Neuroscience-informed classification of prevention interventions in substance use disorders: An RDoC-based approach.

Neuroscience has contributed to uncover the mechanisms underpinning substance use disorders (SUD). The next frontier is to leverage these mechanisms as active targets to create more effective interventions for SUD treatment and prevention. Recent large-scale cohort studies from early childhood are generating multiple levels of neuroscience-based information with the potential to inform the development and refinement of future preventive strategies. However, there are still no available well-recognized frameworks to guide the integration of these multi-level datasets into prevention interventions. The Research Domain Criteria (RDoC) provides a neuroscience-based multi-system framework that is well suited to facilitate translation of neurobiological mechanisms into behavioral domains amenable to preventative interventions. We propose a novel RDoC-based framework for prevention science and adapted the framework for the existing preventive interventions. From a systematic review of randomized controlled trials using a person-centered drug/alcohol preventive approach for adolescents, we identified 22 unique preventive interventions. By teasing apart these 22 interventions into the RDoC domains, we proposed distinct neurocognitive trajectories which have been recognized as precursors or risk factors for SUDs, to be targeted, engaged and modified for effective addiction prevention.

Accuracy of the Depression, Anxiety and Stress Scale (DASS-21) for Screening on Comorbid Internalizing Disorders among Youth in Substance Use Disorder Treatment.

INTRODUCTION: Major depression, anxiety disorders, and post-traumatic stress disorder (PTSD) are among the most prevalent comorbid mental disorders in youth addiction treatment. Hence, screening for these internalizing disorders should be part of the standard routine at intake in substance use disorder treatment. We investigated the usefulness of the Depression, Anxiety and Stress Scale (DASS-21) as a screener for this purpose. METHODS: A nationally representative sample of 421 treatment-seeking youths aged 16-22 years with a primary cannabis, alcohol, cocaine, or amphetamine use disorder participated in the study. At intake, we administered the DASS-21 and the Mini International Neuropsychiatric Interview (MINI; Sheehan et al., 1998) based on the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), as "gold standard," as part of a broader baseline assessment of the Youth in transition study [Moska et al. BMC Psychiatry. 2021;21(1):1-11]. RESULTS: At comparable sensitivity (0.80-0.84), based on the optimal cut-off value, specificity was higher for the DASS-21 total score detecting any DSM-5 internalizing disorder (0.62) than for the DASS subscales specifically detecting depression, anxiety, or PTSD (0.44, 0.49, and 0.51, respectively). Receiver operating characteristic curve analyses showed an area under the curve (AUC) value of 0.80 for the DASS total score to detect any internalizing disorder ("good discrimination"), compared with AUC values of 0.70-0.75 of the DASS depression and anxiety subscales to detect DSM-5 depression, anxiety, and PTSD ("fair discrimination"). The optimal DASS total score cut-off value of ≥44 for detecting any internalizing disorder resulted in 0.81 sensitivity, 0.62 specificity, 0.80 positive predictive value, and 0.64 negative predictive value. CONCLUSION: Given the high prevalence of comorbid internalizing disorders in youth addiction care, the need to address these comorbid disorders in treatment, and the favorable accuracy of the DASS to detect these disorders, we recommend to implement the DASS-21 as routine screener in youth addiction treatment in the Netherlands.

Systematic Client Feedback in Youth Mental Health and Addiction Care: A Controlled Study Comparing Two Treatment Cohorts.

