Peter de Boer

Janssen Pharmaceutica, Beersse, Flanders, Belgium

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Publications (19)47 Total impact

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    ABSTRACT: Major depressive disorder (MDD) is a heterogeneous disease. More homogeneous psycho(patho)logical dimensions would facilitate MDD research as well as clinical practice. The first aim of this study was to find potential dimensions within a broad psychopathological assessment in depressed patients. Second, we aimed at examining how these dimensions predicted course in MDD. Ten psychopathological variables were assessed in 75 MDD inpatients. Factor and regression analyses assessed putative relations between psychopathological factors and depression severity and outcome after 8 weeks of treatment. A 3-factor model (eigenvalue: 54.4%) was found, representing a psychomotor change, anhedonia and negative affect factor. Anhedonia and negative affect predicted depression severity (R(2)=0.37, F=20.86, p<0.0001). Anhedonia predicted non-response (OR 6.00, CI 1.46-24.59) and both negative affect (OR 5.69, CI 1.19-27.20) and anhedonia predicted non-remission (OR 9.28, CI 1.85-46.51). The sample size of the study was relatively modest, limiting the number of variables included in the analysis. Results confirm that psychomotor change, anhedonia and negative affect are key MDD dimensions, two of which are related to treatment outcome.
    Journal of affective disorders 10/2013; · 3.76 Impact Factor
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    ABSTRACT: The highly selective and fast dissociating D2 receptor antagonist JNJ-37822681 may be associated with lower risk for weight gain and undesirable metabolic effects compared with available antipsychotics. In this double-blind, randomized study, patients were randomly assigned (1:1:1:1:1) to 12 weeks of JNJ-37822681 (10 mg, 20 mg, or 30 mg, twice daily) or olanzapine (10 mg/d during week 1; 15 mg/d after week 1), or 6 weeks of placebo (followed by 6 weeks of olanzapine, 15 mg/d). Metabolic and body mass parameters were assessed at weeks 6 and 12. For metabolic parameters, at week 6 none of the JNJ-37822681 groups demonstrated significant change vs placebo; however, significant changes (P < .05) were observed in the olanzapine vs placebo group in triglycerides, low-density lipoprotein (LDL) and very-LDL cholesterol, and free fatty acids. For all JNJ-37822681 groups, mean weight changes at week 12 (-0.3 [10 mg], + 0.3 [20 mg], + 0.8 kg [30 mg]) were significantly less (P < .001) than for the olanzapine group (+ 2.7 kg). A higher percentage of overweight or obese patients (baseline body mass index: ≥25 kg/m2) receiving olanzapine had ≥7% increase in weight than those receiving JNJ-37822681 (9.8% vs 2.3%, respectively). JNJ-37822681 treatment was associated with a more favorable outcome on weight and metabolic adverse effects vs olanzapine for treating schizophrenia; the 10 mg twice-daily dose demonstrated minimal to no weight gain.
    Annals of Clinical Psychiatry 08/2013; 25(3):173-83. · 1.54 Impact Factor
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    ABSTRACT: RATIONALE: Smoking withdrawal has been widely established to produce a range of impairments to the quality of several major domains of cognitive function including attention, working memory and episodic memory. OBJECTIVES: This study was conducted to determine the degree to which smoking withdrawal will produce impairments in cognitive function in phase I clinical trials. METHODS: Healthy male volunteers who were housed in a clinical trial facility for 16 days underwent periods of ad libitum smoking and smoking withdrawal. RESULTS: Smoking withdrawal disrupted aspects of attention and episodic verbal recall and recognition. CONCLUSIONS: This study confirms previous work showing cognitive declines in smoking withdrawal and illustrates that such effects occur in ongoing safety and tolerability studies of new medicines and thus require careful consideration for the assessment of cognitive function in such trials as well as the accurate attribution of adverse events to the safety profiles of the medicines.
