Effect of antidepressants for cessation therapy in betel-quid use disorder: a randomised, double-blind, placebo-controlled trial.

AIMS: More than one-half of betel-quid (BQ) chewers have betel-quid use disorder (BUD). However, no medication has been approved. We performed a randomised clinical trial to test the efficacy of taking escitalopram and moclobemide antidepressants on betel-quid chewing cessation (BQ-CC) treatment. METHODS: We enrolled 111 eligible male BUD patients. They were double-blinded, placebo-controlled and randomised into three treatment groups: escitalopram 10 mg/tab daily, moclobemide 150 mg/tab daily and placebo. Patients were followed-up every 2 weeks and the length of the trial was 8 weeks. The primary outcome was BQ-CC, defined as BUD patients who continuously stopped BQ use for ⩾6 weeks. The secondary outcomes were the frequency and amount of BQ intake, and two psychological rating scales. Several clinical adverse effects were measured during the 8-week treatment. RESULTS: Intention-to-treat analysis shows that after 8 weeks, two (5.4%), 13 (34.2%) and 12 (33.3%) of BUD patients continuously quit BQ chewing for ⩾6 weeks among placebo, escitalopram, moclobemide groups, respectively. The adjusted proportion ratio of BQ-CC was 6.3 (95% CI 1.5-26.1) and 6.8 (95% CI 1.6-28.0) for BUD patients who used escitalopram and moclobemide, respectively, as compared with those who used placebo. BUD patients with escitalopram and moclobemide treatments both exhibited a significantly lower frequency and amount of BQ intake at the 8th week than those with placebo. CONCLUSIONS: Prescribing a fixed dose of moclobemide and escitalopram to BUD patients over 8 weeks demonstrated treatment benefits to BQ-CC. Given a relatively small sample, this study provides preliminary evidence and requires replication in larger trials.

A Single Ketamine Infusion Combined With Mindfulness-Based Behavioral Modification to Treat Cocaine Dependence: A Randomized Clinical Trial.

OBJECTIVE: Research has suggested that subanesthetic doses of ketamine may work to improve cocaine-related vulnerabilities and facilitate efforts at behavioral modification. The purpose of this trial was to test whether a single ketamine infusion improved treatment outcomes in cocaine-dependent adults engaged in mindfulness-based relapse prevention. METHODS: Fifty-five cocaine-dependent individuals were randomly assigned to receive a 40-minute intravenous infusion of ketamine (0.5 mg/kg) or midazolam (the control condition) during a 5-day inpatient stay, during which they also initiated a 5-week course of mindfulness-based relapse prevention. Cocaine use was assessed through self-report and urine toxicology. The primary outcomes were end-of-study abstinence and time to relapse (defined as first use or dropout). RESULTS: Overall, 48.2% of individuals in the ketamine group maintained abstinence over the last 2 weeks of the trial, compared with 10.7% in the midazolam group (intent-to-treat analysis). The ketamine group was 53% less likely (hazard ratio=0.47; 95% CI=0.24, 0.92) to relapse (dropout or use cocaine) compared with the midazolam group, and craving scores were 58.1% lower in the ketamine group throughout the trial (95% CI=18.6, 78.6); both differences were statistically significant. Infusions were well tolerated, and no participants were removed from the study as a result of adverse events. CONCLUSIONS: A single ketamine infusion improved a range of important treatment outcomes in cocaine-dependent adults engaged in mindfulness-based behavioral modification, including promoting abstinence, diminishing craving, and reducing risk of relapse. Further research is needed to replicate these promising results in a larger sample.

Nociceptin Receptors Upregulated in Cocaine Use Disorder: A Positron Emission Tomography Imaging Study Using [11C]NOP-1A.

