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1.  Coping styles in substance use disorder (SUD) patients with and without co-occurring attention deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD) 
BMC Psychiatry  2015;15:159.
Patients with a substance use disorder (SUD) and co-occurring attention deficit hyperactivity disorder (ADHD) or autism spectrum disorder (ASD) often start using substances in an attempt to cope with the stress related to their ADHD or ASD. To improve treatment for these patient groups, it is important to identify and compare the various coping styles between SUD patients with and without ADHD or ASD and with subjects from a general population sample.
Cross-sectional study using the Utrecht Coping List (UCL) in 50 SUD patients, 41 SUD + ADHD patients, 31 SUD + ASD patients and 1,200 railway employees.
Compared with the reference group, all three SUD groups showed a significant higher mean on the Palliative reaction, Avoidance, and Passive reaction subscales of the UCL. The scores for all UCL subscales of the SUD and the SUD + ADHD groups were very similar. However, the SUD + ASD group scored higher on Passive reaction and lower on Reassuring thoughts than the SUD and the SUD + ADHD groups and lower on Expression of emotions subscale in comparison with the SUD + ADHD group.
Regardless of the presence of a co-occurring disorder, SUD patients reported more palliative, avoidant and passive coping when confronted than people in the general population. In addition, SUD patients with co-occurring ASD were different from other SUD patients in their coping and professionals should take this into account when working on more adaptive coping strategies with these patients.
PMCID: PMC4501102  PMID: 26169586
Coping styles; Substance Use Disorder; Attention Deficit/Hyperactivity Disorder; Autism Spectrum Disorder
2.  Brain volume in male patients with recent onset schizophrenia with and without cannabis use disorders 
Schizophrenia is highly comorbid with cannabis use disorders (CUDs), and this comorbidity is associated with an unfavourable course. Early onset or frequent cannabis use may influence brain structure. A key question is whether comorbid CUDs modulate brain morphology alterations associated with schizophrenia.
We used surface-based analysis to measure the brain volume, cortical thickness and cortical surface area of a priori–defined brain regions (hippocampus, amygdala, thalamus, caudate, putamen, orbitofrontal cortex, anterior cingulate cortex, insula, parahippocampus and fusiform gyrus) in male patients with schizophrenia or related disorders with and without comorbid CUDs and matched healthy controls. Associations between age at onset and frequency of cannabis use with regional grey matter volume were explored.
We included 113 patients with (CUD, n = 80) and without (NCUD, n = 33) CUDs and 84 controls in our study. As expected, patients with schizophrenia (with or without a CUD) had smaller volumes of most brain regions (amygdala, putamen, insula, parahippocampus and fusiform gyrus) than healthy controls, and differences in cortical volume were mainly driven by cortical thinning. Compared with the NCUD group, the CUD group had a larger volume of the putamen, possibly driven by polysubstance use. No associations between age at onset and frequency of use with regional grey matter volumes were found.
We were unable to correct for possible confounding effects of smoking or antipsychotic medication.
Patients with psychotic disorders and comorbid CUDs have larger putamen volumes than those without CUDs. Future studies should elaborate whether a large putamen represents a risk factor for the development of CUDs or whether (poly)substance use causes changes in putamen volume.
PMCID: PMC4409437  PMID: 25510948
3.  Substance use disorders, trauma, and PTSD 
European Journal of Psychotraumatology  2015;6:10.3402/ejpt.v6.27632.
PMCID: PMC4393537
4.  Effect of extended-release naltrexone on striatal dopamine transporter availability, depression and anhedonia in heroin-dependent patients 
Psychopharmacology  2015;232(14):2597-2607.
Extended-release naltrexone (XRNT), an opioid receptor antagonist, is successfully used in the treatment of opioid dependence. However, naltrexone treatment of opioid-dependent patients may reduce striatal dopamine transporter (DAT) availability and cause depression and anhedonia.
The aim of this study is to investigate changes in striatal DAT availability and symptoms of depression (Beck Depression Inventory (BDI)) and anhedonia (Snaith Hamilton Pleasure Scale (SHAPS)) before and during XRNT treatment.
At baseline, ten detoxified heroin-dependent patients and 11 matched healthy controls underwent [123I]FP-CIT single photon emission computed tomography (SPECT) imaging to assess striatal DAT binding. Patients underwent a second SPECT scan 2 weeks after an intramuscular injection with XRNT.
At baseline, the mean binding potential (BPND) in the putamen was at a trend level lower and the mean BDI score was significantly higher in heroin patients (n = 10) than in controls (n = 11) (3.45 ± 0.88 vs. 3.80 ± 0.61, p = 0.067, d = −0.48 and 12.75 ± 7.40 vs. 5.20 ± 4.83, p = 0.019, d = 1.24, respectively). Post hoc analyses in subgroups with negative urine analyses for opioids and cocaine showed significantly lower baseline putamen BPND in heroin patients (n = 8) than controls (n = 10) (3.19 ± 0.43 vs. 3.80 ± 0.64, p = 0.049, d = −1.03). XRNT treatment in heroin patients was not significantly associated with changes in striatal DAT availability (p = 0.348, d = 0.48), but the mean BDI score after XRNT treatment was significantly lower than before treatment (7.75 ± 7.21 vs. 12.75 ± 7.40, p = 0.004, d = −0.68).