    Psychopharmacology 04/2013; · 4.06 Impact Factor
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    ABSTRACT: Schizophrenia patients are characterized by severe social impairments. Recently, social cognition has been put forward as an important mediator in schizophrenia between the often-reported neurocognitive deficits and functional outcome and is thus an important target for treatments. Nicotine has been reported to improve neurocognitive processes in schizophrenia patients but no studies have investigated possible nicotine-induced facilitation of social cognition. The current placebo-controlled crossover study aimed at bridging this gap by investigating whether the administration of active (1 mg or 2 mg) or placebo oromucosal nicotine spray resulted in improved social decision-making in non-smoking (N = 15) and smoking (N = 16) schizophrenia patients. All patients played the role of responder in a variant of the ultimatum game that allowed detailed measurements of fairness and intentionality considerations. The results showed impaired social decision-making in the non-smoking patients under placebo, but not in the smoking patients. Interestingly, this impairment normalized after administration of 1 mg of nicotine, but not after 2 mg of nicotine. Nicotine had no effect on performance in the smoking patients. The present study indicates that nicotine improves social decision-making in non-smoking patients. The present results suggest that acute nicotine effects may result in a facilitation of proactive control through improved attentional processes. However, the efficacy seems limited and although nicotine may thus be an interesting target for (social) cognitive enhancement in the subset of patients that do not smoke, more research is needed on the long-lasting effects of nicotine-based treatments.
    Frontiers in Neuroscience 01/2013; 7:197.
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    ABSTRACT: BACKGROUND: Reduced reward learning might contribute to the onset and maintenance of major depressive disorder (MDD). In particular, the inability to utilize rewards to guide behavior is hypothesized to be associated with anhedonia, a core feature and potential trait marker of MDD. Few studies have investigated whether reduced reward learning normalizes with treatment and/or reward learning predicts clinical outcome. Our goal was to test whether MDD is characterized by reduced reward learning, especially in the presence of anhedonic symptoms, and to investigate the relationship between reward learning and MDD diagnosis after 8 weeks of treatment. METHODS: Seventy-nine inpatients and 63 healthy control subjects performed a probabilistic reward task yielding an objective measure of participants' ability to modulate behavior as a function of reward. We compared reward responsiveness between depressed patients and control subjects, as well as high- versus low-anhedonic MDD patients. We also evaluated whether reward-learning deficits predicted persistence of MDD after 8 weeks of treatment. RESULTS: Relative to control subjects, MDD patients showed reduced reward learning. Moreover, patients with high anhedonia showed diminished reward learning compared with patients with low anhedonia. Reduced reward learning at study entry increased the odds of a persisting diagnosis of MDD after 8 weeks of treatment (odds ratio 7.84). CONCLUSIONS: Our findings indicate that depressed patients, especially those with anhedonic features, are characterized by an impaired ability to modulate behavior as a function of reward. Moreover, reduced reward learning increased the odds for the diagnosis of MDD to persist after 8 weeks of treatment.
    Biological psychiatry 12/2012; · 8.93 Impact Factor
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    ABSTRACT: Early predictability of sustained response to atypical antipsychotics in patients with schizophrenia has important implications for clinical decision making. In order to investigate whether early onset of efficacy correlates with week-6 response for the selective fast-dissociating D(2) receptor antagonist JNJ-37822681, we analysed data from a 12-week placebo- and active-controlled (olanzapine) study designed to evaluate efficacy and safety of JNJ-37822681. Factors, including baseline Positive and Negative Syndrome Scale (PANSS) total score, waist circumference, weight, body mass index group, number of previous hospitalisations, age at diagnosis, race, sex and age at study entry, and relative (%) change from baseline on day 3 (early improvement) in PANSS total score, were analysed using logistic regression models and receiver operator characteristic (ROC) curve analysis, to predict the week-6 efficacy response (≥30% improvement in PANSS total score). Results showed that week-6 response with JNJ-37822681 30mg bid treatment could be reliably predicted by improvement in PANSS total score on day 3, the number of previous hospitalisations, and race (80% accuracy [ROC area under curve]). Early improvement (day 3) in PANSS score had the highest predictive value as a single factor across all JNJ-37822681 doses. At a specificity of 70%, sensitivity for predicting week-6 response was: 0.60, 0.64, and 0.74 in the 10-, 20-, and 30mg bid JNJ-37822681 groups, respectively; 0.40 in olanzapine group. Early improvement in PANSS may be a simple and reliable way to predict sustained response with JNJ-37822681 in patients with acute schizophrenia.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 09/2012; · 3.68 Impact Factor