OBJECTIVE: Nociceptin/orphanin FQ (N/OFQ) is an antistress neuropeptide transmitter in the brain that counteracts corticotropin-releasing factor (CRF)-mediated stress and anxiety symptoms during drug and alcohol withdrawal. It also inhibits the release of a wide array of neurotransmitters, including dopamine and glutamate, which allows for it to block the rewarding properties of cocaine. Chronic cocaine administration in rodents has been shown to decrease N/OFQ and increase nociceptive opioid peptide (NOP) receptors in the nucleus accumbens. No previous studies have reported on the in vivo status of NOP in chronic cocaine-abusing humans. METHODS: [11C]NOP-1A and positron emission tomography (PET) were used to measure in vivo NOP binding in 24 individuals with cocaine use disorder and 26 healthy control subjects matched for age, sex, and smoking status. Participants with cocaine use disorder with no comorbid psychiatric or medical disorders were scanned after 2 weeks of outpatient-monitored abstinence. [11C]NOP-1A distribution volume (VT) was measured with kinetic analysis using the arterial input function in brain regions that mediate reward and stress behaviors. Participants with cocaine use disorder were followed up for 12 weeks after PET scanning to document relapse and relate it to VT. RESULTS: A significant increase in [11C]NOP-1A VT was observed in the cocaine use disorder group compared with the healthy control group. This increase, which was generalized across all regions of interest (approximately 10%), was most prominent in the midbrain, ventral striatum, and cerebellum. However, increased VT in these regions did not predict relapse. CONCLUSIONS: Increased NOP in cocaine use disorder suggests an adaptive response to decreased N/OFQ, or increased CRF transmission, or both. Future studies should examine the interactions between CRF and NOP to elucidate their role in negative reinforcement and relapse. NOP agonist medications to enhance N/OFQ should be explored as a therapeutic to treat cocaine use disorder.

A Contagion Model for Within-Family Transmission of Drug Abuse.

OBJECTIVE: The purpose of this study was to determine whether, controlling for genetic effects, drug abuse was transmitted within families as predicted by a contagion model. METHODS: The authors examined 65,006 parent-offspring, sibling, and cousin pairs ascertained from Swedish population registries in which the primary case subject had a drug abuse registration. The rate of drug abuse registration among at-risk secondary case subjects ages 19-23 was studied. Utilizing matched control pairs, a difference-in-difference approach was used to infer causal effects. RESULTS: In offspring, risk for drug abuse registration in the 3 years after an index registration of a parent residing in the same household, neighborhood, or municipality increased 5.9%, 3.4%, and 1.8%, respectively. For siblings of sibling index case subjects, parallel results were 5.9%, 3.9%, and 1.2%. For cousins of cousin index case subjects, excess risk for those in the same neighborhood or municipality was 2.9% and 0.9%, respectively. In all sets of relatives, drug abuse transmission was strongest in male-male pairs and in pairs closest in age. In sibling pairs, stronger transmission was observed in older to younger siblings compared with younger to older siblings. Transmission was stronger within than across the two drug classes with sufficient data (opiates and cannabis). CONCLUSIONS: These results suggest that drug abuse can be transmitted within families by an environmentally mediated temporally defined model of contagion. The most important methodological limitation is that drug abuse registration is an inaccurate measure of the onset of drug abuse. Indeed, as predicted, drug abuse risk increased among potential secondary case subjects in the year before drug abuse registration of the index case subject.

Connectome-Based Prediction of Cocaine Abstinence.

OBJECTIVE: The authors sought to identify a brain-based predictor of cocaine abstinence by using connectome-based predictive modeling (CPM), a recently developed machine learning approach. CPM is a predictive tool and a method of identifying networks that underlie specific behaviors ("neural fingerprints"). METHODS: Fifty-three individuals participated in neuroimaging protocols at the start of treatment for cocaine use disorder, and again at the end of 12 weeks of treatment. CPM with leave-one-out cross-validation was conducted to identify pretreatment networks that predicted abstinence (percent cocaine-negative urine samples during treatment). Networks were applied to posttreatment functional MRI data to assess changes over time and ability to predict abstinence during follow-up. The predictive ability of identified networks was then tested in a separate, heterogeneous sample of individuals who underwent scanning before treatment for cocaine use disorder (N=45). RESULTS: CPM predicted abstinence during treatment, as indicated by a significant correspondence between predicted and actual abstinence values (r=0.42, df=52). Identified networks included connections within and between canonical networks implicated in cognitive/executive control (frontoparietal, medial frontal) and in reward responsiveness (subcortical, salience, motor/sensory). Connectivity strength did not change with treatment, and strength at posttreatment assessment also significantly predicted abstinence during follow-up (r=0.34, df=39). Network strength in the independent sample predicted treatment response with 64% accuracy by itself and 71% accuracy when combined with baseline cocaine use. CONCLUSIONS: These data demonstrate that individual differences in large-scale neural networks contribute to variability in treatment outcomes for cocaine use disorder, and they identify specific abstinence networks that may be targeted in novel interventions.

