Early Onset of Antipsychotic Action in Schizophrenia

Kinon, Bruce J.; Chen, Lei; Stauffer, Virginia L.; Sniadecki, Jennifer; Ascher-Svanum, Haya; Kollack-Walker, Sara; Jacob, Jayanthi; Kapur, Shitij

doi:10.1097/jcp.0b013e3181dcb7c3

Cited by 13 publications

(14 citation statements)

References 19 publications

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“…By analogy to the MAM-treated rat, this would be consistent with a condition in which the patients showing the greatest DA neuron population activity would also be more susceptible to the rapid induction of depolarization block. Indeed, Kapur has shown that the response of the patient to initial APD treatment best predicts their eventual therapeutic efficacy (Kinon et al, 2010), which would again be consistent with a DA system that is most readily overdriven by the APD.…”

Section: Discussionmentioning

confidence: 81%

“…Previous reports have shown that APDs are present at target receptors within an hour following acute administration to schizophrenia patients (Kapur and Remington, 2001; Agid et al, 2003; Kinon et al, 2010); thus, we first investigated whether acute administration of APD produces any change in the activity of MAM VTA DA neurons. In saline offspring injected with vehicle, the mean value of spontaneously active DA neurons per electrode track averaged 0.9 ± 0.1 (SAL + VHC: n= 8 rats, 53 DA neurons) (Floresco et al, 2003; Valenti and Grace, 2010).…”

Section: Resultsmentioning

confidence: 99%

“…Thus, although APDs exert therapeutic benefit during the first days of administration (Kapur and Seeman, 2001; Kinon et al, 2010), the maximal antipsychotic action requires weeks to develop (Johnstone et al, 1978). In contrast, based solely on DA receptor antagonism, the maximal antipsychotic action should occur immediately, with tolerance developing over the ensuing weeks (Palmstierna and Wistedt, 1987; Baldessarini et al, 1988; Nyberg et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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Antipsychotic Drugs Rapidly Induce Dopamine Neuron Depolarization Block in a Developmental Rat Model of Schizophrenia

Valenti¹,

Cifelli²,

Gill³

et al. 2011

J. Neurosci.

111

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Repeated administration of antipsychotic drugs to normal rats has been shown to induce a state of dopamine neuron inactivation known as depolarization block, which correlates with the ability of the drugs to exhibit antipsychotic efficacy and extrapyramidal side-effects in schizophrenia patients. Nonetheless, in normal rats depolarization block requires weeks of antipsychotic drug administration, whereas schizophrenia patients exhibit initial effects soon after initiating antipsychotic drug treatment. We now report that, in a developmental disruption rat model of schizophrenia (methyl-azoxymethanol acetate (20 mg/kg i.p.) injected into G17 pregnant female rats, with offspring tested as adults), the extant hyperdopaminergic state combines with the excitatory actions of a first (haloperidol; 0.6 mg/kg, i.p.)- and second (sertindole; 2.5 mg/kg, i.p.)-generation antipsychotic drug to rapidly induce depolarization block in ventral tegmental area dopamine neurons. Acute injection of either antipsychotic drug induced an immediate reduction in the number of spontaneously active dopamine neurons (cells per electrode track; termed population activity). Repeated administration of either antipsychotic drug for 1 day, 3 days, 7 days, 15 days, and 21 days continued to reduce dopamine neuron population activity. Both acute and repeated effects on population activity were reversed by acute apomorphine injections, which is consistent with the reversal of dopamine neuron depolarization block. Although this action may account for the effects of D2 antagonist drugs on alleviating psychosis and the lack of development of tolerance in humans, the drugs appear to do so by inducing an offsetting deficit rather than attacking the primary pathology present in schizophrenia.

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Section: Discussionmentioning

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Antipsychotic Drugs Rapidly Induce Dopamine Neuron Depolarization Block in a Developmental Rat Model of Schizophrenia

Valenti¹,

Cifelli²,

Gill³

et al. 2011

J. Neurosci.

111

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“…Most of the studies on early prediction of antipsychotic response demonstrated that later response/non-response can be predicted as early as two weeks in both chronic and first-episode patients with schizophrenia [13][14][15][16][17][18] . On the contrary, in a study evaluating response status in first-episode patients; it was shown that symptom severity show a progressive reduction in subsequent weeks and week 4 (but not week 2) was found to be associated with responder status at week 16 19.…”

Section: Introductionmentioning

confidence: 99%

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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“…[1][2][3][4][5][6][7][8][9][10] Strategies for addressing early nonresponse have not been well studied, however, resulting in little empirical evidence to inform clinical decision-making for patients with schizophrenia who demonstrate an inadequate initial response to treatment. Potential management strategies for early nonresponse include continuation of the initial treatment (ie, waiting for further improvement), dose escalation, augmentation with adjunctive treatments, or a switch to another antipsychotic medication.…”

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confidence: 99%