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1.  Grey Matter Changes Associated with Heavy Cannabis Use: A Longitudinal sMRI Study 
PLoS ONE  2016;11(5):e0152482.
Cannabis is the most frequently used illicit drug worldwide. Cross-sectional neuroimaging studies suggest that chronic cannabis exposure and the development of cannabis use disorders may affect brain morphology. However, cross-sectional studies cannot make a conclusive distinction between cause and consequence and longitudinal neuroimaging studies are lacking. In this prospective study we investigate whether continued cannabis use and higher levels of cannabis exposure in young adults are associated with grey matter reductions. Heavy cannabis users (N = 20, age baseline M = 20.5, SD = 2.1) and non-cannabis using healthy controls (N = 22, age baseline M = 21.6, SD = 2.45) underwent a comprehensive psychological assessment and a T1- structural MRI scan at baseline and 3 years follow-up. Grey matter volumes (orbitofrontal cortex, anterior cingulate cortex, insula, striatum, thalamus, amygdala, hippocampus and cerebellum) were estimated using the software package SPM (VBM-8 module). Continued cannabis use did not have an effect on GM volume change at follow-up. Cross-sectional analyses at baseline and follow-up revealed consistent negative correlations between cannabis related problems and cannabis use (in grams) and regional GM volume of the left hippocampus, amygdala and superior temporal gyrus. These results suggests that small GM volumes in the medial temporal lobe are a risk factor for heavy cannabis use or that the effect of cannabis on GM reductions is limited to adolescence with no further damage of continued use after early adulthood. Long-term prospective studies starting in early adolescence are needed to reach final conclusions.
doi:10.1371/journal.pone.0152482
PMCID: PMC4880314  PMID: 27224247
2.  Risk Factors for Borderline Personality Disorder in Treatment Seeking Patients with a Substance Use Disorder: An International Multicenter Study 
European addiction research  2015;21(4):188-194.
Borderline personality disorder (BPD) and substance use disorders (SUDs) often co-occur, partly because they share risk factors. In this international multicenter study, risk factors for BPD were examined for SUD patients. In total, 1,205 patients were comprehensively examined by standardized interviews and questionnaires on psychiatric diagnosis and risk factors, and it was found that 1,033 (85.7%) had SUDs without BPD (SUD) and 172 (14.3%) had SUD with BPD (SUD + BPD). SUD + BPD patients were significantly younger, more often females and more often diagnosed with comorbid adult attention deficit/hyperactivity disorder. SUD + BPD patients did not differ from SUD patients on most risk factors typical for SUD such as maternal use of drugs during pregnancy or parents having any SUD. However, SUD + BPD patients did have a higher risk of having experienced emotional and physical abuse, neglect, or family violence in childhood compared to SUD patients, suggesting that child abuse and family violence are BPD-specific risk factors in patients with SUDs.
doi:10.1159/000371724
PMCID: PMC4869722  PMID: 25832736
Risk factors; Substance use disorder; Borderline personality disorder; Comorbidity
3.  Impact of DSM-5 Changes on the Diagnosis and Acute Treatment of Schizophrenia 
Schizophrenia Bulletin  2014;41(3):637-643.
Objective:
To examine the consequences and validity of changes in Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 diagnostic criteria for schizophrenia, eg, omission of subtypes, using a large dataset of double-blind, randomized, placebo-controlled schizophrenia trials.
Methods:
Data from 22 short-term efficacy registration trials of second generation antipsychotics for the treatment of acute psychotic episodes in patients with schizophrenia (N = 5233), submitted to the Dutch regulatory authority were analyzed. We examined whether patients in these pre-DSM-5 trials met the diagnostic criteria for schizophrenia according to DSM-5. Using linear regression, we examined differences in effect size between DSM-IV subtypes and between DSM-5 symptom dimensions.
Results:
Over 99.5% of the patients met DSM-5 diagnostic criteria for schizophrenia and no differences in effect size were found between schizophrenia subtypes (P = .65). Symptom dimensions that respond best to treatment with second generation antipsychotics were hallucinations, delusions, disorganized speech, and mania (Hedge’s g −0.23 to −0.31).