INTRODUCTION: We investigated the value of systematic client feedback in youth mental health and addiction care. In the present study, we examined whether a client feedback intervention would result in improved therapeutic alliance and treatment outcomes. METHODS: Two hundred and four adolescents participated in the study using a - non-randomized - between-group A/B design. In the first study group, 127 patients were offered 4 months of treatment as usual (TAU), and in the second study group, 77 patients received the client feedback intervention as an add-on to TAU during 4 months. RESULTS: Youths who received systematic client feedback in addition to TAU did not show better treatment outcomes or better alliance ratings after 4 months than youths receiving TAU only. Sensitivity analyses, in which we compared the more adherent patients of the second study group with patients receiving TAU, did not show significant beneficial effects of client feedback either. Also, the client feedback intervention did not result in lower rates of early treatment drop-out. DISCUSSION/CONCLUSION: Our results cautiously suggest that client feedback does not have incremental effects on alliance and the treatment outcome for youth in mental health and addiction treatment. Moreover, our study highlights the challenges of implementing client feedback in clinical practice and the need for additional research addressing these challenges.

The Added Value of Pharmacotherapy to Cognitive Behavior Therapy And Vice Versa in the Treatment of Alcohol Use Disorders: A Systematic Review.

AIM: To explore whether combined interventions i.e. psychotherapeutic plus psychosocial interventions are more effective than monotherapies in the treatment of alcohol use disorders. METHODS: Systematic review of the results of randomized controlled trials that compared combined therapies with monotherapies (either pharmacotherapy or psychotherapy). RESULTS: The search resulted in 28 eligible studies. Data from these RCTs showed that 10 out of 19 RCTs (53%) demonstrated an added value of combined therapy (psychotherapy + pharmacotherapy) compared to psychotherapy only, whereas only three out of nine RCTs (33%) comparing combined therapy with pharmacotherapy showed a possible added value for combined therapy. CONCLUSIONS: Pharmacotherapy is effective to treat AUD with or without psychotherapy and that psychotherapy can best be offered in combination with pharmacotherapy.

Youth in transition: Study protocol of a prospective cohort study into the long-term course of addiction, mental health problems and social functioning in youth entering addiction treatment.

BACKGROUND: Substance use disorders (SUDs) are prevalent in the general population, tend to follow a chronic course, are associated with many individual and social problems, and often have their onset in adolescence. However, the knowledge base from prospective population surveys and treatment-outcome studies on the course of SUD in adolescents is limited at best. The present study aims to fill this gap and focuses on a subgroup that is particularly at risk for chronicity: adolescents in addiction treatment. We will investigate the rate of persistent SUD and its predictors longitudinally from adolescence to young adulthood among youth with DSM-5 SUD from the start of their addiction treatment to 2 and 4 years following treatment-entry. In addition to SUD, we will investigate the course of comorbid mental disorders, social functioning, and quality of life and their association with SUD over time. METHODS/DESIGN: In a naturalistic, multi-center prospective cohort design, we will include youths (n = 420), who consecutively enter addiction treatment at ten participating organizations in the Netherlands. Inclusion is prestratified by treatment organization, to ensure a nationally representative sample. Eligible youths are 16 to 22 years old and seek help for a primary DSM-5 cannabis, alcohol, cocaine or amphetamine use disorder. Assessments focus on lifetime and current substance use and SUD, non-SUD mental disorders, family history, life events, social functioning, treatment history, quality of life, chronic stress indicators (hair cortisol) and neuropsychological tests (computerized executive function tasks) and are conducted at baseline, end of treatment, and 2 and 4 years post-baseline. Baseline data and treatment data (type, intensity, duration) will be used to predict outcome - persistence of or desistance from SUD. DISCUSSION: There are remarkably few prospective studies worldwide that investigated the course of SUD in adolescents in addiction treatment for longer than 1 year. We are confident that the Youth in Transition study will further our understanding of determinants and consequences of persistent SUD among high-risk adolescents during the critical transition from adolescence to young adulthood. TRIAL REGISTRATION: The Netherlands National Trial Register Trial NL7928 . Date of registration January 17, 2019.

Game Design in Mental Health Care: Case Study-Based Framework for Integrating Game Design Into Therapeutic Content.

