Andrew Glass

The Utility of Attention-Deficit/Hyperactivity Disorder Screening Instruments in Individuals Seeking Treatment for Substance Use Disorders

OBJECTIVE Several screening tools for attention-deficit/hyperactivity disorder (ADHD) have been validated in non-substance-abusing populations, but limited data are available regarding their utility in adults with current substance use disorders. The aim of this study was to determine the sensitivity, specificity, and positive and negative predictive values of 3 commonly used ADHD screening instruments in cocaine-dependent individuals. METHOD Adults seeking treatment for cocaine dependence (N = 102) were administered 3 self-report instruments between May 2009 and April 2011: the Conners Adult ADHD Rating Scale (CAARS), the Wender Utah Rating Scale (WURS), and the Adult ADHD Self-Report Scale-Version 1.1 (ASRS-V1.1). They then met with masters-level clinicians who administered the Conners Adult ADHD Diagnostic Interview for DSM-IV (CAADID). With the CAADID serving as the gold standard, the validity of the screening instruments was determined, both singly and in combination. RESULTS Twenty-five (25%) of the 102 patients met DSM-IV criteria for ADHD or ADHD not otherwise specified (NOS) based on the CAADID. Kappa scores determining agreement between the screening tools and the CAADID (with ADHD NOS labeled as ADHD or labeled as not ADHD) ranged from 0.37 to 0.69. Sensitivity scores for the broadest range of ADHD cases were 80.0%, 87.5%, and 60.9% for the CAARS, WURS, and ASRS-V1.1, respectively. Positive predictive value was highest for the CAARS, at 74.1%, and negative predictive value was highest for the WURS, at 95.1%. The highest sensitivity (96.0%) was found with coadministration of the WURS and CAARS. CONCLUSION While all of the screening instruments were found to have adequate sensitivity and specificity, the CAARS outperformed the other instruments in regard to agreement with the CAADID and positive predictive values. However, the WURS, with the highest sensitivity in regard to the broadest range of ADHD cases, may be the single best instrument for preliminary screening purposes. Further, because the ASRS-V1.1 is the simplest and shortest instrument to administer, it may have advantages when a large number of patients need to be screened.

Naltrexone Maintenance Decreases Cannabis Self-Administration and Subjective Effects in Daily Cannabis Smokers

Given that cannabis use is increasing in the United States, pharmacological treatment options to treat cannabis use disorder are needed. Opioid antagonists modulate cannabinoid effects and may offer a potential approach to reducing cannabis use. In this double-blind, placebo-controlled human laboratory study, we assessed the effects of naltrexone maintenance on the reinforcing, subjective, psychomotor, and cardiovascular effects of active and inactive cannabis. Nontreatment-seeking, daily cannabis smokers were randomized to receive naltrexone (50 mg: n=18 M and 5 F) or placebo (0 mg; n=26 M and 2 F) capsules for 16 days. Before, during, and after medication maintenance, participants completed 10 laboratory sessions over 4–6 weeks, assessing cannabis’ behavioral and cardiovascular effects. Medication compliance was verified by observed capsule administration, plasma naltrexone, and urinary riboflavin. Relative to placebo, maintenance on naltrexone significantly reduced both active cannabis self-administration and its positive subjective effects (‘good effect’). Participants in the placebo group had 7.6 times (95% CI: 1.1–51.8) the odds of self-administering active cannabis compared with the naltrexone group. This attenuation of reinforcing and positive subjective effects also influenced cannabis use in the natural ecology. Naltrexone had intrinsic effects: decreasing ratings of friendliness, food intake, and systolic blood pressure, and increasing spontaneous reports of stomach upset and headache, yet dropout rates were comparable between groups. In summary, we show for the first time that maintenance on naltrexone decreased cannabis self-administration and ratings of ‘good effect’ in nontreatment-seeking daily cannabis smokers. Clinical studies in patients motivated to reduce their cannabis use are warranted to evaluate naltrexone’s efficacy as a treatment for cannabis use disorder.

The effects of ibudilast, a glial activation inhibitor, on opioid withdrawal symptoms in opioid‐dependent volunteers

Glial activation is hypothesized to contribute directly to opioid withdrawal. This study investigated the dose‐dependent effects of a glial cell modulator, ibudilast, on withdrawal symptoms in opioid‐dependent volunteers after abrupt discontinuation of morphine administration. Non‐treatment‐seeking heroin‐dependent volunteers (n = 31) completed the in‐patient, double‐blind, placebo‐controlled, within‐subject and between‐group study. Volunteers were maintained on morphine (30 mg, QID) for 14 days and placebo (0 mg, QID) for the last 7 days of the 3‐week study. Volunteers also received placebo (0 mg, PO, BID) capsules on days 1–7. On days 8–21, volunteers were randomized to receive ibudilast (20 or 40 mg, PO, BID) or placebo capsules. Subjective and clinical ratings of withdrawal symptoms were completed daily using daily using the Subjective Opioid Withdrawal Scale (SOWS) and Clinical Opioid Withdrawal Scale (COWS). Medication side effects were also monitored. Relative to the first 2 weeks, all groups exhibited withdrawal during the third week as assessed by the SOWS and COWS (P ≤ 0.0001). Although overall SOWS scores did not differ between groups, exploratory analyses pooling the two ibudilast groups demonstrated that they had lower ratings of withdrawal symptoms on SOWS items (‘anxious,’ ‘perspiring,’ ‘restless,’ ‘stomach cramps’) during detoxification relative to the placebo group. Ibudilast was well tolerated; no serious adverse events occurred during the study. Pharmacological modulation of glial activity with ibudilast decreased some subjective ratings of opioid withdrawal symptoms. These exploratory findings are the first to demonstrate the potential clinical utility of glial modulators for treating opioid withdrawal in humans.