Medications for Alcohol and Opioid Use Disorders and Risk of Suicidal Behavior, Accidental Overdoses, and Crime.

OBJECTIVE: The authors examined associations between medications for alcohol and opioid use disorders (acamprosate, naltrexone, methadone, and buprenorphine) and suicidal behavior, accidental overdoses, and crime. METHOD: In this total population cohort study, 21,281 individuals who received treatment with at least one of the four medications between 2005 and 2013 were identified. Data on medication use and outcomes were collected from Swedish population-based registers. A within-individual design (using stratified Cox proportional hazards regression models) was used to compare rates of suicidal behavior, accidental overdoses, and crime for the same individuals during the period when they were receiving the medication compared with the period when they were not. RESULTS: No significant associations with any of the primary outcomes were found for acamprosate. For naltrexone, there was a reduction in the hazard ratio for accidental overdoses during periods when individuals received treatment compared with periods when they did not (hazard ratio=0.82, 95% CI=0.70, 0.96). Buprenorphine was associated with reduced arrest rates for all crime categories (i.e., violent, nonviolent, and substance-related) as well as reduction in accidental overdoses (hazard ratio=0.75, 95% CI=0.60, 0.93). For methadone, there were significant reductions in the rate of suicidal behaviors (hazard ratio=0.60, 95% CI=0.40-0.88) as well as reductions in all crime categories. However, there was an increased risk for accidental overdoses among individuals taking methadone (hazard ratio=1.25, 95% CI=1.13, 1.38). CONCLUSIONS: Medications currently used to treat alcohol and opioid use disorders also appear to reduce suicidality and crime during treatment.

Randomized Clinical Trial of Computerized and Clinician-Delivered CBT in Comparison With Standard Outpatient Treatment for Substance Use Disorders: Primary Within-Treatment and Follow-Up Outcomes.

OBJECTIVE: Previous trials have demonstrated the efficacy and durability of computer-based cognitive-behavioral therapy (CBT4CBT) as an add-on to standard outpatient care in a range of treatment-seeking populations. In this study, the authors evaluated the efficacy and safety of CBT4CBT as a virtual stand-alone treatment, delivered with minimal clinical monitoring, and clinician-delivered cognitive-behavioral therapy (CBT) compared with treatment as usual in a heterogeneous sample of treatment-seeking outpatients with substance use disorders. METHOD: This was a randomized clinical trial in which 137 individuals who met DSM-IV-TR criteria for current substance abuse or dependence were randomly assigned to receive treatment as usual, weekly individual CBT, or CBT4CBT with brief weekly monitoring. RESULTS: Rates of treatment exposure differed by group, with the best retention in the CBT4CBT group and the poorest in the individual CBT group. Participants who received CBT or CBT4CBT reduced their frequency of substance use significantly more than those who received treatment as usual. Six-month follow-up outcomes indicated continuing benefit of CBT4CBT (plus monitoring) over treatment as usual, but not for clinician-delivered CBT over treatment as usual. Analysis of secondary outcomes indicated that participants in the CBT4CBT group demonstrated the best learning of cognitive and behavioral concepts, as well as the highest satisfaction with treatment. CONCLUSIONS: This first trial of computerized CBT as a virtual stand-alone intervention delivered in a clinical setting to a diverse sample of patients with current substance use disorders indicated that it was safe, effective, and durable relative to standard treatment approaches and was well-liked by participants. Clinician-delivered individual CBT, while efficacious within the treatment period, was unexpectedly associated with a higher dropout rate and lower effects at follow-up.

Prevalence and Correlates of Prescription Stimulant Use, Misuse, Use Disorders, and Motivations for Misuse Among Adults in the United States.