While there has been increasing interest in the use of gamification in mental health care, there is a lack of design knowledge on how elements from games could be integrated into existing therapeutic treatment activities in a manner that is balanced and effective. To help address this issue, we propose a design process framework to support the development of mental health gamification. Based on the concept of experienced game versus therapy worlds, we highlight 4 different therapeutic components that could be gamified to increase user engagement. By means of a Dual-Loop model, designers can balance the therapeutic and game design components and design the core elements of a mental health care gamification. To support the proposed framework, 4 cases of game design in mental health care (eg, therapeutic protocols for addiction, anxiety, and low self-esteem) are presented.

Treatment of Adolescents with Concurrent Substance Use Disorder and Attention-Deficit/Hyperactivity Disorder: A Systematic Review.

Childhood attention-deficit/hyperactivity disorder (ADHD) is a risk factor for the development of substance abuse and substance use disorders (SUD) in adolescence and (early) adulthood. ADHD and SUD also frequently co-occur in treatment-seeking adolescents, which complicates diagnosis and treatment, and is associated with poor treatment outcomes. In this study, we provide a systematic review of controlled studies on the effectiveness of pharmacological, psychosocial, and complementary treatments of ADHD in adolescents with and without comorbid SUD. In addition, we review the longitudinal association between pharmacotherapy for childhood ADHD and the development of SUD in adolescence and early adulthood. We conducted a systematic review of the research literature published since 2000 using Medline, PsycINFO, and the Cochrane Database of Systematic Reviews databases to select randomized clinical trials, observational studies, and meta-analyses. The quality of the evidence from each study was rated using the SIGN grading system. Based on the limited evidence available, strong clinical recommendations are not justified, but provisionally, we conclude that stimulant treatment in children with ADHD may prevent the development of SUD in adolescence or young adulthood, that high-dose stimulant treatment could be an effective treatment for adolescents with ADHD and SUD comorbidity, that cognitive behavior therapy might have a small beneficial effect in these patients, and that alternative treatments are probably not effective. More studies are needed to draw definitive conclusions that will allow for strong clinical recommendations.

Mental Health Therapy Protocols and eHealth Design: Focus Group Study.

BACKGROUND: Electronic health (eHealth) programs are often based on protocols developed for the original face-to-face therapies. However, in practice, therapists and patients may not always follow the original therapy protocols. This form of personalization may also interfere with the intended implementation and effects of eHealth interventions if designers do not take these practices into account. OBJECTIVE: The aim of this explorative study was to gain insights into the personalization practices of therapists and patients using cognitive behavioral therapy, one of the most commonly applied types of psychotherapy, in a youth addiction care center as a case context. METHODS: Focus group discussions were conducted asking therapists and patients to estimate the extent to which a therapy protocol was followed and about the type and reasons for personalization of a given therapy protocol. A total of 7 focus group sessions were organized involving therapists and patients. We used a commonly applied protocol for cognitive behavioral therapy as a therapy protocol example in youth mental health care. The first focus group discussions aimed at assessing the extent to which patients (N=5) or therapists (N=6) adapted the protocol. The second focus group discussions aimed at estimating the extent to which the therapy protocol is applied and personalized based on findings from the first focus groups to gain further qualitative insight into the reasons for personalization with groups of therapists and patients together (N=7). Qualitative data were analyzed using thematic analysis. RESULTS: Therapists used the protocol as a "toolbox" comprising different therapy tools, and personalized the protocol to enhance the therapeutic alliance and based on their therapy-provision experiences. Therapists estimated that they strictly follow 48% of the protocol, adapt 30%, and replace 22% by other nonprotocol therapeutic components. Patients personalized their own therapy to conform the assignments to their daily lives and routines, and to reduce their levels of stress and worry. Patients estimated that 29% of the provided therapy had been strictly followed by the therapist, 48% had been adjusted, and 23% had been replaced by other nonprotocol therapeutic components. CONCLUSIONS: A standard cognitive behavioral therapy protocol is not strictly and fully applied but is mainly personalized. Based on these results, the following recommendations for eHealth designers are proposed to enhance alignment of eHealth to therapeutic practice and implementation: (1) study and copy at least the applied parts of a protocol, (2) co-design eHealth with therapists and patients so they can allocate the components that should be open for user customization, and (3) investigate if components of the therapy protocol that are not applied should remain part of the eHealth applied. To best generate this information, we suggest that eHealth designers should collaborate with therapists, patients, protocol developers, and mental health care managers during the development process.