The effects of dronabinol during detoxification and the initiation of treatment with extended release naltrexone

BACKGROUND Evidence suggests that the cannabinoid system is involved in the maintenance of opioid dependence. We examined whether dronabinol, a cannabinoid receptor type 1 partial agonist, reduces opioid withdrawal and increases retention in treatment with extended release naltrexone (XR-naltrexone). METHODS Opioid dependent participants were randomized to receive dronabinol 30mg/d (n=40) or placebo (n=20), under double-blind conditions, while they underwent inpatient detoxification and naltrexone induction. Before discharge all participants received an injection of XR-naltrexone, with an additional dose given four weeks later. Dronabinol or placebo was given while inpatient and for 5 weeks afterwards. The primary outcomes were the severity of opioid withdrawal, measured with the Subjective Opioid Withdrawal Scale, and retention in treatment at the end of the inpatient phase and at the end of the 8-week trial. RESULTS The severity of opioid withdrawal during inpatient phase was lower in the dronabinol group relative to placebo group (p=0.006). Rates of successful induction onto XR-naltrexone (dronabinol 66%, placebo 55%) and completion of treatment (dronabinol 35%, placebo 35%) were not significantly different. Post hoc analysis showed that the 32% of participants who smoked marijuana regularly during the outpatient phase had significantly lower ratings of insomnia and anxiety and were more likely to complete the 8-week trial. CONCLUSION Dronabinol reduced the severity of opiate withdrawal during acute detoxification but had no effect on rates of XR-naltrexone treatment induction and retention. Participants who elected to smoke marijuana during the trial were more likely to complete treatment regardless of treatment group assignment.

Dronabinol and lofexidine for cannabis use disorder: A randomized, double-blind, placebo-controlled trial ☆

BACKGROUND Cannabis use disorder is associated with substantial morbidity and, after alcohol, is the most common drug bringing adolescents and adults into treatment. At present, there are no FDA-approved medications for cannabis use disorder. Combined pharmacologic interventions might be particularly useful in mitigating withdrawal symptoms and promoting abstinence. OBJECTIVE The purpose of this study was to evaluate the safety and efficacy of dronabinol, a synthetic form of delta-9-tetrahydrocannabinol, a naturally occurring pharmacologically active component of marijuana, and lofexidine, an alpha-2 agonist, in treating cannabis dependence. METHODS One hundred fifty six cannabis-dependent adults were enrolled and following a 1-week placebo lead-in phase 122 were randomized in a double-blind, placebo-controlled, 11-week trial. Participants were randomized to receive dronabinol 20mg three times a day and lofexidine 0.6 mg three times a day or placebo. Medications were maintained until the end of week eight, were then tapered over two weeks and patients were monitored off medications during the last study week. All participants received weekly motivational enhancement and relapse prevention therapy. Marijuana use was assessed using the timeline follow-back method. RESULTS There was no significant difference between treatment groups in the proportion of participants who achieved 3 weeks of abstinence during the maintenance phase of the trial (27.9% for the medication group and 29.5% for the placebo group), although both groups showed a reduction over time. CONCLUSIONS Based on this treatment study, the combined intervention did not show promise as a treatment for cannabis use disorder.

COMBINED MIRTAZAPINE AND SSRI TREATMENT OF PTSD: A PLACEBO-CONTROLLED TRIAL

Combined treatment with a selective serotonin reuptake inhibitor (SSRI) plus mirtazapine has shown superior efficacy in some studies of depression, but has not been studied in posttraumatic stress disorder (PTSD). This study aimed to assess acceptability of combined sertraline plus mirtazapine treatment for PTSD and to estimate its effect size relative to sertraline plus placebo.

A placebo-controlled trial of memantine as an adjunct to injectable extended-release naltrexone for opioid dependence

There is preclinical support for using NMDA receptor glutamatergic antagonists to aid in naltrexone-based treatment of opioid dependence. We hypothesized that adding memantine will improve efficacy of extended-release (XR) naltrexone to prevent relapse. In this double blind study opioid-dependent participants (N=82) underwent inpatient detoxification and naltrexone induction. During naltrexone initiation participants were randomized to receive memantine 40 mg or placebo and continued treatment for 12-weeks with XR naltrexone and relapse-prevention therapy. Sixty eight percent of participants completed detoxification and received the first dose of XR naltrexone. Rates of trial completion were significantly greater in participants receiving placebo than memantine (70% vs. 43%, p<0.05). Severity of opioid withdrawal symptoms during the first 3 weeks of the trial appeared to be lower in the group receiving memantine (p=0.07). Adding memantine does not appear to increase the effectiveness of injectable XR naltrexone as a relapse prevention strategy in opioid dependence and may lead to an increase in treatment drop-out.

