Robbert-Jan Verkes

Radboud University Nijmegen, Nymegen, Gelderland, Netherlands

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Publications (15)63.92 Total impact

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    ABSTRACT: Objectives: Neuropsychiatric symptoms (NPS) are highly prevalent in dementia, but effective pharmacotherapy without important side effects is lacking. This study aims to assess the efficacy and safety of oral tetrahydrocannabinol (THC) in the treatment of NPS in dementia. Design: Randomized, double-blind, placebo-controlled, repeated crossover trial, consisting of six treatment blocks of 2 weeks each. Setting: Two hospital sites in The Netherlands, September 2011 to December 2013. Participants: Patients with dementia and clinically relevant NPS. Intervention: Within each block THC (0.75 mg twice daily in blocks 1-3 and 1.5 mg twice daily in blocks 4-6) and placebo were administered in random order for 3 consecutive days, followed by a 4-day washout. Measurements: Primary outcome was change in Neuropsychiatric Inventory (NPI) score. Analyses were performed intention-to-treat. Data from all subjects were used without imputation. Sample size required for a power of 80% was 20 patients, because of repeated crossover. Results: 22 patients (15 men, mean age 76.4 [5.3] years) were included, of whom 20 (91%) completed the trial. THC did not reduce NPI compared to placebo (blocks 1-3: 1.8, 97.5% CI: -2.1 to 5.8; blocks 4-6: -2.8, 97.5% CI: -7.4 to 1.8). THC was well tolerated, as assessed by adverse event monitoring, vital signs, and mobility. The incidence of adverse events was similar between treatment groups. Four non-related serious adverse events occurred. Conclusions: This is the largest randomized controlled trial studying the efficacy of THC for NPS, to date. Oral THC did not reduce NPS in dementia, but was well tolerated by these vulnerable patients, supporting future higher dosing studies.
    No preview · Article · Jul 2015 · The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry
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    ABSTRACT: Objective: To study the efficacy and safety of low-dose oral tetrahydrocannabinol (THC) in the treatment of dementia-related neuropsychiatric symptoms (NPS). Methods: This is a randomized, double-blind, placebo-controlled study. Patients with dementia and clinically relevant NPS were randomly assigned to receive THC 1.5 mg or matched placebo (1:1) 3 times daily for 3 weeks. Primary outcome was change in Neuropsychiatric Inventory (NPI), assessed at baseline and after 14 and 21 days. Analyses were based on intention-to-treat. Results: Twenty-four patients received THC and 26 received placebo. NPS were reduced during both treatment conditions. The difference in reduction from baseline between THC and placebo was not significant (mean difference NPItotal: 3.2, 95% confidence interval [CI] 23.6 to 10.0), nor were changes in scores for agitation (Cohen-Mansfield Agitation Inventory 4.6, 95%CI 23.0 to 12.2), quality of life (Quality of Life–Alzheimer’s Disease 20.5, 95% CI 22.6 to 1.6), or activities of daily living (Barthel Index 0.6, 95% CI 20.8 to 1.9). The number of patients experiencing mild or moderate adverse events was similar (THC, n 5 16; placebo, n 5 14, p 5 0.36). No effects on vital signs, weight, or episodic memory were observed. Conclusions: Oral THC of 4.5 mg daily showed no benefit in NPS, but was well-tolerated, which adds valuable knowledge to the scarce evidence on THC in dementia. The benign adverse event profile of this dosage allows study of whether higher doses are efficacious and equally welltolerated. Classification of evidence: This study provides Class I evidence that for patients with dementiarelated NPS, low-dose THC does not significantly reduce NPS at 21 days, though it is welltolerated.
    Full-text · Article · Jun 2015 · Neurology
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    ABSTRACT: There is a lack of detailed information on the role of substance use disorders (SUD) as a substantial factor in offences and treatment in forensic psychiatric patients. The aim of this study was to get a better understanding of these specifics. Clinical records of 193 male patients admitted to a Dutch forensic psychiatric hospital were scrutinized on anamnestic, diagnostic and risk assessment data. One of the central findings was that the prevalence of SUDs was high. Patients with an SUD had a more extensive criminal history, unstable and deviant lifestyle and higher risk of violent behavior than patients without a substance use disorder. No differences were found in duration of treatment, aggressive incidents and leave. Another important finding was that a distinction could be made between patients with substance use as a primary criminogenic risk factor and patients with substance use as a secondary risk factor. Although substance use is identified as a general risk factor, this study supports the idea of sub categorization of patients with an SUD and emphasizes the need for a different treatment approach. Further study is needed to identify specific treatment approaches, based on more differentiated profiles of these patients.