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    ABSTRACT: RATIONALE: JNJ-37822681 is a highly selective, fast dissociating dopamine D(2)-receptor antagonist being developed for the treatment of schizophrenia. A single dose [(11)C]raclopride positron emission tomography (PET) imaging study had yielded an estimated clinical dose range. Receptor occupancy at steady state was explored to test the validity of the single-dose estimates during chronic treatment. OBJECTIVES: The aims of this study are to characterize single and multiple dose pharmacokinetics and obtain striatal D(2)-receptor occupancies to predict doses for efficacy studies and assess the safety and tolerability of JNJ-37822681. METHODS: An open-label single- and multiple-dose study with 10 mg JNJ-37822681 (twice daily for 13 doses) was performed in 12 healthy men. Twenty [(11)C]raclopride PET scans (up to 60 h after the last dose) from 11 subjects were used to estimate D(2)-receptor occupancy. A direct effect O (max) model was applied to explore the relationship between JNJ-37822681 plasma concentration and striatal D(2)-receptor occupancy. RESULTS: Steady state was reached after 4-5 days of twice daily dosing. JNJ-37822681 plasma concentrations of 3.17 to 63.0 ng/mL resulted in D(2) occupancies of 0 % to 62 %. The concentration leading to 50 % occupancy was 18.5 ng/mL (coefficient of variation 3.9 %) after single dose and 26.0 ng/mL (8.2 %) at steady state. JNJ-37822681 was well tolerated. CONCLUSIONS: Receptor occupancy after single dose and at steady state differed for JNJ-37822681 and the robustness of the estimates at steady state will be tested in phase 2 studies. Dose predictions indicated that 10, 20, and 30 mg JNJ-37822681 twice daily could be suitable for these studies.
    Psychopharmacology 07/2012; · 4.06 Impact Factor
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    ABSTRACT: In rodents 5-hydroxytryptamine type 7 (5-HT(7)) receptor blockade has been shown to be effective in models of depression and to increase the latency to rapid eye movement (REM) sleep and decrease REM duration. In the clinic, the REM sleep reduction observed with many antidepressants may serve as a biomarker. We report here the preclinical and clinical evaluation of a 5-HT(7) receptor antagonist, (3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1-(phenylmethyl)pyrazolo[3,4-d]azepine 2-hydroxy-1,2,3-propanetricarboxylate) (JNJ-18038683). In rodents, JNJ-18038683 increased the latency to REM sleep and decreased REM duration, and this effect was maintained after repeated administration for 7 days. The compound was effective in the mouse tail suspension test. JNJ-18038683 enhanced serotonin transmission, antidepressant-like behavior, and REM sleep suppression induced by citalopram in rodents. In healthy human volunteers JNJ-18038683 prolonged REM latency and reduced REM sleep duration, demonstrating that the effect of 5-HT(7) blockade on REM sleep translated from rodents to humans. Like in rats, JNJ-18038683 enhanced REM sleep suppression induced by citalopram in humans, although a drug-drug interaction could not be ruled out. In a double-blind, active, and placebo-controlled clinical trial in 225 patients suffering from major depressive disorder, neither treatment with pharmacologically active doses of JNJ-18038683 or escitalopram separated from placebo, indicating a failed study lacking assay sensitivity. Post hoc analyses using an enrichment window strategy, where all the efficacy data from sites with an implausible high placebo response [placebo group Montgomery-Åsberg Depression Rating Scale (MADRS) < = 12] and from sites with no placebo response (MADRS > = 28) are removed, there was a clinically meaningful difference between JNJ-18038683 and placebo. Further clinical studies are required to characterize the potential antidepressant efficacy of JNJ-18038683.
    Journal of Pharmacology and Experimental Therapeutics 05/2012; 342(2):429-40. · 3.89 Impact Factor
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    ABSTRACT: JNJ-37822681 is a novel, fast-dissociating dopamine D(2) receptor antagonist, currently in development as an antipsychotic drug candidate. A previous first-in-human study demonstrated mild central nervous system effects of JNJ-37822681 in healthy male volunteers. Significant but transient serum prolactin elevations were demonstrated, whereas other neurophysiological effects were relatively small. To investigate striatal dopamine D(2) receptor occupancy by variable single doses of JNJ-37822681, an open-label [(11)C]raclopride positron emission tomography study was performed in 12 healthy male volunteers, using the simplified reference tissue model with cerebellum as reference tissue. Oral administration of JNJ-37822681 resulted in dose-dependent dopamine D(2) receptor occupancy. Receptor occupancy increased from 9-19% at 2 mg doses to 60-74% at 20 mg doses of JNJ-37822681. Therefore, single oral doses of JNJ-37822681 can produce occupancy levels that are generally associated with clinical efficacy for registered antipsychotic drugs.