The results of this study suggest that XRNT treatment does not reduce striatal DAT availability and has no significant effect on anhedonia, but is associated with a significant reduction of depressive symptoms.
Electronic supplementary material
The online version of this article (doi:10.1007/s00213-015-3891-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4480848  PMID: 25757673
Dopamine transporter; Abstinence; Addiction; Brain imaging; In vivo; Opioid receptor
5.  The International ADHD in Substance Use Disorders Prevalence (IASP) study: background, methods and study population 
Attention deficit/hyperactivity disorder (ADHD) is an increasingly recognized comorbid condition in subjects with substance use disorders (SUDs).
This paper describes the methods and study population of the International ADHD in Substance Use Disorders Prevalence (IASP) study. Objectives of the IASP are to determine the prevalence of ADHD in adult treatment seeking patients with SUD in different countries and SUD populations, determine the reliability and validity of the Adult ADHD Self-report Scale V 1.1 (ASRS) as ADHD screening instrument in SUD populations, investigate the comorbidity profile of SUD patients with and without ADHD, compare risk factors and protective factors in SUD patients with and without a comorbid diagnosis of ADHD, and increase our knowledge about the relationship between ADHD and the onset and course of SUD.
In this cross-sectional, multi-centre two stage study, subjects were screened for ADHD with the ASRS, diagnosed with the Conner’s Adult ADHD Diagnostic Interview for DSM-IV (CAADID), and evaluated for SUD, major depression, bipolar disorder, anti social personality disorder and borderline personality disorder.
Three thousand five hundred and fifty-eight subjects from 10 countries were included. Of these 40.9% screened positive for ADHD.
This is the largest international study on this population evaluating ADHD and comorbid disorders. Copyright © 2013 John Wiley & Sons, Ltd.
PMCID: PMC4085151  PMID: 24022983
ADHD; substance use disorders; prevalence; attention/deficit hyperactivity disorder
6.  Cannabinoid-1 receptor antagonist rimonabant (SR141716) increases striatal dopamine D2 receptor availability 
Addiction biology  2011;18(6):10.1111/j.1369-1600.2011.00369.x.
The cannabinoid 1 (CB1) receptor antagonist rimonabant (SR141716) alters rewarding properties and intake of food and drugs. Additionally, striatal dopamine D2 receptor (DRD2) availability has been implicated in reward function. This study shows that chronic treatment of rats with rimonabant (1.0 and 3.0 mg/kg/day) dose-dependently increased DRD2 availability in the dorsal striatum (14% and 23%) compared to vehicle. High-dose rimonabant also increased DRD2 availability in the ventral striatum (12%) and reduced weight gain. Thus, upregulation of striatal DRD2 by chronic rimonabant administration may be an underlying mechanism of action and confirms the interactions of the endocannabinoid and dopaminergic systems.
PMCID: PMC3252421  PMID: 21955259
cannabinoid 1 receptor; dopamine D2 receptor; IBZM; nucleus accumbens; rimonabant; striatum
7.  Everyday life consequences of substance use in adult patients with a substance use disorder (SUD) and co-occurring attention deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD): a patient’s perspective 
BMC Psychiatry  2014;14:264.
Although the prevalence of substance use disorder (SUD) with co-occurring attention deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD) is relatively high in adult patients, there is hardly any knowledge about these dual diagnoses. A recent study reported met- and unmet needs for several life domains regarding these patient groups. To improve treatment, it is necessary to identify the everyday life consequences of SUD and co-occurring ADHD or ASD in adult patients.
Qualitative study using in-depth interviews. 11 SUD + ADHD and 12 SUD + ASD patients participated in the study. The interview transcripts were coded and analysed according to the seven steps for descriptive phenomenology by Colaizzi.
Both patients with ADHD and patients with ASD can get caught in a jumble of thoughts and emotions which can often lead to agitation and impulsivity in the case of ADHD or passivity and melancholia in the case of ASD with co-occurring SUD in both cases. Initially substance use ameliorates the symptoms and related problems, but both patient groups can later experience even greater problems: difficulties with the structuring of daily life due to a lack of planning (SUD + ADHD) or due to a lack of initiative (SUD + ASD). Both groups indicate that structure helps them function better. They also recognize that substance use disorganizes their lives and that an absence of structure contributes to substance use in what becomes a vicious circle which needs to be broken for effective treatment and care.
This study provides insight into the daily life consequences of SUD with a co-occurring ADHD or ASD. Substance use is reported to solve some ADHD- or ASD-related problems in the short run but have negative consequences in the long run (i.e., contribute to already impaired cognitive functioning). Insight is provided into what clinicians can do to break this vicious circle and thus help ADHD patients to refrain from action and ASD patients to take action.
PMCID: PMC4173065  PMID: 25234344
Substance use disorders; Attention deficit hyperactivity disorder; Autism spectrum disorder; Everyday life consequences; Adults
8.  Variability in the prevalence of adult ADHD in treatment seeking substance use disorder patients: Results from an international multi-center study exploring DSM-IV and DSM-5 criteria☆☆ 
Drug and alcohol dependence  2013;134:158-166.