    Full-text · Article · Feb 2014 · International Journal of Law and Psychiatry
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    ABSTRACT: This study examined whether cognitive measures of response inhibition derived from the AX-CPT are able to differentiate between adult attention deficit/hyperactivity disorder (ADHD), borderline personality disorder (BPD), and healthy controls (HC). Current DSM-IV-TR symptoms of ADHD and BPD were assessed by structured diagnostic interviews, and parent developmental interviews were used to assess childhood ADHD symptoms. Patients (14 ADHD, 12 BPD, 7 ADHD and BPD, and 37 HC) performed the AX-CPT. Seventy percent of AX-CPT trials were target (AX) trials, creating a bias to respond with a target response to X probes in the nontarget (AY, BX, BY) trials. On BX trials, context, i.e. the non-'A' letter, must be used to inhibit this prepotent response tendency. On AY trials context actually causes individuals to false alarm. The effects of ADHD and BPD on AX-CPT outcome were tested using two-way ANOVA. BPD was associated with higher percentage of errors across the task and more errors and slower responses on BX trials, whereas ADHD was associated with slower responses on AY trials. The findings suggest response inhibition problems to be present in both ADHD and BPD, and patients with BPD to be particularly impaired due to poor context processing.
    Full-text · Article · Dec 2013
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    ABSTRACT: Resting-state studies in depressed patients have revealed increased connectivity within the default mode (DMN) and task-positive (TPN) networks. This has been associated with heightened rumination, which is the tendency to repetitively think about symptoms of distress. Here, we performed a pharmacological neuroimaging study in healthy volunteers to investigate whether short-term antidepressant administration could reduce DMN connectivity. We recorded resting-state functional magnetic resonance imaging (fMRI) scans in twenty-three healthy volunteers after two week intake of the combined serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine in a double-blind, placebo-controlled, crossover study. Duloxetine improved mood in part as a result of increased resilience to the mood-worsening effects of scanning, and reduced DMN and TPN connectivity. Within the DMN, duloxetine reduced connectivity between the medial prefrontal cortex (MPFC) and the lateral parietal cortex (LPC) and uncoupled the MPFC from the dorsolateral prefrontal cortex (DLPFC). Within the TPN, duloxetine uncoupled the intraparietal sulcus (IPS) from the inferior occipital gyrus. These results show that two-week antidepressant administration reduces DMN and TPN connectivity in healthy volunteers, which may contribute to their antidepressant effects in depression.
    No preview · Article · Nov 2013 · NeuroImage
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    ABSTRACT: Genetic factors and childhood adverse experiences contribute to the vulnerability to alcohol dependence. However, empirical data on the interplay between specific genes and adverse experiences are few. The COMT Val158Met and DRD2/ANKK1 Taq1A genotypes have been suggested to affect both stress sensitivity and the risk for alcohol dependence. This study tested the hypothesis that genetic variation in COMT Val158Met and DRD2/ANKK1 Taq1A interacts with childhood adverse experiences to predict alcohol dependence. Male abstinent alcohol-dependent patients (n = 110) and age-matched healthy male controls (n = 99) were genotyped for the COMT Val158Met and the DRD2/ANKK1 Taq1A genotypes. Childhood adverse events were measured using three self-report questionnaires. Alcohol dependence severity, age of onset and duration of alcohol dependence were analyzed as secondary outcome measures. Statistical analysis involved logistic regression analysis and analysis of variance. Alcohol-dependent patients reported increased childhood adversity. The interaction between childhood adversity and the COMT Val158Met genotype added significantly to the prediction model. This gene-environment interaction was confirmed in the analysis of the secondary outcome measures, i.e. alcohol dependence severity, age of onset and duration of alcohol dependence. The DRD2/ANKK1 Taq1A genotype was not related to alcohol dependence, nor did it interact with childhood adversity in predicting alcohol dependence. This study provides evidence for a gene-environment interaction in alcohol dependence, in which an individual's sensitivity to childhood adverse experience is moderated by the COMT genotype. Exposed carriers of a low-activity Met allele have a higher risk to develop severe alcohol dependence than individuals homozygous for the Val allele.