Conclusions:
Results of clinical trials in patients with pre-DSM-5 schizophrenia also apply to patients diagnosed with DSM-5 schizophrenia. Omission of the classic subtypes is justified as they are not predictive of response to treatment. The DSM-5 C-RDPSS scale adds valuable information to the categorical diagnosis of schizophrenia, which is relevant for antipsychotic response.
doi:10.1093/schbul/sbu172
PMCID: PMC4393695  PMID: 25528758
antipsychotics; clinical trials; diagnostic criteria
4.  Doubt in the Insula: Risk Processing in Obsessive-Compulsive Disorder 
Extensive cleaning or checking of patients with obsessive-compulsive disorder (OCD) are often interpreted as strategies to avoid harm and as an expression of the widespread belief that OCD patients are more risk-averse. However, despite its clinical significance, the neural basis of risk attitude in OCD is unknown. Here, we investigated neural activity during risk processing using functional magnetic resonance imaging and simultaneously assessed risk attitude using a separate behavioral paradigm in OCD patients with different symptoms versus healthy controls (HCs). We found opposite insula responses to high versus low risk in OCD patients compared to HCs: a positive correlation between insula activity and risk-aversion in patients versus a negative correlation in controls. Although OCD patients overall were not more risk-averse than controls, there were differences between subgroups of OCD patients: patients with doubt/checking symptoms were more risk-averse than other patients. Taken together, OCD patients show a reversed pattern of risk processing by the insula compared to HCs. Moreover, the data suggest that increased activation of the insula signals an abnormal urge to avoid risks in the subpopulation of OCD patients with doubt and checking symptoms. These results indicate a role for the insula in excessive risk-avoidance relevant to OCD.
doi:10.3389/fnhum.2016.00283
PMCID: PMC4905944  PMID: 27378883
insula; obsessive-compulsive disorder; risk processing; risk avoidance; fMRI
5.  Aversive Counterconditioning Attenuates Reward Signaling in the Ventral Striatum 
Appetitive conditioning refers to the process of learning cue-reward associations and is mediated by the mesocorticolimbic system. Appetitive conditioned responses are difficult to extinguish, especially for highly salient reward such as food and drugs. We investigate whether aversive counterconditioning can alter reward reinstatement in the ventral striatum in healthy volunteers using functional magnetic resonance imaging (fMRI). In the initial conditioning phase, two different stimuli were reinforced with a monetary reward. In the subsequent counterconditioning phase, one of these stimuli was paired with an aversive shock to the wrist. In the following extinction phase, none of the stimuli were reinforced. In the final reinstatement phase, reward was reinstated by informing the participants that the monetary gain could be doubled. Our fMRI data revealed that reward signaling in the ventral striatum and ventral tegmental area following reinstatement was smaller for the stimulus that was counterconditioned with an electrical shock, compared to the non-counterconditioned stimulus. A functional connectivity analysis showed that aversive counterconditioning strengthened striatal connectivity with the hippocampus and insula. These results suggest that reward signaling in the ventral striatum can be attenuated through aversive counterconditioning, possibly by concurrent retrieval of the aversive association through enhanced connectivity with hippocampus and insula.
doi:10.3389/fnhum.2016.00418
PMCID: PMC4990538  PMID: 27594829
ventral striatum; reward reinstatement; fMRI; counterconditioning
6.  Burden and Expressed Emotion of Caregivers in Cases of Adult Substance Use Disorder with and Without Attention Deficit/Hyperactivity Disorder or Autism Spectrum Disorder 
Objective
To identify and compare caregiver burden and expressed emotion (EE) in adult substance use disorder (SUD) patients with and without co-occurring attention deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD). To examine possible differences in correlations between caregiver burden and EE across patient groups.
Design and Methods
Cross-sectional study with measures of perceived burden (Involvement Evaluation Questionnaire: IEQ), subjective stress (General Health Questionnaire: GHQ) and perceptions of expressed emotion (Level of Expressed Emotion: LEE) in informal caregivers for patients with SUD, SUD+ADHD or SUD+ASD.
Findings
No differences in caregiver burden or expressed emotion when caregivers for patients with SUD were compared to caregivers for patients with SUD+ADHD. A moderate but non-significant difference for caregivers of patients with SUD versus SUD+ASD, which disappeared when the number of contact hours between patient and caregiver for the SUD only group was controlled for. The IEQ sum scores also substantially correlated with the LEE sum scores.
Conclusion
Informal caregivers for patients with only SUD show higher levels of burden and EE than informal caregivers for patients with SUD and a co-occurring ASD. This difference was largely explained by the higher number of contact hours between patient and caregiver in the SUD only group.
doi:10.1007/s11469-015-9567-9
PMCID: PMC4710653  PMID: 26798327
Burden; Expressed emotions; Substance use disorder; Attention deficit/hyperactivity disorder; Autism spectrum disorder
7.  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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/s12888-015-0530-x
PMCID: PMC4501102  PMID: 26169586
Coping styles; Substance Use Disorder; Attention Deficit/Hyperactivity Disorder; Autism Spectrum Disorder
8.  Brain volume in male patients with recent onset schizophrenia with and without cannabis use disorders 
Background
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.
Methods
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.
Results
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.
Limitations
We were unable to correct for possible confounding effects of smoking or antipsychotic medication.
