CYP2D6 mutations and therapeutic outcome in schizophrenic patients.

STUDY OBJECTIVE: To investigate whether a relationship exists between the most common known cytochrome P450 (CYP) isozyme 2D6 mutations and schizophrenia. Because most antipsychotic and antidepressant agents interact with CYP2D6, we also investigated clinical outcomes in schizophrenic poor metabolizers (PMs) and extensive metabolizers (EMs). DESIGN: Prospective, observational study. SETTING: Two psychiatric hospitals and a university-affiliated nonpsychiatric hospital. SUBJECTS: Thirty-nine consecutive schizophrenic patients (POP 1), 89 schizophrenics of French Canadian origin (POP 2), and 384 healthy French Canadians (POP 3). INTERVENTION: All study subjects were genotyped for CYP2D6 mutant alleles. POP 1 patients were evaluated before and after 21 or more days of treatment with antipsychotic drugs metabolized at least in part by CYP2D6. MEASUREMENTS AND MAIN RESULTS: Whole blood was collected to determine CYP2D6 alleles *1, *3, *4, *5, *6, and *7 using standard restriction fragment length polymorphisms and polymerase chain reaction techniques. In comparison, CYP2D6 genotypes were determined in POP 2 and POP 3. Twenty-three (59.0%) of 39 patients in POP 1 were genotypically EM homozygotes, 15 (38.4%) were EM heterozygotes, and 1 (2.6%) was a PM. Similar genotype distributions were determined in POP 2 and in POP 3. Genotype distributions for all three populations were in Hardy-Weinberg equilibrium (p>0.05), and there was no significant difference among them (p=0.857). In POP 1, no differences were seen among genotypes in disease symptom severity, number and severity of adverse drug effects, or attitudes toward drug treatment at baseline and at the end of the study. In fact, all patients improved significantly during their hospital stay (all p<0.05), although independent of the CYP2D6 genotype. CONCLUSION: Common CYP2D6 mutant alleles were not associated with schizophrenia or with disease symptoms, antipsychotic-related adverse effects, or attitudes toward treatment.

Evaluation of inpatient depot antipsychotic prescribing.

OBJECTIVE: To assess the use of fluphenazine decanoate and haloperidol decanoate in an inpatient setting. DESIGN: A prospective observational study conducted over a 3-month period. SETTING: A 400-bed state psychiatric hospital. INTERVENTIONS: The psychiatric pharmacy staff evaluated the medical records and new orders of 30 consecutive patients receiving depot antipsychotic formulations using a detailed evaluation form and the hospital pharmacy computer database. Criteria for evaluation were derived from the medical literature and product information, and included the following areas: diagnosis, stabilization on a short-acting form of the antipsychotic, appropriateness of dosage conversion to depot therapy, concomitant administration of short-acting antipsychotics (and duration of concomitant medications), and plasma concentration monitoring. RESULTS: Only 7 patients (23%) received what would be considered optimal depot antipsychotic therapy. These patients were receiving a stable dosage of a short-acting antipsychotic prior to conversion to depot therapy (i.e., > or = 7 d), received optimal dose conversion to a depot form, and received optimum overlap with a short-acting preparation (i.e., overlap < or = 7 d with fluphenazine HCI and 7-30 d with haloperidol HCI). When length of stay data were evaluated, no significant differences were observed in patients who received optimal therapy versus those who did not. There was also no difference in length of stay when the study group was compared with an age-, sex-, and diagnosis-matched cohort group. However, quantitatively fewer adverse effects were reported for patients whose treatment was considered optimal on the basis of the evaluation criteria. CONCLUSIONS: Depot antipsychotic therapy frequently did not meet the criteria for optimal use. This did not affect length of hospital stay in these individuals. However, individuals who met the criteria experienced quantitatively fewer adverse events.

Pharmacotherapy of aggressive behavior.

OBJECTIVE: To review the definition, clinical characteristics, prevalence, etiology, neurochemistry, and pharmacologic treatment of aggressive behavior, and provide recommendations regarding the use of specific pharmacologic agents for treating aggressive behavior. DATA SOURCES: Data from the scientific literature were analyzed, interpreted, and summarized. An English-language MEDLINE search yielded clinical trials, case reports, letters, and review articles addressing the etiology and pharmacotherapy of aggression. STUDY SELECTION: Because few well-controlled studies are available in aggression research, all literature addressing the pharmacologic treatment of aggressive behavior, as well as the neurochemistry and psychobiology of aggressive behavior, was reviewed. DATA EXTRACTION: The literature was reviewed on the basis of the particular pharmacotherapy and the specific population used. A separate review of the treatment of aggressive behavior in the elderly was included. DATA SYNTHESIS: The literature was assessed for applicability to clinical practice and usefulness to the general clinician. Recommendations were made from the primary literature in conjunction with trends in clinical practice. Pharmacotherapy is a primary mainstay of treatment for aggressive patients. In individuals for whom behavioral intervention alone is unsuccessful, drug therapy should be initiated along with continued nonpharmacologic intervention. Short-acting benzodiazepines and high-potency antipsychotic agents are effective in treating acute aggression on a short-term or as needed basis. Agents such as lithium, beta adrenergic blockers, carbamazepine, valproic acid, buspirone, trazodone, serotonin reuptake inhibitors, and clozapine may be useful in the chronic management of aggressive behavior. Every attempt should be made to streamline drug therapy in patients with chronic aggression and comorbid psychiatric disorders. CONCLUSIONS: On the basis of available research and extensive clinical experience, lithium or propranolol should be considered as first-line antiaggressive agents in patients without comorbid psychiatric disorders. A minimum trial period for assessing drug efficacy should last at least 6-8 weeks at maximum tolerated dosages. Patients responding to pharmacotherapy should be reevaluated every 3-6 months, and periodic medication tapers and/or drug-free periods should be attempted.