clozapine and cariprazine

The dose-response relationships of antipsychotic drugs for schizophrenia are not well defined, but such information would be important for decision making by clinicians. The authors sought to fill this gap by conducting dose-response meta-analyses.. A search of multiple electronic databases (through November 2018) was conducted for all placebo-controlled dose-finding studies for 20 second-generation antipsychotic drugs and haloperidol (oral and long-acting injectable, LAI) in people with acute schizophrenia symptoms. Dose-response curves were constructed with random-effects dose-response meta-analyses and a spline model. The outcome measure was total score reduction from baseline on the Positive and Negative Syndrome Scale or the Brief Psychiatric Rating Scale. The authors identified 95% effective doses, explored whether higher or lower doses than the currently licensed ones might be more appropriate, and derived dose equivalencies from the 95% effective doses.. Sixty-eight studies met the inclusion criteria. The 95% effective doses and the doses equivalent to 1 mg of oral risperidone, respectively, were as follows: amisulpride for patients with positive symptoms, 537 mg/day and 85.8 mg; aripiprazole, 11.5 mg/day and 1.8 mg; aripiprazole LAI (lauroxil), 463 mg every 4 weeks and 264 mg; asenapine, 15.0 mg/day and 2.4 mg; brexpiprazole, 3.36 mg/day and 0.54 mg; haloperidol, 6.3 mg/day and 1.01 mg; iloperidone, 20.13 mg/day and 3.2 mg; lurasidone, 147 mg/day and 23.5 mg; olanzapine, 15.2 mg/day and 2.4 mg; olanzapine LAI, 277 mg every 2 weeks and 3.2 mg; paliperidone, 13.4 mg/day and 2.1 mg; paliperidone LAI, 120 mg every 4 weeks and 1.53 mg; quetiapine, 482 mg/day and 77 mg; risperidone, 6.3 mg/day and 1 mg; risperidone LAI, 36.6 mg every 2 weeks and 0.42 mg; sertindole, 22.5 mg/day and 3.6 mg; and ziprasidone, 186 mg/day and 30 mg. For amisulpride and olanzapine, specific data for patients with predominant negative symptoms were available. The authors have made available on their web site a spreadsheet with this method and other updated methods that can be used to estimate dose equivalencies in practice.. In chronic schizophrenia patients with acute exacerbations, doses higher than the identified 95% effective doses may on average not provide more efficacy. For some drugs, higher than currently licensed doses might be tested in further trials, because their dose-response curves did not plateau.

Topics: Acute Disease; Administration, Oral; Antipsychotic Agents; Aripiprazole; Clozapine; Delayed-Action Preparations; Dose-Response Relationship, Drug; Haloperidol; Humans; Imidazoles; Indoles; Isoxazoles; Lurasidone Hydrochloride; Olanzapine; Paliperidone Palmitate; Piperazines; Piperidines; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Schizophrenic Psychology; Thiazoles; Thiophenes