A dual perspective on first-session therapeutic alliance: strong predictor of youth mental health and addiction treatment outcome.

We investigated the potential role of first-session therapeutic alliance ratings to serve as an early marker of treatment outcome in youth mental health and addiction treatment. The present study is among the first to incorporate both a youths' and a therapists' perspective of the therapeutic alliance in order to maximize predictive value of the alliance for treatment outcome. One hundred and twenty-seven adolescents participated in a multi-site prospective naturalistic clinical cohort study, with assessments at baseline and at 4 months post-baseline. Main outcome measure was favorable or unfavorable treatment outcome status at 4-month follow-up. Early therapeutic alliance had a medium and robust association with treatment outcome for youth' (b = 1.29) and therapist' (b = 1.12) perspectives and treatment setting. Based on the two alliance perspectives four subgroups were distinguished. Incorporating the alliance-ratings from both perspectives provided a stronger predictor of treatment outcome than using one perspective. Youth with a strong alliance according to both perspectives had an eightfold odds of favorable treatment outcome compared with youth with a weak alliance according to both perspectives. The association between therapeutic alliance and treatment outcome in youth mental health and addiction treatment may be substantially stronger than earlier assumed when both a youths' and therapists' perspective on alliance is considered.

Clinical effects beyond cocaine use of sustained-release dexamphetamine for the treatment of cocaine dependent patients with comorbid opioid dependence: secondary analysis of a double-blind, placebo-controlled randomized trial.

BACKGROUND AND AIMS: Sustained-release (SR) formulations of dexamphetamine and mixed amphetamine salts have shown positive effects in the treatment of patients with a cocaine use disorder. We previously demonstrated the efficacy of SR-dexamphetamine for patients with cocaine dependence in terms of cocaine use reductions. In this secondary analysis, we assessed whether SR-dexamphetamine treatment also improves the health status of these patients. DESIGN: Multi-centre randomized, double-blind placebo-controlled trial. SETTING: Four supervised heroin-assisted treatment (HAT) out-patient clinics in the Netherlands. In HAT, methadone treatment-refractory opioid-dependent patients can self-administer individually titrated doses of pharmaceutical grade diacetylmorphine, coprescribed with oral methadone. PARTICIPANTS: Seventy-three cocaine-dependent patients (90% males; average age = 48.7 years), participating in HAT for their treatment-refractory comorbid opioid dependence. INTERVENTIONS: Twelve weeks pharmacotherapy with once-daily, supervised intake of two tablets of SR-dexamphetamine (2 × 30 mg/day) or two identical placebo tablets. MEASUREMENTS: Assessment every 4 weeks: cocaine use (time-line follow-back), physical health (Maudsley Addiction Profile-Health Symptoms Scale), mental health (Brief Symptom Inventory) and illegal activities (Addiction Severity Index). Primary outcome was 'overall health', a dichotomous, multi-domain response index based on physical health, mental health and social functioning. FINDINGS: Compared with placebo, SR-dexamphetamine resulted in larger increases in the number of cocaine abstinent days (P = 0.004) and the proportion of overall health treatment responders (P = 0.045) from the 4 weeks preceding baseline to the final 4 weeks of treatment. While the number of cocaine abstinent days was not associated with overall health in the total study sample, it was positively associated with overall health among patients in poor overall health at the start of SR-dexamphetamine treatment (n = 50), i.e. patients with the potential to improve on this multi-domain response index (odds ratio = 1.076; 95% confidence interval = 1.025-1.130). CONCLUSIONS: SR-dexamphetamine reduces cocaine use and may improve clinically relevant health-related outcomes in patients with cocaine dependence who are participating in heroin-assisted treatment for their comorbid heroin dependence.

