) has been frequently found in anxiety disorder samples, but its distribution both within and beyond this category is unclear. Attention bias has been studied extensively in social anxiety disorder (SAD) but relatively little in obsessive compulsive disorder (OCD), historically considered an anxiety disorder, or anorexia nervosa (AN), which is often characterized by interpersonal as well as body image/eating fears.nnnMETHODSnMedication-free adults with SAD (nxa0=xa043), OCD (nxa0=xa050), or AN (nxa0=xa030), and healthy control volunteers (HC, nxa0=xa074) were evaluated for attention bias with an established dot probe task presenting images of angry and neutral faces. Additional outcomes included attention bias variability (ABV), which summarizes fluctuation in attention between vigilance and avoidance, and has been reported to have superior reliability. We hypothesized that attention bias would be elevated in SAD and associated with SAD severity.nnnRESULTSnAttention bias in each disorder did not differ from HC, but within the SAD group attention bias correlated significantly with severity of social avoidance. ABV was significantly lower in OCD versus HC, and it correlated positively with severity of OCD symptoms within the OCD group.nnnCONCLUSIONSnFindings do not support differences from HC in attention bias to threat faces for SAD, OCD, or AN. Within the SAD sample, the association of attention bias with severity of social avoidance is consistent with evidence that attention bias moderates development of social withdrawal. The association of ABV with OCD diagnosis and severity is novel and deserves further study.

Validity of proposed DSM-5 diagnostic criteria for nicotine use disorder: results from 734 Israeli lifetime smokers.

BACKGROUNDnThe fifth edition of the diagnostic and statistical manual of mental disorders (DSM-5) proposes aligning nicotine use disorder (NUD) criteria with those for other substances, by including the current DSM fourth edition (DSM-IV) nicotine dependence (ND) criteria, three abuse criteria (neglect roles, hazardous use, interpersonal problems) and craving. Although NUD criteria indicate one latent trait, evidence is lacking on: (1) validity of each criterion ; (2) validity of the criteria as a set ; (3) comparative validity between DSM-5 NUD and DSM-IV ND criterion sets ; and (4) NUD prevalence.nnnMETHODnNicotine criteria (DSM-IV ND, abuse and craving) and external validators (e.g., smoking soon after awakening, number of cigarettes per day) were assessed with a structured interview in 734 lifetime smokers from an Israeli household sample. Regression analysis evaluated the association between validators and each criterion. Receiver operating characteristic analysis assessed the association of the validators with the DSM-5 NUD set (number of criteria endorsed) and tested whether DSM-5 or DSM-IV provided the most discriminating criterion set. Changes in prevalence were examined.nnnRESULTSnEach DSM-5 NUD criterion was significantly associated with the validators, with strength of associations similar across the criteria. As a set, DSM-5 criteria were significantly associated with the validators, were significantly more discriminating than DSM-IV ND criteria, and led to increased prevalence of binary NUD (two or more criteria) over ND.nnnCONCLUSIONSnAll findings address previous concerns about the DSM-IV nicotine diagnosis and its criteria and support the proposed changes for DSM-5 NUD, which should result in improved diagnosis of nicotine disorders.

Prepulse inhibition deficits only in females with obsessive-compulsive disorder

Deficits in sensorimotor gating have been hypothesized to underlie the inability to inhibit repetitive thoughts and behaviors. To test this hypothesis, this study assessed prepulse inhibition (PPI), a measure of sensorimotor gating, across three psychiatric disorders (obsessive–compulsive disorder [OCD], social anxiety disorder [SAD], and anorexia nervosa [AN]) whose clinical presentations include repetitive thoughts and behaviors

Examining heterotypic continuity of psychopathology: a prospective national study.

BACKGROUNDnIndividuals with one psychiatric disorder are at increased risk for incidence and recurrence of other disorders. We characterize whether the magnitude of such heterotypic continuity varies based on whether the first disorder remits or persists over time.nnnMETHODnCohorts were selected from participants in the National Epidemiologic Survey on Alcohol and Related Conditions wave 1 (2001-2002) and wave 2 (2004-2005) surveys with ⩾1 mood, anxiety, or substance use disorder at wave 1. Among respondents remitting (n = 6719) or not remitting (n = 3435) from ⩾1 of disorder at wave 2, the analyses compared the odds of developing new disorders.nnnRESULTSnAs compared with adults whose disorders persisted from wave 1 to wave 2, those with ⩾1 remission had lower odds of incidence or recurrence of another disorder. Remission from alcohol dependence [odds ratio (OR) 0.4, 95% confidence interval (CI) 0.3-0.5] and drug dependence (OR 0.4, 95% CI 0.3-0.6) were associated with the lowest odds of incidence of another disorder. Social anxiety disorder was associated with the lowest adjusted odds of recurrence (adjusted OR = 0.2, 95% CI 0.1-0.6). Remission of disorders within one class (mood, anxiety, substance use) was consistently associated with lower odds of incidence or recurrence of disorders from the same class than with developing disorders from the other classes.nnnCONCLUSIONSnRemission from common psychiatric disorders tends to decrease the risk for incidence or recurrence of disorders and this effect is stronger within than across disorder classes. These results do not support the concept of heterotypic continuity as a substitution of one disorder for another.

Results of a Coordinated Specialty Care Program for Early Psychosis and Predictors of Outcomes

OBJECTIVEnThis study prospectively evaluated outcomes of OnTrackNY, a statewide coordinated specialty care (CSC) program for treatment of early psychosis in community settings, as well as predictors of outcomes.nnnMETHODSnThe sample included 325 individuals ages 16-30 with recent-onset nonaffective psychosis who were enrolled in OnTrackNY and who had at least one three-month follow-up. Clinicians provided data at baseline and quarterly up to one year. Domains assessed included demographic and clinical characteristics, social and occupational functioning, medications, suicidality and violence, hospitalization, and time to intervention. Primary outcomes included the symptoms, occupational functioning, and social functioning scales of the Global Assessment of Functioning (GAF), as adapted by the U.S. Department of Veterans Affairs Mental Illness Research, Education and Clinical Center; education and employment status; and psychiatric hospitalization rate.nnnRESULTSnEducation and employment rates increased from 40% to 80% by six months, hospitalization rates decreased from 70% to 10% by three months, and improvement in GAF scores continued for 12 months. Female gender, non-Hispanic white race-ethnicity, and more education at baseline predicted better education and employment status at follow-up.nnnCONCLUSIONSnIndividuals with early psychosis receiving CSC achieved significant improvements in education and employment and experienced a decrease in hospitalization rate. Demographic variables and baseline education predicted education and employment outcomes. CSC teams should make particular effort to support the occupational goals of individuals at increased risk of not engaging in work or school, including male participants and participants from racial and ethnic minority groups.