    No preview · Article · Apr 2012 · Addiction Biology
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    ABSTRACT: The inability of individuals with Alcohol Use Disorders (AUD) to recognize and describe their feelings and cravings may be due to alexithymia. Previous researches have shown evidence for a negative influence of alexithymia on treatment outcomes in patients with AUD. Therefore, it was hypothesized that high alexithymic patients with AUD would benefit less from cognitive behavioral therapy (CBT) compared with low alexithymic patients. One hundred alcohol-dependent inpatients (DSM IV) were assessed with the Mini International Neuropsychiatric Interview for psychiatric disorders, the Toronto Alexithymia Scale (TAS-20), and the European Addiction Severity Index (EuropASI). Baseline alexithymia, as a categorical and continuous variable, was used to compare or relate baseline demographic and addiction characteristics, time in treatment, abstinence, and differences in addiction severity at 1-year follow-up. Analyses were performed using χ(2) test, analysis of variance or Kruskal-Wallis, paired t-tests or Wilcoxon's signed rank tests, multivariate logistic, and linear regression models, as appropriate. The prevalence of high alexithymia (TAS-20 > 61) was 45%. The total TAS-20 score correlated negatively with years of education (r = -.21; p = .04) and positively with the psychiatry domain of the EuropASI (r = .23; p = .04). Alexithymia showed no relation to abstinence, time in treatment, or change in severity of alcohol-related problems on the EuropASI. High alexithymic patients with AUD do benefit equally from inpatient CBT-like treatment as low alexithymic patients with AUD. Multimethod alexithymia assessments with an observer scale have been advised to judge the relationship with resulting outcome in CBT.
    No preview · Article · Apr 2012 · The American Journal of Drug and Alcohol Abuse
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    ABSTRACT: Alcohol dependence is a common neuropsychiatric disorder with high heritability. However, genetic association studies on alcohol dependence are often troubled by nonreplication. The use of intermediate phenotypes may help make clear the mode of action of various candidate genes and improve the reproducibility of genetic association studies. To test central dopamine receptor sensitivity as an intermediate phenotype for alcohol dependence, specifically evaluating the hypothesis that the dopaminergic genes COMT Val158Met and DRD2 Taq1A affect dopamine receptor sensitivity. Case-control pharmacogenetic challenge study. Patients with alcohol dependence admitted for detoxification were compared with healthy control subjects matched for age and level of education. Patients (n = 110) were a consecutive sample, whereas controls (n = 99) were recruited through advertisements in regional newspapers. A dopamine challenge test was subcutaneously administered using the dopamine agonist apomorphine hydrochloride (0.005 mg/kg). Outcome measures were plasma growth hormone levels and results of a continuous performance task. Central dopamine receptor sensitivity is reduced in alcohol dependence, and this is modulated by dopaminergic genes. Specifically, DRD2 Taq1A genotype affected dopamine receptor sensitivity as measured by plasma growth hormone levels, and COMT Val158Met genotype affected dopamine receptor sensitivity as measured by performance on a continuous performance task. In a logistic regression analysis, reduced dopamine receptor sensitivity on both measures predicted alcohol dependence, without an additive effect of the COMT Val158Met and DRD2 Taq1A genotypes. COMT Val158Met and DRD2 Taq1A may affect the intermediate phenotype of central dopamine receptor sensitivity. COMT Val158Met and DRD2 Taq1A may confer their risk of alcohol dependence through reduced dopamine receptor sensitivity in the prefrontal cortex and hindbrain, respectively.
    No preview · Article · Apr 2012 · Archives of general psychiatry
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    ABSTRACT: Hyperreactivity and impaired sensory gating of the acoustic startle response in alcohol dependence has been suggested to reflect a residual effect of previous detoxifications, increasing the severity of subsequent withdrawal episodes. Previous studies on the acoustic startle only included early-onset alcohol-dependent patients. The observed abnormalities may therefore also be specific for this subtype of alcohol dependence. We investigated the acoustic startle response in alcohol-dependent patients and healthy controls and hypothesized that (i) early-onset alcohol-dependent patients show increased acoustic startle responses compared with late-onset alcohol-dependent patients and healthy controls, and (ii) the duration of alcohol dependence or the number of prior detoxifications would not explain the differences in the acoustic startle between early- and late-onset alcohol dependence. The acoustic startle reflex was assessed in detoxified, male alcohol-dependent patients (N = 83) and age-matched healthy male controls (N = 86). Reflex eye blink responses to an auditory startle stimulus were measured by means of electromyographic recordings over the right orbicularis oculi muscle. Reflex amplitudes and levels of prepulse inhibition (PPI) were analyzed. There was no association between number of previous withdrawals and the startle response or PPI. Early-onset alcohol-dependent patients showed higher acoustic startle amplitudes compared with late-onset alcohol-dependent patients and healthy controls [75/105 dB: F(2, 166) = 9.2, p < 0.001; 85/105 dB: F(2, 166) = 12.1, p < 0.001; 95 dB: F(2, 166) = 8.2, p < 0.001; 105 dB: F(2, 166) = 9.7, p < 0.001], and there were no differences in PPI. Increased acoustic startle response in detoxified early-onset alcohol-dependent patients may reflect a trait marker specifically involved in early-onset alcohol dependence. The findings of the current study do not support the hypothesis that the increased startle response is a residual state marker.