Available studies vary in their estimated prevalence of attention deficit/hyperactivity disorder (ADHD) in substance use disorder (SUD) patients, ranging from 2 to 83%. A better understanding of the possible reasons for this variability and the effect of the change from DSM-IV to DSM-5 is needed.
A two stage international multi-center, cross-sectional study in 10 countries, among patients form inpatient and outpatient addiction treatment centers for alcohol and/or drug use disorder patients. A total of 3558 treatment seeking SUD patients were screened for adult ADHD. A subsample of 1276 subjects, both screen positive and screen negative patients, participated in a structured diagnostic interview.
Prevalence of DSM-IV and DSM-5 adult ADHD varied for DSM-IV from 5.4% (CI 95%: 2.4–8.3) for Hungary to 31.3% (CI 95%:25.2–37.5) for Norway and for DSM-5 from 7.6% (CI 95%: 4.1–11.1) for Hungary to 32.6% (CI 95%: 26.4–38.8) for Norway. Using the same assessment procedures in all countries and centers resulted in substantial reduction of the variability in the prevalence of adult ADHD reported in previous studies among SUD patients (2–83%→ 5.4–31.3%). The remaining variability was partly explained by primary substance of abuse and by country (Nordic versus non-Nordic countries). Prevalence estimates for DSM-5 were slightly higher than for DSM-IV.
Given the generally high prevalence of adult ADHD, all treatment seeking SUD patients should be screened and, after a confirmed diagnosis, treated for ADHD since the literature indicates poor prognoses of SUD in treatment seeking SUD patients with ADHD.
PMCID: PMC4133781  PMID: 24156882
Prevalence; Substance use disorder; Attention deficit hyperactivity disorder; DSM-5; Adults
9.  Psychiatric comorbidity in treatment-seeking substance use disorder patients with and without attention deficit hyperactivity disorder: results of the IASP study 
Addiction (Abingdon, England)  2013;109(2):262-272.
To determine comorbidity patterns in treatment-seeking substance use disorder (SUD) patients with and without adult attention deficit hyperactivity disorder (ADHD), with an emphasis on subgroups defined by ADHD subtype, taking into account differences related to gender and primary substance of abuse.
Data were obtained from the cross-sectional International ADHD in Substance use disorder Prevalence (IASP) study.
Forty-seven centres of SUD treatment in 10 countries.
A total of 1205 treatment-seeking SUD patients.
Structured diagnostic assessments were used for all disorders: presence of ADHD was assessed with the Conners’ Adult ADHD Diagnostic Interview for DSM-IV (CAADID), the presence of antisocial personality disorder (ASPD), major depression (MD) and (hypo)manic episode (HME) was assessed with the Mini International Neuropsychiatric Interview-Plus (MINI Plus), and the presence of borderline personality disorder (BPD) was assessed with the Structured Clinical Interview for DSM-IV Axis II (SCID II).
The prevalence of DSM-IV adult ADHD in this SUD sample was 13.9%. ASPD [odds ratio (OR) = 2.8, 95% confidence interval (CI) = 1.8–4.2], BPD (OR = 7.0, 95% CI = 3.1–15.6 for alcohol; OR = 3.4, 95% CI = 1.8–6.4 for drugs), MD in patients with alcohol as primary substance of abuse (OR = 4.1, 95% CI = 2.1–7.8) and HME (OR = 4.3, 95% CI = 2.1–8.7) were all more prevalent in ADHD+ compared with ADHD− patients (P < 0.001). These results also indicate increased levels of BPD and MD for alcohol compared with drugs as primary substance of abuse. Comorbidity patterns differed between ADHD subtypes with increased MD in the inattentive and combined subtype (P < 0.01), increased HME and ASPD in the hyperactive/impulsive (P < 0.01) and combined subtypes (P < 0.001) and increased BPD in all subtypes (P < 0.001) compared with SUD patients without ADHD. Seventy-five per cent of ADHD patients had at least one additional comorbid disorder compared with 37% of SUD patients without ADHD.
Treatment-seeking substance use disorder patients with attention deficit hyperactivity disorder are at a very high risk for additional externalizing disorders.
PMCID: PMC4112562  PMID: 24118292
ADHD; antisocial personality disorder; bipolar disorder; borderline personality disorder; comorbidity; depression; substance use disorder
10.  Validity of the Adult ADHD Self-Report Scale (ASRS) as a screener for adult ADHD in treatment seeking substance use disorder patients 
Drug and alcohol dependence  2013;132(3):587-596.
To detect attention deficit hyperactivity disorder (ADHD) in treatment seeking substance use disorders (SUD) patients, a valid screening instrument is needed.
To test the performance of the Adult ADHD Self-Report Scale V1.1(ASRS) for adult ADHD in an international sample of treatment seeking SUD patients for DSM-IV-TR; for the proposed DSM-5 criteria; in different subpopulations, at intake and 1–2 weeks after intake; using different scoring algorithms; and different externalizing disorders as external criterion (including adult ADHD, bipolar disorder, antisocial and borderline personality disorder).