OBJECTIVE: The authors sought to simultaneously examine the prevalence and correlates of prescription stimulant use, misuse, use disorders, and motivations for misuse in the U.S. adult population. METHOD: This was a nationally representative household population study of adults age 18 or older from the 2015 and 2016 National Surveys on Drug Use and Health (N=102,000). Measurements included prescription stimulant use, use without misuse, misuse without use disorders, and misuse with use disorders, as well as sociodemographic characteristics, health conditions, and mental health factors. RESULTS: Among U.S. adults, 6.6% (annual average) used prescription stimulants overall; 4.5% used without misuse, 1.9% misused without use disorders, and 0.2% had use disorders. Adults with past-year prescription stimulant use disorders did not differ from those with misuse without use disorders in any of the examined sociodemographic characteristics and in many of the examined substance use problems. The most commonly reported motivations for misuse were to help be alert or concentrate (56.3%). The most likely source of misused prescription stimulants was by obtaining them free from friends or relatives (56.9%). More frequent prescription stimulant misuse and use disorder were associated with an increased likelihood of obtaining medications from physicians or from drug dealers or strangers and less likelihood of obtaining them from friends or relatives. CONCLUSIONS: Approximately 16.0 million U.S. adults used prescription stimulants in the preceding year (annual average), 5.0 million misused prescription stimulants, and 0.4 million had use disorders. Cognitive enhancement was the most commonly reported reason for misusing prescription stimulants. Patients who are using their medication for cognitive enhancement or diverting their medication to others present a high risk.

Rates and Predictors of Conversion to Schizophrenia or Bipolar Disorder Following Substance-Induced Psychosis.

OBJECTIVE: The authors investigated the rates of conversion to schizophrenia and bipolar disorder after a substance-induced psychosis, as well as risk factors for conversion. METHOD: All patient information was extracted from the Danish Civil Registration System and the Psychiatric Central Research Register. The study population included all persons who received a diagnosis of substance-induced psychosis between 1994 and 2014 (N=6,788); patients were followed until first occurrence of schizophrenia or bipolar disorder or until death, emigration, or August 2014. The Kaplan-Meier method was used to obtain cumulative probabilities for the conversion from a substance-induced psychosis to schizophrenia or bipolar disorder. Cox proportional hazards regression models were used to calculate hazard ratios for all covariates. RESULTS: Overall, 32.2% (95% CI=29.7-34.9) of patients with a substance-induced psychosis converted to either bipolar or schizophrenia-spectrum disorders. The highest conversion rate was found for cannabis-induced psychosis, with 47.4% (95% CI=42.7-52.3) converting to either schizophrenia or bipolar disorder. Young age was associated with a higher risk of converting to schizophrenia. Self-harm after a substance-induced psychosis was significantly linked to a higher risk of converting to both schizophrenia and bipolar disorder. Half the cases of conversion to schizophrenia occurred within 3.1 years after a substance-induced psychosis, and half the cases of conversion to bipolar disorder occurred within 4.4 years. CONCLUSIONS: Substance-induced psychosis is strongly associated with the development of severe mental illness, and a long follow-up period is needed to identify the majority of cases.

Service Use Preceding Opioid-Related Fatality.

OBJECTIVE: This study analyzed health service patterns before opioid-related death among nonelderly individuals in the Medicaid program, focusing on decedents with and without past-year diagnoses of noncancer chronic pain. METHODS: The authors identified opioid-related decedents, age ≤64 years, in the Medicaid program and characterized their clinical diagnoses, filled medication prescriptions, and nonfatal poisoning events during the 30 days and 12 months before death. The study group included 13,089 opioid-related deaths partitioned by presence or absence of chronic noncancer pain diagnoses in the last year of life. RESULTS: Most decedents (61.5%) had received clinical diagnoses of chronic noncancer pain conditions in the last year of life. As compared with decedents without chronic pain diagnoses, those with these diagnoses were significantly more likely to have filled prescriptions for opioids (49.0% versus 17.2%) and benzodiazepines (52.1% versus 26.6%) during the last 30 days of life, while diagnoses of opioid use disorder during this period were uncommon in both groups (4.2% versus 4.3%). The chronic pain group was also significantly more likely than the nonpain group to receive clinical diagnoses of drug use (40.8% versus 22.1%), depression (29.6% versus 13.0%) or anxiety (25.8% versus 8.4%) disorders during the last year of life. CONCLUSIONS: Persons dying of opioid-related causes, particularly those who were diagnosed with chronic pain conditions, commonly received services related to drug use disorders and mental disorders in the last year of life, though opioid use disorder diagnoses near the time of death were rare.