    No preview · Article · Jan 2012 · Alcoholism Clinical and Experimental Research
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    ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) and borderline personality disorder (BPD) are frequently comorbid. To contribute to a better understanding of the associations regularly found between ADHD and BPD, on the one hand, and the developmental pathways for these disorders, on the other hand, latent class analyses (LCA) were undertaken to identify classes differing in profiles of childhood symptoms of ADHD and adult symptoms of ADHD and BPD. Diagnostic interviews with 103 female outpatients meeting the criteria for ADHD and/or BPD were used to assess current DSM-IV symptoms; childhood symptoms of ADHD were assessed in parent interviews. The latent classes were examined in relation to the DSM-IV conceptualizations of ADHD and BPD. And relations between childhood and adult classes were examined to hypothesize about developmental trajectories. LCA revealed an optimal solution with four distinct symptom profiles: only ADHD symptoms; BPD symptoms and only ADHD symptoms of hyperactivity; BPD symptoms and ADHD symptoms of inattention and hyperactivity; BPD symptoms and ADHD symptoms of inattention, hyperactivity and impulsivity. All patients with BPD had some ADHD symptoms in both adulthood and childhood. Hyperactivity was least discriminative of adult classes. Adult hyperactivity was not always preceded by childhood hyperactivity; some cases of comorbid ADHD and BPD symptoms were not preceded by significant childhood ADHD symptoms; and some cases of predominantly BPD symptoms could be traced back to combined symptoms of ADHD in childhood. The results underline the importance of taking ADHD diagnoses into account with BPD. ADHD classification subtypes may not be permanent over time, and different developmental pathways to adult ADHD and BPD should therefore be investigated.
    Full-text · Article · Jul 2011 · Psychiatry Research
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    ABSTRACT: Typical users of 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") are polydrug users, combining MDMA with alcohol or cannabis [most active compound: delta-9-tetrahydrocannabinol (THC)]. The aim of the present study was to investigate whether co-administration of alcohol or THC with MDMA differentially affects ongoing electroencephalogram (EEG) oscillations compared to the administration of each drug alone. In two separate experiments, 16 volunteers received four different drug conditions: (1) MDMA (100 mg); (2) alcohol clamp (blood alcohol concentration = 0.6‰) or THC (inhalation of 4, 6 and 6 mg, interval of 1.5 h); (3) MDMA in combination with alcohol or THC; and (4) placebo. Before and after drug administration, electroencephalography was recorded during an eyes closed resting state. Theta and alpha power increased after alcohol intake compared to placebo and reduced after MDMA intake. No interaction between alcohol and MDMA was found. Significant MDMA x THC effects for theta and lower-1-alpha power indicated that the power attenuation after the combined intake of MDMA and THC was less than the sum of each drug alone. For the lower-2-alpha band, the intake of MDMA or THC alone did not significantly affect power, but the intake of combined MDMA and THC significantly decreased lower-2-alpha power. The present findings indicate that the combined intake of MDMA and THC, but not of MDMA and alcohol, affects ongoing EEG oscillations differently than the sum of either one drug alone. Changes in ongoing EEG oscillations may be related to the impaired task performance that has often been reported after drug intake.
    Full-text · Article · Oct 2010 · Psychopharmacology
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    ABSTRACT: Reduced metabolic activity in frontal brain regions, and reduced striatal dopamine receptor densities have been shown in alcohol dependent patients. Little is known on functional changes in the fronto-striatal-thalamic dopaminergic neurocircuitry in these patients. The objective of this study was to assess sensitivity of prefrontal dopamine receptors in alcohol dependent patients. Male alcohol dependent patients (N=40) and healthy controls (N=39) performed an AX-continuous performance test before and after administration of the DA agonist apomorphine (0.005 mg/kg). At baseline alcohol dependent patients were slower and less accurate compared to healthy controls. After administration of apomorphine, performance improved in alcohol dependent patients and deteriorated in healthy controls. Reduced cognitive performance in alcohol dependent patients compared with healthy controls may indicate dopamine dysfunctioning at the prefrontal level. Improvement of cognitive performance in alcohol dependent patients after administration of apomorphine and deterioration in healthy controls provides evidence for an inverted U-shape relation between dopaminergic functioning and cognitive performance.