Affect, motivation, temptation, and drinking among alcohol-dependent outpatients trying to maintain abstinence: An Ecological Momentary Assessment study.

OBJECTIVES: Using Ecological Momentary Assessment we aimed to describe the time course of temptation episodes in alcohol-dependent outpatients in a real-life setting. We also examined whether affective and motivational variables were cross-sectionally and prospectively associated with temptation episodes. Additionally, we tested whether outpatients who drank against treatment goals (i.e., "lapsers") differed in craving, affect, and motivation from abstainers. METHODS: Participants were 43 alcohol-dependent outpatients (13 female). Using personal digital assistants (PDAs), patients were signaled to complete three random assessments per day for 4 weeks. They were also instructed to complete a temptation assessment whenever they experienced the temptation to drink alcohol. RESULTS: The number of temptation assessments declined over time and did not differ between lapsers and abstainers. Overall, craving was generally higher in lapsers (n = 14) than abstainers (n = 27). In lapsers, but not abstainers, abstinence motivation was lower at temptation assessments vs. random assessments. Across all patients, negative affect was prospectively associated with entry of temptation assessments later the same day. There were no significant effects for positive affect. CONCLUSIONS: In alcohol-dependent outpatients attempting to remain abstinent, negative affect is cross-sectionally associated with entry of temptation assessments. There is more evidence that negative affect precipitates temptations than vice versa. Professionals should be watchful of outpatients who report generally high levels of craving, and who report more negative affect and lower abstinence motivation, when tempted.

Multidimensional family therapy in adolescents with a cannabis use disorder: long-term effects on delinquency in a randomized controlled trial.

BACKGROUND: Substance use and delinquency are considered to be mutual risk factors. Previous studies have shown that multidimensional family therapy (MDFT) is effective in tackling both conditions on the short term. The current study examines the long-term effects of MDFT on criminal offending. METHODS: 109 adolescents with cannabis use disorder and comorbid problem behavior were randomly assigned to either MDFT or cognitive behavioral therapy (CBT). Police arrest data were collected for 6 years: 3 years prior to and 3 years after treatment entry. Using survival analysis and repeated measure General Linear Models (rmGLM), the two treatment groups were compared on number of arrests, type of offence, and severity of offence. Moderator analyses looking at age, disruptive behavior disorders, history of crimes, family functioning, and (severe) cannabis use were conducted (rmGLM). RESULTS: While police arrest rates increased in the 3 years before treatment, the rates decreased substantially after the start of both treatments. No differences were found between the treatment groups with respect to either time to first offence from the start of the treatment or changes in frequency or severity of offending over time. A treatment effect trend favoring MDFT was found for property offending in the subgroup of adolescents with high baseline-severity of cannabis use. CONCLUSIONS: Across a follow-up period of 3 years, MDFT and CBT were similarly effective in reducing delinquency in adolescents with a cannabis use disorder.Trial registration ISRCTN51014277, Registered 17 March 2010-Retrospectively registered, http://www.isrctn.com/ISRCTN51014277.

Pharmacokinetics of Sustained-Release Oral Dexamphetamine Sulfate in Cocaine and Heroin-Dependent Patients.

