Treatment-refractory schizophrenia.

PURPOSE OF REVIEW: The aim of this article is to critically review the current literature on treatment-refractory schizophrenia with an emphasis on emergent themes and key findings. RECENT FINDINGS: New information continues to emerge on the impact of each second-generation antipsychotic on the treatment-refractory patient population and on the traditionally more difficult-to-treat components (e.g. cognition, suicidality, violence) of the illness. There are continued efforts with pharmacogenetics to predict response and side-effect risk with antipsychotic medications. Polypharmacy continues to be a major and poorly understood treatment practice. SUMMARY: Our field is advancing the therapeutic nuances of therapy with second-generation antipsychotics in treatment-refractory schizophrenia. Additionally, there is a growing appreciation of the emergent adverse-effect profile of antipsychotic medications and these risk-benefit considerations are more pronounced in severely ill patients.

Initial conditions of serotonin transporter kinetics and genotype: influence on SSRI treatment trial outcome.

BACKGROUND: Fifty-one patients with major depression were classified for 5-HTT promoter region polymorphism and platelet 5-HTT kinetics before treatment with fluoxetine, and then examined for treatment outcome. METHODS: Dose was stratified from 1.25 mg to 40 mg per day to allow for the possibility that one genotype could express a lower-dose fluoxetine response. A repeated-measures analysis of variance of 24-item Hamilton depression change through baseline, 1-week placebo lead-in, and 6, 12, and 18 weeks treatment was done to test a genotype effect on outcome. RESULTS: Genotype had a significant effect on outcome (F = 4.7, p <.02), with the initial affinity constant (K(m)) (F = 11.9, p =.001), and dose (F = 6.0, p <.02) being significant covariates on outcome as well. The gene effect, however, was complex in that the 5-HTT promoter region insertion showed two effects: both a placebo response effect (F = 4, p <.025), and a drug dose response effect (r =.40, p <.01). The long allele group was more responsive to placebo, as well as more responsive to drug dose than was the short allele group. CONCLUSIONS: This is the first study to examine the antidepressant dose-response relationship to 5-HTT kinetics and genetics. The findings indicate that both the initial affinity and genotype of 5-HTT may contribute in unique ways to the variation in the outcome of depression treatment trials.