In 1138 treatment seeking SUD subjects, ASRS performance was determined using diagnoses based on Conner’s Adult ADHD Diagnostic Interview for DSM-IV (CAADID) as gold standard.
The prevalence of adult ADHD was 13.0% (95% CI: 11.0–15.0%). The overall positive predictive value (PPV) of the ASRS was 0.26 (95% CI: 0.22–0.30), the negative predictive value (NPV) was 0.97 (95% CI: 0.96–0.98). The sensitivity (0.84, 95% CI: 0.76–0.88) and specificity (0.66, 95% CI: 0.63–0.69) measured at admission were similar to the sensitivity (0.88,95% CI: 0.83–0.93) and specificity (0.67,95% CI: 0.64–0.70) measured 2 weeks after admission. Sensitivity was similar, but specificity was significantly better in patients with alcohol compared to (illicit) drugs as the primary substance of abuse (0.76 vs. 0.56). ASRS was not a good screener for externalizing disorders other than ADHD.
The ASRS is a sensitive screener for identifying possible ADHD cases with very few missed cases among those screening negative in this population.
PMCID: PMC4083506  PMID: 23660242
ADHD; Substance use disorders; Prevalence; Attention/deficit hyperactivity disorder; Validity; ASRS; Addiction; Psychiatry
11.  The Role of Habits and Motivation in Human Drug Addiction: A Reflection 
PMCID: PMC3905212  PMID: 24523702
habits; habit formation; motivation; addiction; goal-directed behavior
12.  Cue Reactivity Is Associated with Duration and Severity of Alcohol Dependence: An fMRI Study 
PLoS ONE  2014;9(1):e84560.
With the progression of substance dependence, drug cue-related brain activation is thought to shift from motivational towards habit pathways. However, a direct association between cue-induced brain activation and dependence duration has not yet been shown. We therefore examined the relationship between alcohol cue-reactivity in the brain, cue-induced subjective craving and alcohol dependence duration and severity. Since alcohol dependence is highly comorbid with depression/anxiety, which may modulate brain responses to alcohol cues, we also examined the relation between comorbid depression/anxiety and cue-reactivity.
We compared 30 alcohol dependent patients with 15 healthy controls and 15 depression/anxiety patients during a visual alcohol cue-reactivity task using functional magnetic resonance imaging blood oxygenated level-dependent responses and subjective craving as outcomes. Within the alcohol dependent group we correlated cue-reactivity with alcohol dependence severity and duration, with cue-induced craving and with depression/anxiety levels.
Alcohol dependent patients showed greater cue-reactivity in motivational brain pathways and stronger subjective craving than depression/anxiety patients and healthy controls. Depression/anxiety was not associated with cue-reactivity, but depression severity in alcohol dependent patients was positively associated with craving. Within alcohol dependence, longer duration of alcohol dependence was associated with stronger cue-related activation of the posterior putamen, a structure involved in habits, whereas higher alcohol dependence severity was associated with lower cue-reactivity in the anterior putamen, an area implicated in goal-directed behavior preceding habit formation.
Cue-reactivity in alcohol dependence is not modulated by comorbid depression or anxiety. More importantly, the current data confirm the hypothesis of a ventral to dorsal striatal shift of learning processes with longer dependence duration, which could underlie increasingly habitual substance use with progressing substance dependence.
PMCID: PMC3882248  PMID: 24400099
13.  Reduced Frontal Brain Volume in Non-Treatment-Seeking Cocaine-Dependent Individuals: Exploring the Role of Impulsivity, Depression, and Smoking 
In cocaine-dependent patients, gray matter (GM) volume reductions have been observed in the frontal lobes that are associated with the duration of cocaine use. Studies are mostly restricted to treatment-seekers and studies in non-treatment-seeking cocaine abusers are sparse. Here, we assessed GM volume differences between 30 non-treatment-seeking cocaine-dependent individuals and 33 non-drug using controls using voxel-based morphometry. Additionally, within the group of non-treatment-seeking cocaine-dependent individuals, we explored the role of frequently co-occurring features such as trait impulsivity (Barratt Impulsivity Scale, BIS), smoking, and depressive symptoms (Beck Depression Inventory), as well as the role of cocaine use duration, on frontal GM volume. Smaller GM volumes in non-treatment-seeking cocaine-dependent individuals were observed in the left middle frontal gyrus. Moreover, within the group of cocaine users, trait impulsivity was associated with reduced GM volume in the right orbitofrontal cortex, the left precentral gyrus, and the right superior frontal gyrus, whereas no effect of smoking severity, depressive symptoms, or duration of cocaine use was observed on regional GM volumes. Our data show an important association between trait impulsivity and frontal GM volumes in cocaine-dependent individuals. In contrast to previous studies with treatment-seeking cocaine-dependent patients, no significant effects of smoking severity, depressive symptoms, or duration of cocaine use on frontal GM volume were observed. Reduced frontal GM volumes in non-treatment-seeking cocaine-dependent subjects are associated with trait impulsivity and are not associated with co-occurring nicotine dependence or depression.