INTRODUCTION: Research has shown that sustained-release (SR) dexamphetamine is a promising agonist treatment for cocaine dependence. However, little is known about the pharmacokinetics (PKs) of SR oral dexamphetamine. This study examined the PKs of a new SR dexamphetamine formulation in cocaine plus heroin-dependent patients currently in heroin-assisted treatment. METHODS: The study was designed as an open-label PK study in 2 cohorts: n = 5 with once daily 60 mg and n = 7 with once daily 30 mg SR oral dexamphetamine. Five days of blood plasma dexamphetamine concentrations measured with liquid chromatography-mass spectrometry with PK parameter estimates using noncompartmental analysis. RESULTS: Twelve cocaine-dependent plus heroin-dependent patients in heroin-assisted treatment were included. The initial cohort 1 dose of 60 mg once daily was adjusted to 30 mg after mild to moderate adverse events. After oral administration, tmax values (coefficient of variation %) were 6.0 (17.0%) and 6.3 (16.3%) hours and t1/2 were 11 (24.6%) and 12 (25.4%) hours for 60 mg and 30 mg SR dexamphetamine, respectively. At steady state, CSSmax values were reached at 100 (27.5%) ng/mL and 58.4 (14.4%) ng/mL, whereas CSSmin values were 39.5 (38.9%) ng/mL and 21.8 (19.8%) ng/mL for 60 mg and 30 mg, respectively. CONCLUSIONS: The investigated SR formulation of dexamphetamine showed favorable slow-release characteristics in cocaine and heroin-dependent patients. A dose-proportional steady-state concentration was achieved within 3 days. These findings support the suitability of the SR formulation in the treatment of cocaine dependence.

Multidimensional Family Therapy Reduces Self-Reported Criminality Among Adolescents With a Cannabis Use Disorder.

Multidimensional family therapy (MDFT) is an established treatment program for youth displaying multiproblem behavior. We examined whether MDFT decreased criminal offending among cannabis abusing adolescents, as compared with individual psychotherapy (IP). In a Western European randomized controlled trial comparing MDFT with IP, a sample of 169 adolescents with a cannabis disorder completed self-reports on criminal offending. Half indicated they had committed one or more criminal offenses in the 90 days before the baseline assessment. Follow-up assessments were at 6 and 12 months after randomization. The proportion of adolescents reporting nondelinquency increased during the study period, most so in the MDFT condition. In addition, MDFT lowered the number of violent offenses more than IP. This difference was not seen for property crimes. In cannabis abusing adolescents, MDFT is an effective treatment to prevent and reduce criminal offending. MDFT outperforms IP for violent crimes.

The cost-effectiveness of family/family-based therapy for treatment of externalizing disorders, substance use disorders and delinquency: a systematic review.

BACKGROUND: Family therapy and family-based treatment has been commonly applied in children and adolescents in mental health care and has been proven to be effective. There is an increased interest in economic evaluations of these, often expensive, interventions. The aim of this systematic review is to summarize and evaluate the evidence on cost-effectiveness of family/family-based therapy for externalizing disorders, substance use disorders and delinquency. METHODS: A systematic literature search was performed in PubMed, Education Resource information Centre (ERIC), Psycinfo and Cochrane reviews including studies conducted after 1990 and before the first of August of 2013. Full economic evaluations investigating family/family-based interventions for adolescents between 10 and 20 years treated for substance use disorders, delinquency or externalizing disorders were included. RESULTS: Seven hundred thirty-one articles met the search criteria and 51 studies were initially selected. The final selection resulted in the inclusion of 11 studies. The quality of these studies was assessed. Within the identified studies, there was great variation in the specific type of family/family-based interventions and disorders. According to the outcomes of the checklists, the overall quality of the economic evaluations was low. Results varied by study. Due to the variations in setting, design and outcome it was not feasible to pool results using a meta-analysis. CONCLUSIONS: The quality of the identified economic evaluations of family/family-based therapy for treatment of externalizing disorders, adolescent substance use disorders and delinquency was insufficient to determine the cost-effectiveness. Although commonly applied, family/family-based therapy is costly and more research of higher quality is needed.

Efficacy of cocaine contingency management in heroin-assisted treatment: Results of a randomized controlled trial.