There are many psychotropic drugs available for treatment of schizophrenia. The clinician's choice of the most effective first-line antipsychotic treatment for patients with schizophrenia should balance considerations of differential efficacy of antipsychotics against the relative risk of different side effects.. We reviewed recent studies using meta-analytic techniques and additional studies of new antipsychotics which quantitatively evaluate the efficacy of side effects of first- and second-generation antipsychotics and studies of the efficacy on add-on secondary medications. We present an integrated summary of these results to guide a clinician's decision-making.. Recent meta-analyses have suggested that antipsychotics are not equivalent in efficacy. Clozapine (effect size [SMD] 0.88 vs. placebo), amisulpride (effect size 0.6 vs placebo), olanzapine (effect size 0.59 vs. placebo), and risperidone (effect size 0.56 vs placebo) show small but statistically significant differences compared to a number of other antipsychotics on measures of overall efficacy (effect sizes 0.33-0.50). However, increasing placebo response remains a concern in interpreting these data. Amisulpride (effect size 0.47 vs placebo) and cariprazine (effect size in one trial compared to risperidone 0.29) have the strongest evidence indicating greater efficacy for treating primary negative symptoms relative to other antipsychotics. In terms of side effects, clozapine and olanzapine have among the highest weight gain potential and sertindole and amisulpride have more effects on QTc prolongation than other commonly used antipsychotics. Prolactin elevation is highest with paliperidone, risperidone, and amisulpride. Adjunctive treatment with an antidepressant drug may improve response in patients with schizophrenia who also have severe depressive or negative symptoms. For multi-episode patients with an inadequate response to an adequate dose and duration of the initial antipsychotic choice, switching to another antipsychotic, with a different receptor profile, may improve response, although evidence is very limited. In first-episode patients, a recent study on switching to another antipsychotic, with a different receptor profile after 4 weeks demonstrated no beneficial effects. There is little evidence to support using doses above the therapeutic range other than in exceptional circumstances.. Our review of recent studies using meta-analytic techniques has provided evidence that all antipsychotics are not equal in the severity of different side effects and in some measures of clinical efficacy. Comparative analysis and rankings from network meta-analyses can provide guidance to clinicians in choosing the most appropriate antipsychotic for first-line treatment, if used in conjunction with available information of the patient's history of previous clinical response or higher risks for specific side effects.

Topics: Amisulpride; Antidepressive Agents; Antipsychotic Agents; Clozapine; Depression; Humans; Imidazoles; Indoles; Olanzapine; Piperazines; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Animals; Antipsychotic Agents; Piperazines; Rats; Rats, Wistar; Receptors, Serotonin; Schizophrenia

Aripiprazole is the first dopamine D(2)/D(3) receptor partial agonist successfully developed and ultimately approved for treatment of a broad spectrum of psychiatric and neurological disorders. Aripiprazole's dopamine D(2) and serotonin 5-HT(1A) receptor partial agonist activities have been postulated to confer clinical efficacy without marked sedation, and a relatively favorable overall side-effect profile. Using aripiprazole's unique profile as a benchmark for new dopamine partial agonist development may facilitate discovery of new antipsychotics. We conducted an in vitro comparative analysis between aripiprazole, and its human metabolite OPC-14857 (7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl)butoxy)-2(1H)-quinolinone)); RGH-188 (trans-1-[4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl]-3,3-dimethylurea), and its metabolite didesmethyl-RGH-188 (DDM-RGH-188); as well as bifeprunox, sarizotan, N-desmethylclozapine (NDMC; clozapine metabolite), and SDZ 208-912 (N-[(8α)-2-chloro-6-methylergolin-8-yl]-2,2-dimethylpropanamide). In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cell lines expressing D(2S), D(2L), D(3) Ser-9 and D(3) Gly-9 for human dopamine receptors. All test compounds behaved as dopamine D(2)/D(3) receptor partial agonists. Aripiprazole's intrinsic activity at dopamine D(2S) and D(2L) receptors was similar to that of OPC-14857 and RGH-188; lower than that of dopamine and bifeprunox; and higher than that of DDM-RGH-188, SDZ 208-912, sarizotan, and NDMC. Aripiprazole's intrinsic activity at dopamine D(3) Ser-9 and D(3) Gly-9 receptors was similar to that of OPC-14857 and sarizotan; lower than that of dopamine, bifeprunox, RGH-188 and DDM-RGH-188; and higher than that of SDZ 208-912 and NDMC. A consolidated assessment of these findings may help defining the most appropriate magnitude of intrinsic activity at dopamine D(2)/D(3) receptors for clinical efficacy and safety.

Topics: Animals; Aripiprazole; CHO Cells; Clozapine; Cricetinae; Cricetulus; Cyclic AMP; Dopamine; Drug Partial Agonism; Humans; Organic Chemicals; Piperazines; Quinolones; Receptors, Dopamine D2; Receptors, Dopamine D3; Substrate Specificity