    Journal of Psychopharmacology 02/2012; 26(8):1128-35. · 3.37 Impact Factor
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    ABSTRACT: Using the rate of dissociation from the D(2) receptor as a means to screen novel compounds for antipsychotic drug candidates, the centrally acting and fast-dissociating selective dopamine D(2) receptor antagonist JNJ-37822681 was developed. In a blinded, placebo-controlled, randomized first-in-human study, JNJ-37822681 was administered orally to 27 healthy male volunteers at doses of 0.5, 2, 5, 10, 15 and 20 mg. Safety, pharmacokinetics and central nervous system effects were evaluated by measuring prolactin levels, eye movements, adaptive tracking, visual analogue scales, body sway, finger tapping and electroencephalography. JNJ-37822681 was well tolerated and somnolence was the most frequently reported adverse effect. Peak plasma concentrations increased more than proportional to dose, but increases in the area under curve (AUC) were dose-proportional. Prolactin elevations started at doses of 5 mg, whereas small decreases in adaptive tracking were demonstrated at 10 mg doses. At higher doses, JNJ-37822681 caused a small decrease in saccadic peak velocity, smooth pursuit, alertness, finger tapping and electroencephalography activity, and an increase in body sway. This effect profile is likely to be the result of the selectivity of JNJ-37822681 for the D(2) receptor, leading to strong D(2) receptor-mediated elevations in serum prolactin, but fewer effects on more complex central nervous system functions, which are likely to involve multiple neurotransmitters.
    Journal of Psychopharmacology 09/2011; 26(8):1119-27. · 3.37 Impact Factor
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    ABSTRACT: • The cholinergic system is important for different central nervous system functions, including memory, learning and attention. Scopolamine, a centrally active muscarinic antagonist, has been used to model dementia and to demonstrate the pharmacological effects of cholinergic drugs, but for most effects the concentration-effect relationships are unknown. • We determined the pharmacokinetic-pharmacodynamic relationships of scopolamine using a multidimensional central nervous system test battery in a large group of healthy volunteers. The results suggested there are various functional cholinergic systems with different pharmacological characteristics, which can be used to study the effects of drugs that directly or indirectly modify cholinergic systems. The design of such studies should take the different concentration-effect relationships into account. AIM(S) Although scopolamine is a frequently used memory impairment model, the relationships between exposure and corresponding central nervous system (CNS) effects are mostly unknown. The aim of our study was to characterize these using pharmacokinetic-pharmacodynamic (PK-PD) modelling. In two double-blind, placebo-controlled, four-way crossover studies, 0.5-mg scopolamine was administered i.v. to 90 healthy male subjects. PK and PD/safety measures were monitored pre-dose and up to 8.5 h after administration. PK-PD relationships were modelled using non-linear mixed-effect modelling. Most PD responses following scopolamine administration in 85 subjects differed significantly from placebo. As PD measures lagged behind the plasma PK profile, PK-PD relationships were modelled using an effect compartment and arbitrarily categorized according to their equilibration half-lives (t(1/2) k(eo) ; hysteresis measure). t(1/2) k(eo) for heart rate was 17 min, saccadic eye movements and adaptive tracking 1-1.5 h, body sway, smooth pursuit, visual analogue scales alertness and psychedelic 2.5-3.5 h, pupil size, finger tapping and visual analogue scales feeling high more than 8 h. Scopolamine affected different CNS functions in a concentration-dependent manner, which based on their distinct PK-PD characteristics seemed to reflect multiple distinct functional pathways of the cholinergic system. All PD effects showed considerable albeit variable delays compared with plasma concentrations. The t(1/2) k(eo) of the central effects was longer than of the peripheral effects on heart rate, which at least partly reflects the long CNS retention of scopolamine, but possibly also the triggering of independent secondary mechanisms. PK-PD analysis can optimize scopolamine administration regimens for future research and give insight into the physiology and pharmacology of human cholinergic systems.