A proof-of-concept, randomized controlled trial of DAR-0100A, a dopamine-1 receptor agonist, for cognitive enhancement in schizophrenia:

Background: Evidence from preclinical and human studies indicates the presence of reduced dopamine-1 receptor (D1R) signaling in the cortex, where D1Rs predominate, in patients with schizophrenia (SCZ), which may contribute to their cognitive deficits. Furthermore, studies in nonhuman primates (NHP) have suggested that intermittent administration of low doses of D1R agonists produce long-lasting reversals in cognitive deficits. The purpose of this trial was to test whether a similar design, involving subacute intermittent administration of low doses of a full, selective agonist at D1Rs, DAR-0100A, would improve cognitive deficits in SCZ. Methods: We randomized 49 clinically stable individuals with SCZ to three weeks of intermittent treatment with 0.5 mg or 15 mg of DAR-0100A, or placebo (normal saline). Functional magnetic resonance imaging (fMRI) BOLD was used to evaluate the effects of drug administration on brain activity during a working memory (WM) task. Effects on cognition were also assessed using the MATRICS and the N-back task as primary endpoints. The CogState battery was used as a secondary endpoint. Results: There were no observed treatment effects on either the BOLD fMRI signal during WM tasks or the WM domains of the MATRICS. Moderate improvement was detected on the CogState battery and on the attention domain of the MATRICS. Conclusion: These results suggest that low doses of D1 agonists that do not result in measureable occupancy of the D1R do not reliably improve cognition in SCZ, unlike the observations in NHP. As this drug is limited by its pharmacokinetic profile, better D1R agonists that can achieve adequate levels of D1R occupancy are needed to test the efficacy of this mechanism for cognitive enhancement in SCZ.

The Development of the DSM-5 Cultural Formulation Interview-Fidelity Instrument (CFI-FI): A Pilot Study

This paper reports on the development of the Cultural Formulation Interview-Fidelity Instrument (CFI-FI) which assesses clinician fidelity to the DSM-5 Cultural Formulation Interview (CFI). The CFI consists of a manualized set of standard questions that can precede every psychiatric evaluation. It is based on the DSM-IV Outline for Cultural Formulation, the cross-cultural assessment with the most evidence in psychiatric training. Using the New York sample of the DSM-5 CFI field trial, two independent raters created and finalized items for the CFI-FI based on six audio-taped and transcribed interviews. The raters then used the final CFI-FI to rate the remaining 23 interviews. Inter-rater reliability ranged from .73 to 1 for adherence items and .52 to 1 for competence items. The development of the CFI-FI can help researchers and administrators determine whether the CFI has been implemented with fidelity, permitting future intervention research.

Opioid use and dropout in patients receiving oral naltrexone with or without single administration of injection naltrexone

BACKGROUND Adherence to oral naltrexone has been poor and can be improved somewhat with behavioral therapy. We compared behavioral naltrexone therapy (BNT) to compliance enhancement (CE) and tested efficacy of single-dose injection naltrexone (XR-NTX; 384 mg) with behavioral therapies at further improving adherence to oral naltrexone. METHODS A 24-week, randomized, placebo-controlled trial (n=125) compared four treatment conditions following inpatient detoxification and oral naltrexone induction: (1) BNT+XR-NTX; (2) BNT+placebo injection; (3) CE+XR-NTX; and (4) CE+placebo injection. All participants were maintained on oral naltrexone throughout the trial. Primary outcome was retention in treatment. RESULTS Of 89 randomized participants, 78.7% (70/89) completed 4 weeks, 58.2% (54/89) completed 8 weeks, 47.2% (42/89) completed 12 weeks, and 25.8% (23/89) completed 24 weeks. A Cox proportional hazards regression modeled time to dropout as a function of treatment condition, baseline opioid dependence severity (bags per day of heroin use), and their interaction. Interaction of conditions by baseline severity was significant (X3(2)=9.19, p=0.027). For low-severity patients (≤ 6 bags/day), retention was highest in the BNT-XR-NTX group (60% at 6 months), as hypothesized. For high-severity (>6 bags/day) patients, BNT-XR-NTX did not perform as well, due to high early attrition. CONCLUSION For low-severity heroin users, single-dose XR-NTX improved long-term treatment retention when combined with behavioral therapy. In higher-severity opioid-dependent patients, XR-NTX was less helpful, perhaps because, combined with oral naltrexone, it produced higher blood levels and more withdrawal discomfort. When cost considerations recommend oral naltrexone following XR-NTX, the latter should be phased in slowly.