AIMS: To determine the efficacy of contingency management (CM), targeting cocaine use, as an add-on intervention for heroin dependent patients in supervised heroin-assisted treatment (HAT) with frequent cocaine use. DESIGN: Multi-center, open-label, parallel group, randomized controlled trial. SETTING: Twelve specialized addiction treatment centers for HAT in The Netherlands; April 2006-January 2011. PARTICIPANTS: 214 chronic, treatment-refractory heroin dependent patients in HAT, with frequent cocaine use. INTERVENTIONS: Routine, daily supervised diacetylmorphine treatment, co-prescribed with oral methadone (HAT), with and without 6 months contingency management for cocaine use as an add-on intervention; HAT+CM and HAT-only, respectively. MEASUREMENTS: Primary outcome was the longest, uninterrupted duration of cocaine abstinence, based upon laboratory urinalysis. Secondary outcome measures included other cocaine-related measures, treatment retention in HAT, and multi-domain health-related treatment response. FINDINGS: In an intention-to-treat analysis, HAT+CM was more effective than HAT-only in promoting longer, uninterrupted duration of cocaine abstinence (3.7 weeks versus 1.6 weeks; negative binomial regression: Exp(B)=2.34, 95%-CI: 1.70-3.23; p<0.001). This result remained significant in sensitivity analyses and was supported by all secondary, cocaine-related outcome measures. Treatment retention in HAT was high (91.6%) with no difference between the groups. The improvement in multi-domain health-related treatment response during the trial was numerically higher in HAT+CM (from 37.4% to 53.1%; +15.7%) than in HAT-only (from 44.5% to 46.5%; +2.0%), but this difference was statistically not significant. CONCLUSIONS: Contingency management is an effective add-on intervention to promote longer, uninterrupted periods of cocaine abstinence in chronic, treatment-refractory heroin dependent patients in heroin-assisted treatment with frequent cocaine use. The trial has been registered in The Netherlands National Trial Register under clinical trial registration number NTR4728.

Impulsivity and attentional bias as predictors of modafinil treatment outcome for retention and drug use in crack-cocaine dependent patients: Results of a randomised controlled trial.

BACKGROUND: High impulsivity and attentional bias are common in cocaine-dependent patients and predict poor treatment outcomes. The pharmacological agent modafinil is studied for its cognitive-enhancing capacities and may therefore improve clinical outcomes in crack-cocaine dependent patients. In this study, we investigated first whether pre-treatment impulsivity and attentional bias predict treatment outcome; next whether the drug modafinil given as an add-on treatment to cognitive behavioural therapy (CBT) improves impulsivity and attentional bias; and last, whether changes in impulsivity and attentional bias are related to improvements in treatment outcome. METHODS: Crack-cocaine dependent outpatients (n = 65) were randomised to 12 weeks CBT plus modafinil (400 mg/day) or only CBT. Self-reported impulsivity was assessed at baseline using the Barratt Impulsiveness Scale. At baseline and Week 12, we assessed inhibitory control as a behavioural measure of impulsivity, in terms of cognitive interference (Stroop task) and response inhibition ('stop-signal task'), and attentional bias with the addiction Stroop task. Clinical outcomes were CBT-retention and crack-cocaine use. RESULTS: At baseline, self-reported impulsivity predicted better CBT-retention; low self-reported and behavioural impulsivity and attentional bias predicted less crack-cocaine use. Changes in cognitive performance were not modafinil-related, but most likely due to low adherence. Improvements in impulsivity or attentional bias were not associated with CBT-retention nor changes in crack-cocaine use. CONCLUSIONS: Baseline impulsivity and attentional bias predicted clinical outcomes in crack-cocaine dependent patients. There were no firm indications that modafinil reduced impulsivity nor attentional bias in this population. Future studies involving cognitive-enhancing medications should include strategies to optimise adherence, to be better able to evaluate their potential.

