BACKGROUND: Clozapine is recommended by national and international guidelines for people with treatment-resistant schizophrenia. However, available meta-analyses of randomised controlled trials have not shown superior efficacy of clozapine when compared with other second-generation antipsychotics, with heterogeneity identified between the original studies. We aimed to use individual patient data (IPD) to account for potential reasons of variability and to synthesise an adjusted estimate for the difference in efficacy between clozapine and other second-generation antipsychotics for treatment-resistant schizophrenia. METHODS: In this systematic review and IPD meta-analysis, we searched the Cochrane Schizophrenia Group's Study-Based Register from inception to Jan 24, 2024, and previous reviews for blinded randomised controlled trials comparing clozapine with other second-generation antipsychotics in participants with treatment-resistant schizophrenia. Trials were eligible if they included patients with treatment-resistant schizophrenia and had a duration of at least 6 weeks. IPD were requested from trial investigators. The primary outcome was change in overall schizophrenia symptoms as measured by the Positive and Negative Syndrome Scale (PANSS) between clozapine and other second-generation antipsychotics after 6-8 weeks of treatment. The effect size measure for the primary outcome was mean difference with 95% credible interval (CrI). We fitted a Bayesian random-effects IPD meta-regression model that included duration of illness, baseline severity, and sex as potential prognostic factors or treatment effect modifiers. Confidence in the evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). People with lived experience of mental illness were involved in this study. This study is registered with PROSPERO, CRD42021254986. FINDINGS: We screened 13 876 references and included 19 studies with data for 1599 participants; IPD were available for 12 of 19 trials (n=1052; mean age 37·67 years [SD 11·24; range 10-66]; 348 [33·08%] women and 704 [66·92%] men). Data on ethnicity were not available. The estimated mean difference in change from baseline PANSS total score was -0·64 points (95% CrI -3·97 to 2·63; τ=2·68) in favour of other second-generation antipsychotics. Shorter duration of illness and higher baseline severity were prognostic factors associated with a larger reduction in symptoms, but neither those factors nor sex were found to modify the relative effect between clozapine and other second-generation antipsychotics. The confidence in the evidence was graded as very low. INTERPRETATION: This IPD meta-analysis found a small and uncertain advantage of other second-generation antipsychotics, mainly olanzapine and risperidone, and so did not provide evidence for superior efficacy of clozapine compared with other second-generation antipsychotics in treatment-resistant schizophrenia. It is limited by unavailability of IPD for some studies, uncaptured sources of variance, and uncertainty due to premature study discontinuation. Given the side-effects of clozapine, the observed uncertainty regarding clozapine's superiority warrants prudent use and further research. FUNDING: German Ministry of Education and Research.

• MeSH
• antipsychotika * terapeutické užití   MeSH
• klozapin * terapeutické užití   MeSH
• lidé MeSH
• randomizované kontrolované studie jako téma MeSH
• refrakterní schizofrenie * farmakoterapie   MeSH
• schizofrenie * farmakoterapie   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• systematický přehled MeSH
• Názvy látek
• antipsychotika * MeSH
• klozapin * MeSH

After administration of the serotonergic antidepressant citalopram (CIT) to Beagle dogs, the dogs may experience severe convulsive attacks in relation to the considerably higher plasma concentrations of the metabolite didesmethyl-CIT (DDCIT), when compared to those in humans medicated with CIT. This pilot study aimed at determining the role of cytochrome P-450 (CYP450) isozymes in the in vitro metabolism of CIT to desmethyl-CIT (DCIT), and of DCIT to DDCIT in the liver microsomes of a single Beagle dog. Incubations with racemic CIT or DCIT reveal a high-affinity enzyme with Km between 0.3 μM and 1.4 μM for S- and R-DCIT and S- and R-DDCIT productions, respectively. In comparison to human enzymes, the intrinsic clearance values of this high-affinity enzyme are between 15 μl/(min × mg of protein) and 52 μl/(min × mg of protein), i.e., very high. In vitro experiments with inhibitors suggest that CYP2D15, which shows an analogy with human CYP2D6, is by far the main CYP450 isozyme involved in the production of DCIT and DDCIT, whereas CYP3A12 and CYP2C21/41 showed a weak implication. These observations partly explain why, in humans, the plasma concentrations of the toxic DDCIT are considerably lower than those observed in dogs, after administration of CIT.

• Klíčová slova
• cytochrome P-450, liver microsomes, stereoselectivity,
• Publikační typ
• časopisecké články MeSH

We report on a serious side effect in a severely depressed 55-year-old woman, who presented an erythematous pigmented skin rash on the whole body under combination treatment with antidepressants, atypical antipsychotic drugs, the mood stabilizer lithium and the lipid-lowering drug pravastatin. The skin rash effect was most probably due, in first line, to olanzapine, but the cutaneous skin condition was triggered and aggravated by pravastatin, a 3-hydoxy-3-methylglutaryl-coenzyme A-(HMG-CoA)-reductase inhibitor, and lithium medication. The allergic reaction started to develop after co-administration of pravastatin. Therefore, the combination of atypical antipsychotics with statins should be carefully monitored and the benefits and disadvantages should be balanced.

• MeSH
• anticholesteremika škodlivé účinky   MeSH
• antipsychotika škodlivé účinky   terapeutické užití   MeSH
• benzodiazepiny škodlivé účinky   terapeutické užití   MeSH
• léková dermatitida etiologie   patologie   MeSH
• lékové interakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• olanzapin MeSH
• pravastatin škodlivé účinky   terapeutické užití   MeSH
• rizikové faktory MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• anticholesteremika MeSH
• antipsychotika MeSH
• benzodiazepiny MeSH
• olanzapin MeSH
• pravastatin MeSH

UNLABELLED: While antidepressant prescription rules are established for approved indications by large-scale studies, off-label utilization naturally often lacks the validation by large scientific databases, and is at its best based on expert consensus. The aim of the present survey was to study the prescription habits of hospital psychiatrists with regard to antidepressants, comparing patients treated for depressions and anxiety disorder with patients receiving off-label antidepressant treatment. METHODS: Data on drug use for this study were based on 6 reference days from April 1999 to November 2001 in the 98-bed psychiatric hospital of the University of Lausanne, Switzerland. The drug prescriptions of 174 patients were assessed. RESULTS: Whereas the diagnosis did not influence the choice between newer or older antidepressants, patients presenting an anxiety disorder were 4.5 times more likely (p<0.05) and patients with other diagnoses 8 times more likely (p<0.001) to receive an antipsychotic comedication compared to patients whose primary diagnosis was a depressive disorder. Also, patients receiving concomitantly a nonbenzodiazepine hypnotic were less likely to be prescribed an older antidepressant (p<0.05). While patients with anxiety disorder and those with major depression received their antidepressants at comparable doses, patients with an off-label indication were treated preferentially with lower doses. CONCLUSIONS: The results of this survey suggest, that the prescribing hospital psychiatrists developed preferences with regard to the choice of the antidepressant class, which they then used for both registered and off-label indications. They then seemed to adapt the dose and the comedication according to the diagnosis, confirming the initial study hypothesis.

• MeSH
• antidepresiva terapeutické užití   MeSH
• depresivní poruchy farmakoterapie   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• psychiatrie MeSH
• senioři MeSH
• spotřeba léčiv MeSH
• ústavy pro duševně nemocné MeSH
• úzkostné poruchy farmakoterapie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antidepresiva MeSH