PMCID: PMC3894477  PMID: 24478673
cocaine dependence; drug abuse; voxel-based morphometry; frontal; depression; nicotine
14.  The Role of Study and Work in Cannabis Use and Dependence Trajectories among Young Adult Frequent Cannabis Users 
Life course theory considers events in study and work as potential turning points in deviance, including illicit drug use. This qualitative study explores the role of occupational life in cannabis use and dependence in young adults. Two and three years after the initial structured interview, 47 at baseline frequent cannabis users were interviewed in-depth about the dynamics underlying changes in their cannabis use and dependence. Overall, cannabis use and dependence declined, including interviewees who quit using cannabis completely, in particular with students, both during their study and after they got employed. Life course theory appeared to be a useful framework to explore how and why occupational life is related to cannabis use and dependence over time. Our study showed that life events in this realm are rather common in young adults and can have a strong impact on cannabis use. While sometimes changes in use are temporary, turning points can evolve from changes in educational and employment situations; an effect that seems to be related to the consequences of these changes in terms of amount of leisure time and agency (i.e., feelings of being in control).
PMCID: PMC3739012  PMID: 23950748
frequent cannabis use; cannabis dependence; young adults; qualitative research; life course approach; longitudinal study; education; employment
15.  N-Acetylcysteine Normalizes Glutamate Levels in Cocaine-Dependent Patients: A Randomized Crossover Magnetic Resonance Spectroscopy Study 
Neuropsychopharmacology  2012;37(9):2143-2152.
Treatment with N-acetylcysteine (NAC) normalizes glutamate (Glu) homeostasis and prevents relapse in drug-dependent animals. However, the effect of NAC on brain Glu levels in substance-dependent humans has not yet been investigated. Proton magnetic resonance spectroscopy (1H MRS) was used to investigate Glu changes in the dorsal anterior cingulate cortex (dACC) after a single dose of NAC in cocaine-dependent patients and normal controls. In an open-label, randomized, crossover study, 8 cocaine-dependent patients and 14 healthy controls underwent two scan sessions: one group receiving no compound and the other following a single administration of 2400 mg NAC. The Barratt Impulsiveness Scale was administered to examine the relation between dACC Glu levels and impulsivity. In the medication-free condition, Glu levels in the dACC were significantly higher in cocaine-dependent patients compared with healthy controls. After administration of NAC, Glu levels were reduced in the cocaine-dependent group, whereas NAC had no effect in healthy controls. Higher baseline Glu levels were associated with higher impulsivity, and both were predictive of greater NAC-induced Glu reduction. The current findings indicate that NAC can normalize elevated Glu levels in cocaine-dependent patients. These findings may have important implications for treatment, because abnormal Glu levels are related to relapse, and treatment with NAC prevented relapse in animal studies. Furthermore, clinical studies have indicated beneficial effects of NAC in cocaine-dependent patients, and the current study suggests that these beneficial effects might in part be mediated by the ability of NAC to normalize glutamatergic abnormalities.
PMCID: PMC3398721  PMID: 22549117
cocaine dependence; N-acetylcysteine; glutamate; magnetic resonance spectroscopy; impulsivity; cocaine dependence; N-acetylcysteine; glutamate; magnetic resonance spectroscopy; impulsivity
16.  Efficacy of As-Needed Nalmefene in Alcohol-Dependent Patients with at Least a High Drinking Risk Level: Results from a Subgroup Analysis of Two Randomized Controlled 6-Month Studies 
Aims: The aim of the study was to investigate the efficacy and safety of as-needed use of nalmefene 18 mg versus placebo in reducing alcohol consumption in patients who did not reduce their alcohol consumption after an initial assessment, i.e. the pooled subgroup of patients with at least a high drinking risk level (men: >60 g/day; women: >40 g/day) at both screening and randomization from the two randomized controlled 6-month studies ESENSE 1 (NCT00811720) and ESENSE 2 (NCT00812461). Methods: Nalmefene 18 mg and placebo were taken on an as-needed basis. All the patients also received a motivational and adherence-enhancing intervention (BRENDA). The co-primary outcomes were number of heavy drinking days (HDDs) and mean total alcohol consumption (g/day) in Month 6 measured using the Timeline Follow-back method. Additionally, data on clinical improvement, liver function and safety were collected throughout the study. Results: The pooled population consisted of 667 patients: placebo n = 332; nalmefene n = 335. There was a superior effect of nalmefene compared with placebo in reducing the number of HDDs [treatment difference: −3.2 days (95% CI: −4.8; −1.6); P < 0.0001] and total alcohol consumption [treatment difference: −14.3 g/day (−20.8; −7.8); P < 0.0001] at Month 6. Improvements in clinical status and liver parameters were greater in the nalmefene group compared with the placebo group. Adverse events and adverse events leading to dropout were more common with nalmefene than placebo. Conclusion: As-needed nalmefene was efficacious in reducing alcohol consumption in patients with at least a high drinking risk level at both screening and randomization, and the effect in this subgroup was larger than in the total population.
PMCID: PMC3746807  PMID: 23873853
17.  Investigating the efficacy of integrated cognitive behavioral therapy for adult treatment seeking substance use disorder patients with comorbid ADHD: study protocol of a randomized controlled trial 
BMC Psychiatry  2013;13:132.