Conclusion
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.
doi:10.1503/jpn.140081
PMCID: PMC4409437  PMID: 25510948
9.  Substance use disorders, trauma, and PTSD 
European Journal of Psychotraumatology  2015;6:10.3402/ejpt.v6.27632.
doi:10.3402/ejpt.v6.27632
PMCID: PMC4393537
10.  Effect of extended-release naltrexone on striatal dopamine transporter availability, depression and anhedonia in heroin-dependent patients 
Psychopharmacology  2015;232(14):2597-2607.
Rationale
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.
Objectives
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1007/s00213-015-3891-4
PMCID: PMC4480848  PMID: 25757673
Dopamine transporter; Abstinence; Addiction; Brain imaging; In vivo; Opioid receptor
11.  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.
doi:10.1002/mpr.1397
PMCID: PMC4085151  PMID: 24022983
ADHD; substance use disorders; prevalence; attention/deficit hyperactivity disorder
12.  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.
doi:10.1111/j.1369-1600.2011.00369.x
PMCID: PMC3252421  PMID: 21955259
cannabinoid 1 receptor; dopamine D2 receptor; IBZM; nucleus accumbens; rimonabant; striatum
13.  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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/s12888-014-0264-1
PMCID: PMC4173065  PMID: 25234344
Substance use disorders; Attention deficit hyperactivity disorder; Autism spectrum disorder; Everyday life consequences; Adults
14.  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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.drugalcdep.2013.09.026
PMCID: PMC4133781  PMID: 24156882
Prevalence; Substance use disorder; Attention deficit hyperactivity disorder; DSM-5; Adults
15.  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.
Aims
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.
Design
Data were obtained from the cross-sectional International ADHD in Substance use disorder Prevalence (IASP) study.
Setting
Forty-seven centres of SUD treatment in 10 countries.
Participants
A total of 1205 treatment-seeking SUD patients.
Measurements
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).
Findings
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.
Conclusions
Treatment-seeking substance use disorder patients with attention deficit hyperactivity disorder are at a very high risk for additional externalizing disorders.
doi:10.1111/add.12370
PMCID: PMC4112562  PMID: 24118292
ADHD; antisocial personality disorder; bipolar disorder; borderline personality disorder; comorbidity; depression; substance use disorder
16.  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.
Background
To detect attention deficit hyperactivity disorder (ADHD) in treatment seeking substance use disorders (SUD) patients, a valid screening instrument is needed.
Objectives
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).
Methods
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.
Results
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.
Conclusions
The ASRS is a sensitive screener for identifying possible ADHD cases with very few missed cases among those screening negative in this population.
doi:10.1016/j.drugalcdep.2013.04.010
PMCID: PMC4083506  PMID: 23660242
ADHD; Substance use disorders; Prevalence; Attention/deficit hyperactivity disorder; Validity; ASRS; Addiction; Psychiatry
17.  The Role of Habits and Motivation in Human Drug Addiction: A Reflection 
doi:10.3389/fpsyt.2014.00008
PMCID: PMC3905212  PMID: 24523702
habits; habit formation; motivation; addiction; goal-directed behavior
18.  Cue Reactivity Is Associated with Duration and Severity of Alcohol Dependence: An fMRI Study 
PLoS ONE  2014;9(1):e84560.
Introduction
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1371/journal.pone.0084560
PMCID: PMC3882248  PMID: 24400099
19.  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.
doi:10.3389/fnhum.2014.00007
PMCID: PMC3894477  PMID: 24478673
cocaine dependence; drug abuse; voxel-based morphometry; frontal; depression; nicotine
20.  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).
doi:10.3389/fpsyt.2013.00085
PMCID: PMC3739012  PMID: 23950748
frequent cannabis use; cannabis dependence; young adults; qualitative research; life course approach; longitudinal study; education; employment
21.  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.
doi:10.1038/npp.2012.66
PMCID: PMC3398721  PMID: 22549117
cocaine dependence; N-acetylcysteine; glutamate; magnetic resonance spectroscopy; impulsivity; cocaine dependence; N-acetylcysteine; glutamate; magnetic resonance spectroscopy; impulsivity
22.  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.
doi:10.1093/alcalc/agt061
PMCID: PMC3746807  PMID: 23873853
23.  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.
Background
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.
Methods/design
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.
Discussion
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 http://www.clinicaltrials.gov as NCT01431235.
doi:10.1186/1471-244X-13-132
PMCID: PMC3659028  PMID: 23663651
ADHD; SUD; Cognitive behavioral therapy; Adult; Integrated treatment
24.  Interactions between Affective and Cognitive Processing Systems in Problematic Gamblers: A Functional Connectivity Study 
PLoS ONE  2012;7(11):e49923.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1371/journal.pone.0049923
PMCID: PMC3509135  PMID: 23209619
25.  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.
doi:10.1371/journal.pone.0042394
PMCID: PMC3434213  PMID: 22957019

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