Sustained-release dexamfetamine in the treatment of chronic cocaine-dependent patients on heroin-assisted treatment: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Heroin-assisted treatment is effective for methadone treatment-refractory heroin-dependent patients, but continued comorbid cocaine dependence remains problematic. Sustained-release dexamfetamine is a promising agonist pharmacotherapy for cocaine dependence and we aimed to assess its acceptance, efficacy, and safety. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, patients who were treatment-refractory, as indicated by at least two earlier failed treatments aimed at reducing or abstaining from cocaine use, and who regularly (≥8 days/month) used crack-cocaine were enrolled from four heroin-assisted treatment centres in the Netherlands. Eligible patients were randomly assigned (1:1) to receive either 12 weeks of daily, supervised prescription of 60 mg/day oral sustained-release dexamfetamine or placebo in addition to co-prescribed methadone and diacetylmorphine. Randomisation was done by the collaborating pharmacist, using a computer-generated random number sequence with stratification by treatment centre in blocks of four per stratum. Randomisation was masked to patients, staff, and researchers throughout the study. The primary outcome was the number of self-reported days of cocaine use during study treatment, assessed every 4 weeks. Primary and safety analyses were done in the intention-to-treat population. The study was registered with the European Union Drug Regulating Authorities Clinical Trials (EUdraCT 2013-004024-11) and with The Netherlands Trial Register (NTR2576). FINDINGS: Between Aug 8, 2014, and Feb 27, 2015, 111 patients were assessed for eligibility, of whom 73 were enrolled and randomised; 38 patients were assigned to the sustained-release dexamfetamine group and 35 to the placebo group. Sustained-release dexamfetamine treatment resulted in significantly fewer days of cocaine use than placebo treatment (mean 44·9 days [SD 29·4] vs 60·6 days [24·3], respectively [95% CI of difference 3·1-28·4]; p=0·031; Cohen's standardised effect size d=0·58). One or more adverse events were reported by 28 (74%) patients in the dexamfetamine group and by 16 (46%) patients in the placebo group. Most adverse events were transient and well-tolerated. INTERPRETATION: Sustained-release dexamfetamine is a well accepted, effective, and safe agonist pharmacotherapy for comorbid treatment-refractory cocaine dependence in heroin-dependent patients in heroin-assisted treatment. Future research should aim to replicate these findings in chronic cocaine-dependent and other stimulant-dependent patients in more routine treatment settings, including strategies to optimise treatment adherence like medication management interventions and contingency management. FUNDING: Netherlands Organisation for Health Research and Development.

Modafinil in the treatment of crack-cocaine dependence in the Netherlands: Results of an open-label randomised controlled feasibility trial.

BACKGROUND: Crack-cocaine dependence is a serious disorder with no approved pharmacological treatment. Modafinil is a promising medication with increased cocaine abstinence and reduced craving in some previous studies. In the present study, we examined the acceptance, safety and potential benefits of modafinil as an add-on treatment to cognitive behavioural therapy (CBT) in crack-cocaine dependent patients. METHODS: Sixty-five crack-cocaine dependent outpatients participated in an open-label, randomised feasibility trial. Patients were randomised to receive either 12-week individual CBT plus 400 mg/day modafinil or 12-week individual CBT only. The primary outcome measure was CBT treatment retention. Secondary outcomes included modafinil adherence, tolerability and safety, use of cocaine and other substances, cocaine craving, health, social functioning and patient satisfaction. RESULTS: Modafinil adherence was low, with only 10% treatment completers. Intent-to-treat analyses showed that modafinil did not improve CBT treatment retention or any of the secondary cocaine-related outcomes. Both groups showed similar, large reductions in cocaine use during the study treatment. Post hoc exploratory analyses within the CBT plus modafinil group showed significantly larger baseline to week 12 reductions in cocaine use days in high (⩾ 8 weeks) modafinil adherent patients. CONCLUSIONS: Acceptance and benefits of modafinil were not demonstrated in the present study. Since reduction in cocaine use was observed in high modafinil adherent patients, further research in the treatment of cocaine dependence, in which modafinil adherence is optimised, is warranted.