Attention deficit hyperactivity disorder (ADHD) frequently co-occurs with substance use disorders (SUD). The combination of ADHD and SUD is associated with a negative prognosis of both SUD and ADHD. Pharmacological treatments of comorbid ADHD in adult patients with SUD have not been very successful. Recent studies show positive effects of cognitive behavioral therapy (CBT) in ADHD patients without SUD, but CBT has not been studied in ADHD patients with comorbid SUD.
This paper presents the protocol of a randomized controlled trial to test the efficacy of an integrated CBT protocol aimed at reducing SUD as well as ADHD symptoms in SUD patients with a comorbid diagnosis of ADHD. The experimental group receives 15 CBT sessions directed at symptom reduction of SUD as well as ADHD. The control group receives treatment as usual, i.e. 10 CBT sessions directed at symptom reduction of SUD only. The primary outcome is the level of self-reported ADHD symptoms. Secondary outcomes include measures of substance use, depression and anxiety, quality of life, health care consumption and neuropsychological functions.
This is the first randomized controlled trial to test the efficacy of an integrated CBT protocol for adult SUD patients with a comorbid diagnosis of ADHD. The rationale for the trial, the design, and the strengths and limitations of the study are discussed.
Trial registration
This trial is registered in as NCT01431235.
PMCID: PMC3659028  PMID: 23663651
ADHD; SUD; Cognitive behavioral therapy; Adult; Integrated treatment
18.  Interactions between Affective and Cognitive Processing Systems in Problematic Gamblers: A Functional Connectivity Study 
PLoS ONE  2012;7(11):e49923.
Motivational and cognitive abnormalities are frequently reported in pathological gambling. However, studies simultaneously investigating motivational and cognitive processing in problematic gamblers are lacking, limiting our understanding of the interplay between these systems in problematic gambling. Studies in non-clinical samples indicate that interactions between dorsal “executive” and ventral “affective” processing systems are necessary for adequate responses in various emotive situations.
We conducted a generalized Psycho-Physiological Interaction (gPPI) analysis to assess the influence of affective stimuli on changes in functional connectivity associated with response inhibition in 16 treatment seeking problematic gamblers (PRGs) and 15 healthy controls (HCs) using an affective Go-NoGo fMRI paradigm including neutral, gambling-related, positive and negative pictures as neutral and affective conditions.
Across groups, task performance accuracy during neutral inhibition trials was positively correlated with functional connectivity between the left caudate and the right middle frontal cortex. During inhibition in the gambling condition, only in PRGs accuracy of task performance was positively correlated with functional connectivity within sub-regions of the dorsal executive system. Group interactions showed that during neutral inhibition, HCs exhibited greater functional connectivity between the left caudate and occipital cortex than PRGs. In contrast, during inhibition in the positive condition, PRGs compared to HCs showed greater functional connectivity between the left caudate and occipital cortex. During inhibition trials in the negative condition, a stronger functional connectivity between the left caudate and the right anterior cingulate cortex in PRGs compared to HCs was present. There were no group interactions during inhibition in the gambling condition.
During gamble inhibition PRGs seem to benefit more from functional connectivity within the dorsal executive system than HCs, because task accuracy in this condition in PRGs is positively correlated with functional connectivity, although the groups show similar connectivity patterns during gamble inhibition. Greater functional connectivity between the ventral affective system and the dorsal executive system in PRGs in the affective conditions compared to HCs, suggests facilitation of the dorsal executive system when affective stimuli are present specifically in PRGs.
PMCID: PMC3509135  PMID: 23209619
19.  Approach-Bias Predicts Development of Cannabis Problem Severity in Heavy Cannabis Users: Results from a Prospective FMRI Study 
PLoS ONE  2012;7(9):e42394.
A potentially powerful predictor for the course of drug (ab)use is the approach-bias, that is, the pre-reflective tendency to approach rather than avoid drug-related stimuli. Here we investigated the neural underpinnings of cannabis approach and avoidance tendencies. By elucidating the predictive power of neural approach-bias activations for future cannabis use and problem severity, we aimed at identifying new intervention targets. Using functional Magnetic Resonance Imaging (fMRI), neural approach-bias activations were measured with a Stimulus Response Compatibility task (SRC) and compared between 33 heavy cannabis users and 36 matched controls. In addition, associations were examined between approach-bias activations and cannabis use and problem severity at baseline and at six-month follow-up. Approach-bias activations did not differ between heavy cannabis users and controls. However, within the group of heavy cannabis users, a positive relation was observed between total lifetime cannabis use and approach-bias activations in various fronto-limbic areas. Moreover, approach-bias activations in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) independently predicted cannabis problem severity after six months over and beyond session-induced subjective measures of craving. Higher DLPFC/ACC activity during cannabis approach trials, but lower activity during cannabis avoidance trials were associated with decreases in cannabis problem severity. These findings suggest that cannabis users with deficient control over cannabis action tendencies are more likely to develop cannabis related problems. Moreover, the balance between cannabis approach and avoidance responses in the DLPFC and ACC may help identify individuals at-risk for cannabis use disorders and may be new targets for prevention and treatment.
