Association Between Clozapine-Induced Agranulocytosis and HLA Subtyping

Abstract

Sir: The use of antipsychotic drugs is frequently associated with sexual dysfunction. Symptoms may concern penile erection, lubrication, orgasm, libido, sexual arousal, or overall sexual satisfaction. Different strategies to treat antipsychoticinduced sexual dysfunction have been developed, including drug holidays, dose reduction, switching to another drug, and use of a number of agents for symptomatic therapy. Within the framework of systematic review for the Cochrane Collaboration, 1 our objective was to review the effectiveness of these strategies for the treatment of antipsychotic-induced sexual dysfunction.Data Sources and Study Selection. The trial register of the Cochrane Schizophrenia Group, the Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, and the PsycLIT databases were searched for relevant trials reported through August 2005 using sexual dysfunction symptoms and antipsychotic terms as keywords (see reference 2 for specific terms). First only randomized controlled trials were searched, and then the search was expanded to all available evidence regardless of level of evidence. The first author of each study was contacted for additional references and for any unpublished trials or data, and the reference lists of all identified studies were inspected for additional studies. Companies involved in production of the principal antipsychotics who offer a drug information service and those involved in the production of the possible agents for symptomatic therapy were also contacted to request additional studies. Study selection, data extraction, and assessment of methodological quality (using a classification recommended by the Cochrane Library 2 ) were performed independently by 2 reviewers (M.M.B. and M.H.).Data Synthesis. Two randomized controlled trials concerning symptomatic drug therapy of antipsychotic-induced sexual dysfunction were identified. 3,4 In one of them 3 (N = 10, crossover), no evidence was found for the effectiveness of selegiline (15 mg) in improving sexual functioning in schizophrenic patients maintained on neuroleptic treatment. Another crossover trial 4 evaluating the administration of sildenafil (flexible doses of 25-50 mg; N = 32) found positive effects in all examined outcomes: number of erections sufficient for penetration, mean duration of erections, frequency of satisfactory intercourse, and satisfaction with treatment.Two open-label trials (N = 10, 5 N = 12 6 ) and 2 case reports 7,8 (each with N = 1) also support the effectiveness of sildenafil at doses of 25 to 100 mg in patients with schizophrenia and schizoaffective disorder. One observational study 9 (N = 8) describes the effectiveness of 25 to 50 mg of imipramine as addon therapy in patients with schizophrenia. Two other open-label studies (N = 10, 10 N = 12 11 ) provide evidence for 100 to 300 mg of amantadine as additional medication in patients with schizophrenia. Observational (N = 8 to 20) and case report (N = 1 to 5) evidence was found for the effectiveness of switching to another antipsychotic ...

The Role of Pharmacogenetics in Treating Central Nervous System Disorders

“…For example, there is no apparent doseresponse relationship with this ADR, and genetic studies have been confounded by poor power and the absence of a thorough 'scan' of the genome. Consistent with suggestions that CIA may be immune mediated (47,48), risk association studies repeatedly implicate the HLA locus in risk for CIA (31,49,50). Through a candidate gene case-control study, PGxHealth utilized a candidate gene approach and has demonstrated that variation in HLA-DQB1 is associated with CIA.…”

Toward understanding genetic risk for differential antipsychotic response in individuals with schizophrenia

“…Tardive dyskinesia 3.3 [113][114][115][116] GNB3 Weight gain NA [129,180] HLA Antipsychotic-induced agranulocytosis NA [188,189,[191][192][193] HTR2A Weight gain and tardive dyskinesia …”

“…Glutathione S-transferase µ 1 (GSMT1) and glutathione S-transferase p 1 (GSTP1), are two phase II metabolic enzymes related to oxidative stress, and their genes contain polymorphisms that have been associated with risk of TD [183,187]. Finally, polymorphisms in TNF-a and HLA were associated with the risk of agranulocytosis during treatment with clozapine [188][189][190][191][192][193].…”

Antipsychotics for the treatment of schizophrenia: likelihood to be helped or harmed, understanding proximal and distal benefits and risks

“…The identification of patients particularly likely to respond or not respond would decrease the number of failed treatment courses. The identification of those who are more likely to develop adverse effects, such as agranulocytosis with clozapine [68], or weight gain and metabolic syndrome [69], is of considerable interest. Additionally, when all else is equal, pharmacoeconomics can help guide a clinician in decision-making.…”