Does early improvement predict response to the fast-dissociating D2 receptor antagonist JNJ-37822681 in patients with acute schizophrenia? ☆

Anghelescu, Ion‐George; Janssens, Luc; Kent, Justine; Boer, P. de; Tritsmans, Luc; Daly, Ella; Nueten, Luc Van; Schmidt, Mark E.

doi:10.1016/j.euroneuro.2012.08.017

Cited by 3 publications

(1 citation statement)

References 34 publications

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“…A recent 12‐week phase 2B trial of JNJ‐37822681 showed antipsychotic efficacy in patients with schizophrenia with an acute exacerbation of their illness at oral dose levels of 10, 20 and 30 mg twice daily (Anghelescu et al ., ; Schmidt et al ., ). Other investigations with JNJ‐37822681 included a [ 11 C] raclopride positron emission tomography trial in healthy volunteers demonstrating dose‐dependent D 2 receptor occupancy (te Beek et al ., ) and a single ascending dose (SAD) trial in healthy volunteers focusing on safety, pharmacokinetics and central nervous system effects (te Beek et al ., ).…”

Section: Introductionmentioning

confidence: 97%

Differential responses to JNJ‐37822681, a specific and fast dissociating dopamine D2 receptor antagonist, in cynomolgus monkey and Sprague–Dawley rat general toxicology studies: clinical observations, prolactin levels, mammary histopathology findings and toxicokinetics

Waal

Desmidt

Korte

et al. 2013

J of Applied Toxicology

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JNJ-37822681 is a potent, specific and fast dissociating dopamine D2 receptor antagonist intended for the treatment of schizophrenia. Its nonclinical toxicological profile was investigated in a series of general repeat dose toxicity studies in cynomolgus monkeys and Sprague-Dawley rats. The maximum duration of treatment was 9 and 6 months, respectively. Interspecies differences were noted in the response to JNJ-37822681 in terms of extrapyramidal (EPS)-like clinical signs and prolactin-mediated tissue changes in the mammary gland. Monkeys showed severe EPS-like clinical signs such as abnormal posture, abnormal eye movements and hallucination-like behavior at relatively low exposures compared to those associated with EPS in patients with schizophrenia. The high sensitivity of the monkey to JNJ-37822681-induced EPS-like signs was unexpected based on the fast dissociating properties of the compound. Rats, however, were not prone to EPS. Elevated serum prolactin levels were found in rats and monkeys. While rats showed slight to moderate prolactin-related tissue changes upon histopathological examination in all studies, which among others affected the mammary gland, only minor mammary gland tissue changes were noted in monkeys. Prolactin levels were only slightly increased in patients with schizophrenia receiving relatively high dose levels of JNJ-37822681. The monkey toxicology studies did not provide an exposure-based safety margin, while in rats adverse effects were only noted at exposures considerably higher than those achieved at efficacious plasma concentrations in the clinic. Overall, the available data suggest that the cynomolgus monkey showed better predictivity towards the nature of JNJ-37822681-associated adverse events in humans than the Sprague-Dawley rat.

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Section: Introductionmentioning

confidence: 97%

Differential responses to JNJ‐37822681, a specific and fast dissociating dopamine D2 receptor antagonist, in cynomolgus monkey and Sprague–Dawley rat general toxicology studies: clinical observations, prolactin levels, mammary histopathology findings and toxicokinetics

Waal

Desmidt

Korte

et al. 2013

J of Applied Toxicology

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Antipsychotics and the Dopamine–Serotonin Connection

Ellenbroek

Cesura²

2014

Small Molecule Therapeutics for Schizophrenia

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Prediction of Response to Antipsychotic Drugs in Schizophrenia Patients within the Early Phase of Treatment

Yıldız

Yazıcı

Yağcıoğlu

et al. 2015

Klinik Psikofarmakoloji Bülteni-Bulletin of Clinical Psychophar

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Objective: Currently, schizophrenia guidelines recommend waiting for 3 to 6 weeks before considering a patient as non-responder. However, recent studies indicate that the response to antipsychotic medications starts within the first two weeks of treatment. The aim of this study is to determine the predictive value of early improvement at 2 or 4 weeks for non-response at 6 weeks.Methods: Twenty seven in-and out-patients with a diagnosis of schizophrenia according to DSM-IV, between the ages of 18 to 65 years, who were moderately-to-severely ill (baseline Positive and Negative Syndrome Scale (PANSS) total score ≥ 75, with at least "moderate" level of severity / score>4 on at least 2 of the 4 Brief Psychiatric Rating Scale (BPRS) psychotic cluster items) were included. Ten patients were receiving antipsychotic treatment for the first time, and 17 patients' treatment was changed due to nonresponse to prior antipsychotic treatment. The patients were evaluated with the PANSS and the Clinical Global Impression-Severity (CGI-S) scale at 0, 2, 4 and 6 weeks of antipsychotic treatment. Non-response at endpoint was defined in 3 different ways to reflect the variations in the level of response to medication:"not minimally improved", "not much improved" and "not remitted". As previously described, "not minimally improved" and "not much improved" were defined as less than 28% and 53% improvement in the PANSS total scores, respectively. "Not remitted" was defined according to the criteria developed by "The Remission in Schizophrenia Working Group" without the time criterion. Signal detection methods using receiver operating characteristics (ROC) curves were implemented to detect the optimal threshold of early nonresponse at 2 and 4 weeks. Total accuracy, sensitivity, specificity and positive and negative predictive value of cut-off points were calculated for predicting "not minimally improved", "not much improved" and "not remitted" at endpoint. Results:The early response threshold for predicting "not minimally improved' was less than 15.3% reduction in PANSS total score at week 2, less than 15.5% reduction at week 4. The early response threshold for predicting "not much improved" was less than 22.1% reduction at week 2 and less than 44.3% reduction at week 4; for "not remitted" was less than 17.5% reduction at week 2 and less than 23.2% reduction at week 4. Specific thresholds of "much improvement" and "remission" were not identified at week 2, whereas thresholds calculated for week 4 had good discriminative power. Conclusion:The findings of this study did not support the findings of earlier studies indicating that nonresponse at 2 weeks accurately predicts subsequent lack of response in patients with schizophrenia. Instead, the findings revealed that non-response could best be predicted at 4 weeks as in some other previous studies. The question of which time point for early prediction of response could be best predicted in schizophrenia patients needs to be further addressed in subsequent studies with larger sample size.

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Does early improvement predict response to the fast-dissociating D2 receptor antagonist JNJ-37822681 in patients with acute schizophrenia? ☆

Cited by 3 publications

References 34 publications

Differential responses to JNJ‐37822681, a specific and fast dissociating dopamine D2 receptor antagonist, in cynomolgus monkey and Sprague–Dawley rat general toxicology studies: clinical observations, prolactin levels, mammary histopathology findings and toxicokinetics

Differential responses to JNJ‐37822681, a specific and fast dissociating dopamine D2 receptor antagonist, in cynomolgus monkey and Sprague–Dawley rat general toxicology studies: clinical observations, prolactin levels, mammary histopathology findings and toxicokinetics

Antipsychotics and the Dopamine–Serotonin Connection

Prediction of Response to Antipsychotic Drugs in Schizophrenia Patients within the Early Phase of Treatment

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