PMCID: PMC3434213  PMID: 22957019
20.  The association between cingulate cortex glutamate concentration and delay discounting is mediated by resting state functional connectivity 
Brain and Behavior  2012;2(5):553-562.
Humans vary in their ability to delay gratification and impulsive decision making is a common feature in various psychiatric disorders. The level of delay discounting is a relatively stable psychological trait, and therefore neural processes implicated in delay discounting are likely to be based on the overall functional organization of the brain (under task-free conditions) in which state-dependent shifts from baseline levels occur. The current study investigated whether delay discounting can be predicted by intrinsic properties of brain functioning. Fourteen healthy male subjects performed a delay discounting task. In addition, resting state functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (¹H MRS) were used to investigate the relationship between individual differences in delay discounting and molecular and regional measures of resting state (baseline) activity of dorsal anterior cingulate cortex (dACC). Results showed that delay discounting was associated with both dACC glutamate concentrations and resting state functional connectivity of the dACC with a midbrain region including ventral tegmental area and substantia nigra. In addition, a neural pathway was established, showing that the effect of glutamate concentrations in the dACC on delay discounting is mediated by functional connectivity of the dACC with the midbrain. The current findings are important to acknowledge because spontaneous intrinsic brain processes have been proposed to be a potential promising biomarker of disease and impulsive decision making is associated with several psychiatric disorders.
PMCID: PMC3489808  PMID: 23139901
Anterior cingulate cortex; delay discounting; glutamate; impulsive decision making; magnetic resonance spectroscopy; resting state fMRI
21.  Substrates of neuropsychological functioning in stimulant dependence: a review of functional neuroimaging research 
Brain and Behavior  2012;2(4):499-523.
Stimulant dependence is associated with neuropsychological impairments. Here, we summarize and integrate the existing neuroimaging literature on the neural substrates of neuropsychological (dys)function in stimulant dependence, including cocaine, (meth-)amphetamine, ecstasy and nicotine dependence, and excessive caffeine use, comparing stimulant abusers (SAs) to nondrug using healthy controls (HCs). Despite some inconsistencies, most studies indicated altered brain activation in prefrontal cortex (PFC) and insula in response to reward and punishment, and higher limbic and anterior cingulate cortex (ACC)/PFC activation during craving and attentional bias paradigms in SAs compared with HCs. Impulsivity in SAs was associated with lower ACC and presupplementary motor area activity compared with HCs, and related to both ventral (amygdala, ventrolateral PFC, insula) and dorsal (dorsolateral PFC, dorsal ACC, posterior parietal cortex) systems. Decision making in SAs was associated with low dorsolateral PFC activity and high orbitofrontal activity. Finally, executive function in SAs was associated with lower activation in frontotemporal regions and higher activation in premotor cortex compared with HCs. It is concluded that the lower activations compared with HCs are likely to reflect the neural substrate of impaired neurocognitive functions, whereas higher activations in SAs compared with HCs are likely to reflect compensatory cognitive control mechanisms to keep behavioral task performance to a similar level as in HCs. However, before final conclusions can be drawn, additional research is needed using neuroimaging in SAs and HCs using larger and more homogeneous samples as well as more comparable task paradigms, study designs, and statistical analyses.
PMCID: PMC3432971  PMID: 22950052
Addiction; fMRI; functional imaging; magnetic resonance imaging; stimulant dependence; stimulants
22.  The Relationship between Impulsive Choice and Impulsive Action: A Cross-Species Translational Study 
PLoS ONE  2012;7(5):e36781.
Maladaptive impulsivity is a core symptom in various psychiatric disorders. However, there is only limited evidence available on whether different measures of impulsivity represent largely unrelated aspects or a unitary construct. In a cross-species translational study, thirty rats were trained in impulsive choice (delayed reward task) and impulsive action (five-choice serial reaction time task) paradigms. The correlation between those measures was assessed during baseline performance and after pharmacological manipulations with the psychostimulant amphetamine and the norepinephrine reuptake inhibitor atomoxetine. In parallel, to validate the animal data, 101 human subjects performed analogous measures of impulsive choice (delay discounting task, DDT) and impulsive action (immediate and delayed memory task, IMT/DMT). Moreover, all subjects completed the Stop Signal Task (SST, as an additional measure of impulsive action) and filled out the Barratt impulsiveness scale (BIS-11). Correlations between DDT and IMT/DMT were determined and a principal component analysis was performed on all human measures of impulsivity. In both rats and humans measures of impulsive choice and impulsive action did not correlate. In rats the within-subject pharmacological effects of amphetamine and atomoxetine did not correlate between tasks, suggesting distinct underlying neural correlates. Furthermore, in humans, principal component analysis identified three independent factors: (1) self-reported impulsivity (BIS-11); (2) impulsive action (IMT/DMT and SST); (3) impulsive choice (DDT). This is the first study directly comparing aspects of impulsivity using a cross-species translational approach. The present data reveal the non-unitary nature of impulsivity on a behavioral and pharmacological level. Collectively, this warrants a stronger focus on the relative contribution of distinct forms of impulsivity in psychopathology.
