[Show abstract][Hide abstract] ABSTRACT: Introduction
Repeated use of psychostimulants can alter dopaminergic neurotransmission, leading to behavioral and neurochemical ‘sensitization’. Sensitization might serve as a biomarker to test the effects of novel compounds which have the potential to reverse dopaminergic hypersensitivity. The goal of this study was to explore the possibility of reliably eliciting and predicting amphetamine-induced behavioral changes following four doses of oral dexamphetamine.
16 healthy amphetamine-naive males (mean age 32 years, range 25-44) underwent 5 test days with the NeuroCart® test battery which includes adaptive tracking, body sway, saccadic and smooth pursuit eye movements, finger tapping and the stop signal task (SST). Subjective effects were assessed using Visual Analogue Scales, the Profile of Mood States and the amphetamine sub-scale of the Addiction Research Centre Inventory. Baseline performance was assessed on Day -1. Subsequently, ten subjects received oral dexamphetamine 20 mg (capsule) on study Days 1, 3, 5 and 14. As a control, six subjects received dexamphetamine 20 mg on Days 1 and 14 and placebo on Days 3 and 5. Subjects were blinded to treatment allocation. On each study day, the NeuroCart® test battery was performed twice pre-dose and 1, 2, 3, 4 and 6 hours post-dose. In addition, to investigate the relationship between individual dopamine levels and performance on psychomotor tasks, dopamine D2/D3 receptor occupancy was measured with two [11C]raclopride positron emission tomography (PET) scans: at baseline and at one hour after the first dose of dexamphetamine (Day 1). Repeated measures task data were compared with a mixed model analysis of variance with fixed factors treatment, time and treatment by time, random factor subject, subject by treatment and subject by time and the average pre-value per day, and the average of all Day -1 values as covariate. Dopamine D2/D3 receptor occupancy was calculated using a simplified reference tissue model.
On the first dosing day, subjects showed significant improvement on all NeuroCart® performance tasks. The different parameters on the SST indicated an improvement in both reaction time and accuracy. Although between-subject variability was large, within-subject performance was highly consistent across all study days. There were no significant group differences (2 vs 4 doses) between Day 1 and Day 14 on any of the tasks. The subjective measures also showed a similar pattern of within subject consistency across the study days. Statistically significant [11C]raclopride dopamine receptor occupancy (p<0.05, single-sided paired T-test) was observed in the striatum following dexamphetamine when comparing pre- and post-dose group means. However, up to 7 subjects showed negligible occupancy. The number of missed Go-trials on the SST, measured after PET, correlated negatively with D2/D3 receptor occupancy in the caudate nucleus.
Discussion and conclusion
Dexamphetamine consistently improved performance on the Neurocart® performance tasks, but there were no signs of potentiation after repeated dosing. Therefore, this study did not reproduce earlier findings suggestive of response sensitization. This study does, however, provide evidence of consistent and sustained acute amphetamine effects as well as a positive relationship between SST performance and amphetamine-induced elevated brain dopamine levels.
 Featherstone et al. “The Amphetamine-induced sensitized state as a model of schizophrenia”; Progress in Neuro-Psychopaharmacology & Biological Psychiatry 31 (2007) 1556-1571.
The authors would like to acknowledge the Department of Nuclear Medicine of the VU Medical Center, Amsterdam, the Netherlands, for acquisition of the PET scans and support in PET data analysis.
HC van Gorsel, J van der Aart and JMA van Gerven were fully employed by the Centre for Human Drug Research (CHDR) at the time this study was carried out. P de Boer and M Timmers are fully employed by Janssen Research and Development. CHDR received a research grant from Janssen Research and Development as co-funding for this study.
International Society for CNS Clinical Trials and Methodology, Amsterdam, the Netherlands; 08/2015
[Show abstract][Hide abstract] ABSTRACT: Introduction: The repeated intravenous (IV) administration of sub-anesthetic doses of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine induces antidepressant effects in up to 70% of patients with Treatment Resistant Depression (TRD). However, such effects are transient and chronic repeated administration of ketamine is impractical. Potential strategies to prolong ketamine-induced antidepressant effects include alternative glutamatergic modulators, which show similar downstream effects as ketamine but are devoid of acute psychotomimetic effects. Minocycline has antibiotic and anti-inflammatory properties and may modulate glutamatergic neurotransmission. Therefore, we investigated if minocycline could prevent relapse after successful response to IV ketamine in TRD. Methods: Patients with treatment resistant major depressive disorder (MDD) according to DSM-IV (IDS-C30 score ≥ 34) were included in a blinded, randomized, placebo-controlled, exploratory study. The Montgomery-Åsberg Depression Rating Scale (MADRS) was administered at baseline and throughout the treatment phases. Ketamine 0.5mg/kg IV was administered six times during a 12-day open-label (OL) treatment period, concomitantly with oral (PO) minocycline 200mg/day. Subjects with MADRS total score reductions of ≥ 50% compared to baseline during day 7 to 12 or ≥ 40% on day 12 were considered responders to ketamine. Responders were subsequently randomized to continuation of minocycline 200mg/day, or switched to placebo up to day 54 or until relapse in a blinded treatment period. Relapse was defined as a MADRS total score increase to ≥ 30 at any of the scheduled assessments during treatment. Non/partial-responders to ketamine could participate in an OL minocycline arm of the same duration. Results: Twenty-nine patients (55% female, mean age 51 [range 23 – 74] years old, mean MADRS [SD] = 33 [5.00]) received ketamine and minocycline during the OL phase. On Day 12, the mean MADRS decreased cf baseline (-15.6 [10.62]; n=26). Fourteen (54%) patients met response criteria (mean MADRS on Day 12 = 8.9 [5.5]) and were randomized to either placebo (n=7) or minocycline (n=7). Five of 15 patients who failed to meet response criteria continued OL treatment with minocycline. On day 54, three patients randomized to placebo and one to minocycline had relapsed. No clinical benefit was observed upon OL treatment with minocycline in ketamine non/partial-responders. Both treatments were well tolerated: during OL ketamine treatment dissociative symptoms (41.4%) and headache (37.9%) were the most common adverse events; minocycline treatment caused gastrointestinal symptoms in 20% of all patients. Conclusions: In this proof-of-concept study, 50% of patients with TRD responded to repeated intravenous administration of ketamine combined with orally administered minocycline during two weeks. Fewer responders who were randomized to minocycline met relapse criteria compared to those responders randomized to placebo during the subsequent 6 weeks. These preliminary results provide some support for further evaluation of central anti-inflammatory/glutamatergic modulation in mood disorders as strategies to prolong ketamine’s antidepressant effects.