    British Journal of Clinical Pharmacology 02/2011; 71(6):886-98. · 3.58 Impact Factor
  • European Neuropsychopharmacology - EUR NEUROPSYCHOPHARMACOL. 01/2011; 21.
  • European Neuropsychopharmacology - EUR NEUROPSYCHOPHARMACOL. 01/2011; 21.
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    ABSTRACT: In this study the effects of R213129, a selective glycine transporter 1 inhibitor, on central nervous system function were investigated in healthy males in the absence and presence of scopolamine. This was a double-blind, placebo-controlled, 4-period crossover ascending dose study evaluating the following endpoints: body sway, saccadic and smooth pursuit eye movements, pupillometry, electroencephalography, visual analogue scales for alertness, mood, calmness and psychedelic effects, adaptive tracking, finger tapping, Visual and Verbal Learning Task, Stroop test, hormone levels and pharmacokinetics. R213129 dose levels were selected based on exposure levels that blocked the GlyT1 sites >50% in preclinical experiments. Forty-three of the 45 included subjects completed the study. Scopolamine significantly affected almost every central nervous system parameter measured in this study. R213129 alone compared with placebo did not elicit pharmacodynamic changes. R213129 had some small effects on scopolamine-induced central nervous system impairments. Scopolamine-induced finger tapping impairment was further enhanced by 3 mg R213129 with 2.0 taps/10 seconds (95% CI -4.0, -0.1), electroencephalography alpha power was increased by 10 mg R213129 with respectively 12.9% (0.7, 26.6%), scopolamine-induced impairment of the Stroop test was partly reversed by 10 mg R213129 with 59 milliseconds (-110, -7). Scopolamine produced robust and consistent effects in psychomotor and cognitive function in healthy volunteers. The most logical reason for the lack of R213129 effects seems to be that the central nervous system concentrations were too low. The effects of higher doses in healthy volunteers and the clinical efficacy in patients remain to be established.
    Journal of Psychopharmacology 02/2010; 24(11):1671-9. · 3.37 Impact Factor
  • European Neuropsychopharmacology - EUR NEUROPSYCHOPHARMACOL. 01/2010; 20.
  • European Neuropsychopharmacology - EUR NEUROPSYCHOPHARMACOL. 01/2010; 20.
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    ABSTRACT: The effects of the selective inhibitor of the glycine transporter 1, R231857, in development for schizophrenia, on the central nervous system (CNS) were investigated in healthy males in the absence and presence of scopolamine. This was a double-blind, placebo-controlled, four-period crossover ascending dose study. Pharmacokinetics, body sway, saccadic and smooth pursuit eye movements, pupillometry, pharmacoelectroencephalogram (EEG), Visual Analogue Scales (VAS) for alertness, mood, calmness and psychedelic effects, adaptive tracking, finger tapping, Stroop test, Visual and Verbal Learning Task (VVLT) and hormone levels were assessed. R231857 was administered alone and together with scopolamine to investigate the potential reversal of anticholinergic CNS impairment by the glycine reuptake inhibitor. Forty-two of the 45 included subjects completed the study. Scopolamine significantly affected almost every CNS parameter measured in this study. R231857 alone showed some pharmacodynamic changes compared with placebo. Although these effects might be an indication that R231857 penetrated the CNS, they were not consistent or dose-related. R231857 had some small effects on scopolamine-induced CNS-impairment, which were also not clearly dependent on dose. Scopolamine proved to be an accurate, reproducible and safe model to induce CNS impairment by an anticholinergic mechanism. R231857 lacked consistent dose-related effects in this study, probably because CNS concentrations were too low to produce significant/ reproducible CNS-effects or to affect the scopolamine challenge in healthy volunteers. The effects of higher doses in healthy volunteers and the clinical efficacy in patients remain to be established.
    Journal of Psychopharmacology 08/2009; 24(11):1681-7. · 3.37 Impact Factor
  • European Neuropsychopharmacology - EUR NEUROPSYCHOPHARMACOL. 01/2009; 19.
  • European Neuropsychopharmacology - EUR NEUROPSYCHOPHARMACOL. 01/2008; 18.