PMCID: PMC3344935  PMID: 22574225
23.  Response Inhibition during Cue Reactivity in Problem Gamblers: An fMRI Study 
PLoS ONE  2012;7(3):e30909.
Disinhibition over drug use, enhanced salience of drug use and decreased salience of natural reinforcers are thought to play an important role substance dependence. Whether this is also true for pathological gambling is unclear. To understand the effects of affective stimuli on response inhibition in problem gamblers (PRGs), we designed an affective Go/Nogo to examine the interaction between response inhibition and salience attribution in 16 PRGs and 15 healthy controls (HCs).
Four affective blocks were presented with Go trials containing neutral, gamble, positive or negative affective pictures. The No-Go trials in these blocks contained neutral pictures. Outcomes of interest included percentage of impulsive errors and mean reaction times in the different blocks. Brain activity related to No-Go trials was assessed to measure response inhibition in the various affective conditions and brain activity related to Go trials was assessed to measure salience attribution.
PRGs made fewer errors during gamble and positive trials than HCs, but were slower during all trials types. Compared to HCs, PRGs activated the dorsolateral prefrontal cortex, anterior cingulate and ventral striatum to a greater extent while viewing gamble pictures. The dorsal lateral and inferior frontal cortex were more activated in PRGs than in HCs while viewing positive and negative pictures. During neutral inhibition, PRGs were slower but similar in accuracy to HCs, and showed more dorsolateral prefrontal and anterior cingulate cortex activity. In contrast, during gamble and positive pictures PRGs performed better than HCs, and showed lower activation of the dorsolateral and anterior cingulate cortex.
This study shows that gambling-related stimuli are more salient for PRGs than for HCs. PRGs seem to rely on compensatory brain activity to achieve similar performance during neutral response inhibition. A gambling-related or positive context appears to facilitate response inhibition as indicated by lower brain activity and fewer behavioural errors in PRGs.
PMCID: PMC3316530  PMID: 22479305
24.  Cocaine Addiction Treatments to improve Control and reduce Harm (CATCH): New Pharmacological Treatment Options for Crack-Cocaine Dependence in the Netherlands 
BMC Psychiatry  2011;11:135.
Cocaine, particularly in its base form ('crack'), has become one of the drugs of most concern in the Netherlands, being associated with a wide range of medical, psychiatric and social problems for the individual, and with significant public order consequences for society. Available treatment options for cocaine dependent users are limited, and a substantial part of the cocaine dependent population is not reached by the addiction treatment system. Psychosocial interventions for cocaine dependence generally show modest results, and there are no registered pharmacological treatments to date, despite the wide range of medications tested for this type of dependence.
The present study (Cocaine Addiction Treatments to improve Control and reduce Harm; CATCH) investigates the possibilities and problems associated with new pharmacological treatments for crack dependent patients.
The CATCH-study consists of three separate randomised controlled, open-label, parallel-group feasibility trials, conducted at three separate addiction treatment institutes in the Netherlands. Patients are either new referrals or patients already in treatment. A total of 216 eligible outpatients are randomised using pre-randomisation double-consent design and receive either 12 weeks treatment with oral topiramate (n = 36; Brijder Addiction Treatment, The Hague), oral modafinil (n = 36; Arkin, Amsterdam), or oral dexamphetamine sustained-release (n = 36; Bouman GGZ, Rotterdam) as an add-on to cognitive behavioural therapy (CBT), or receive a 12-week CBT only (controls: n = 3 × 36).
Primary outcome in these feasibility trials is retention in the underlying psychosocial treatment (CBT). Secondary outcomes are acceptance and compliance with the study medication, safety, changes in cocaine (and other drug) use, physical and mental health, social functioning, and patient satisfaction.
To date, the CATCH-study is the first study in the Netherlands that explores new treatment options for crack-cocaine dependence focusing on both abstinence and harm minimisation. It is expected that the study will contribute to the development of new treatments for one of the most problematic substance use disorders.
Trial Registration
The Netherlands National Trial Register NTR2576
The European Union Drug Regulating Authorities Clinical Trials EudraCT2009-010584-16
PMCID: PMC3175153  PMID: 21854580
25.  Brain Imaging Studies in Pathological Gambling 
Current Psychiatry Reports  2010;12(5):418-425.
This article reviews the neuroimaging research on pathological gambling (PG). Because of the similarities between substance dependence and PG, PG research has used paradigms similar to those used in substance use disorder research, focusing on reward and punishment sensitivity, cue reactivity, impulsivity, and decision making. This review shows that PG is consistently associated with blunted mesolimbic-prefrontal cortex activation to nonspecific rewards, whereas these areas show increased activation when exposed to gambling-related stimuli in cue exposure paradigms. Very little is known, and hence more research is needed regarding the neural underpinnings of impulsivity and decision making in PG. This review concludes with a discussion regarding the challenges and new developments in the field of neurobiological gambling research and comments on their implications for the treatment of PG.
PMCID: PMC2933850  PMID: 20676945
Pathological gambling; Addiction; Neuroimaging; Neuropsychology

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