    Full-text · Article · Oct 2008 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
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    ABSTRACT: Mental fatigue is a common phenomenon that either results from sustained mental effort or that is comorbid to a range of psychological and somatic disorders. Important symptoms of mental fatigue comprise cognitive and attentional difficulties, which have adverse effects on task performance and on everyday activities. Yet, little is known about the neurocognitive mechanisms that underlie these effects. In the current study, we explore whether sensorimotor gating is one of the cognitive mechanisms that is disturbed under fatigue. To test this, we compare prepulse inhibition (PPI) between fatigued (n=11) and non-fatigued participants (n=9). Fatigue was induced by 90 min of cognitively demanding work. Results showed that, compared to the non-fatigue group, fatigued participants displayed significantly reduced levels of PPI after the manipulation. These findings are linked to theories about compromised cognitive control under fatigue and to recent ideas about the role of dopamine in fatigue as well as in the regulation of PPI.
    No preview · Article · Nov 2006 · International Journal of Psychophysiology
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    ABSTRACT: Although additional dosages of benzodiazepines in long-term users of benzodiazepines are common, it is unknown whether these additional dosages resort any effect. The effects of an additional 20-mg dosage oxazepam were assessed in a double-blind, balanced-order, crossover randomized study comparing 16 long-term users of oxazepam (patients) with 18 benzodiazepine-naive controls (controls). The effects of 10 and 30 mg oxazepam were assessed at pretest and 2.5 hours after drug administration on: (a) saccadic eye movements as proxy for the sedative effect, (b) acoustic startle response (ASR) as proxy for the anxiolytic effects, (c) memory, (d) reaction time tasks, and (e) subjective measurements. Dose-related effects were found in patients on the peak velocity of saccadic eye movement and on response probability, respectively peak amplitude of the ASR. Comparison with controls, however, suggests that in patients the sedative effects might be mixed up with suppression of sedative withdrawal symptoms, whereas patients were as sensitive as benzodiazepine-naive controls for the effects of an additional dosage on the ASR. Neither 10 nor 30 mg oxazepam challenge affected the reaction time tasks in patients, whereas controls show a dose-related impairment. The memory impairing effects, however, did not differ significantly between patients and controls. In contrast to controls, patients could not discriminate between a 10- and 30-mg dosage as assessed by visual analogue scales and the STAI-DY-1, which might indicate a placebo effect in the 10-mg challenge in patients. We conclude that additional dosages of oxazepam still exert pronounced effects after daily use for more than 10 years.
    Full-text · Article · Mar 2005 · Journal of Clinical Psychopharmacology
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    ABSTRACT: The valid measurement of the concentration of serotonin (5-HT) in blood plasma is important when using the platelet as a model for the serotonergic neuron. The assay is hampered by the release of 5-HT by (residual) platelets during the preparation for assay. We developed an isopycnic method that separates cells gently and completely from plasma by centrifuging a diluted Percoll density-gradient to which whole blood was added. In this study this method was compared with the usual differential centrifugation method. The isopycnic method on average resulted in nine times lower levels of plasma 5-HT. This difference was linearly related to the number of residual platelets in plasma after differential centrifuging. The proportion of intra-individual variation decreased three-fold. Therefore, the use of a Percoll density-gradient may lead to a more precise and more accurate estimate of the level of plasma 5-HT. Copyright 2000 John Wiley & Sons, Ltd.
    No preview · Article · Aug 2000 · Human Psychopharmacology Clinical and Experimental

Publication Stats

132 Citations
63.92 Total Impact Points

Institutions

  • 2011-2015
    • Radboud University Nijmegen
      • • Department of Psychiatry
      • • Donders Institute for Brain, Cognition, and Behaviour
      Nymegen, Gelderland, Netherlands
  • 2005-2014
    • Radboud University Medical Centre (Radboudumc)
      • Department of Psychiatry
      Nymegen, Gelderland, Netherlands
  • 2000
    • Centre for Human Drug Research
      Leyden, South Holland, Netherlands