British Asoociation for Psychopharmacology, Bristol, UK; 07/2015
[Show abstract][Hide abstract] ABSTRACT: The enzyme phosphodiesterase 10A (PDE10A) regulates the activity of striatal, medium spiny neurons (MSNs), which are divided into a behaviorally stimulating, Gs-coupled D1 receptor-expressing “direct” pathway and a behaviorally suppressant, Gi-coupled D2 receptor-expressing “indirect” pathway. Activating both pathways, PDE10A inhibitors (PDE10AIs) combine functional characteristics of D2 antagonists and D1 agonists. While the effects of PDE10AIs on spontaneous and stimulated behavior have been extensively reported, the present study investigates their effects on suppressed behavior under various conditions of reduced dopaminergic neurotransmission: blockade of D1 receptors with SCH-23390, blockade of D2 receptors with haloperidol, or depletion of dopamine with RO-4-1284 or reserpine. In rats, PDE10AIs displayed relatively low cataleptic activity per se. After blocking D1 receptors, however, they induced pronounced catalepsy at low doses close to those required for inhibition of apomorphine-induced behavior; slightly higher doses resulted in behavioral stimulant effects, counteracting the catalepsy. PDE10AIs also counteracted catalepsy and related behaviors induced by D2 receptor blockade or dopamine depletion; catalepsy was replaced by behavioral stimulant effects under the latter but not the former condition. Similar interactions were observed at the level of locomotion in mice. At doses close to those inhibiting d-amphetamine-induced hyperlocomotion, PDE10AIs reversed hypolocomotion induced by D1 receptor blockade or dopamine depletion but not hypolocomotion induced by D2 receptor blockade. It is concluded that PDE10AIs stimulate or inhibit motor behavior dependent on the relative activation state of the direct and indirect striatal output pathways.
[Show abstract][Hide abstract] ABSTRACT: The new phosphodiesterase 10A inhibitor (PDE10AI) JNJ 42314415 (3-[6-(2-methoxyethyl)pyridin-3-yl]-2-methyl-8-morpholin-4-ylimidazo[1,2-a]pyrazine ) was compared with 3 reference PDE10AIs and 8 D2 receptor blockers. Despite displaying relatively low PDE10A activity in vitro, JNJ 42314415 was found to be a relatively potent and specific PDE10AI in vivo. The compound was devoid of effects on prolactin release and of receptor interactions associated with other commonly observed adverse effects of available antipsychotics. Like D2 receptor blockers, the tested PDE10AIs antagonized stimulant-induced behavior and inhibited conditioned avoidance behavior; these effects were observed at doses close to the ED50 for striatal PDE10A occupancy. Relative to the ED50 for inhibition of apomorphine-induced stereotypy, PDE10AIs blocked conditioned avoidance behavior and behaviors induced by non-dopaminergic stimulants (PCP, scopolamine) more efficiently, but behaviors induced by dopaminergic stimulants (apomorphine, d amphetamine) less efficiently than D2 receptor blockers. PDE10AIs also induced less pronounced catalepsy than D2 receptor blockers. The effects of PDE10A inhibition against dopaminergic stimulants and on catalepsy were potentiated by the D1 antagonist SCH 23390 (8-chloro-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol), suggesting that enhancement of D1 receptor-mediated neurotransmission contributes to the behavioral profile of PDE10AIs. By reducing dopamine D2- and concomitantly potentiating dopamine D1 receptor-mediated neurotransmission, PDE10AIs may show antipsychotic activity with an improved side-effect profile relative to D2 receptor blockers. However, the clinical implications of this dual mechanism have to be further explored.
Journal of Pharmacology and Experimental Therapeutics 01/2014; 349(1). DOI:10.1124/jpet.113.211904 · 3.97 Impact Factor
[Show abstract][Hide abstract] 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 10/2013; 7:197. DOI:10.3389/fnins.2013.00197 · 3.66 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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. · 2.36 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
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.
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).
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.
[Show abstract][Hide abstract] 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; 23(9). DOI:10.1016/j.euroneuro.2012.08.017 · 4.37 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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. DOI:10.1124/jpet.112.193995 · 3.97 Impact Factor
[Show abstract][Hide abstract] 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. DOI:10.1177/0269881111435251 · 3.59 Impact Factor
[Show abstract][Hide abstract] 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. DOI:10.1177/0269881111415733 · 3.59 Impact Factor