Clozapine therapy demonstrated superiority to olanzapine therapy in preventing suicide attempts in patients with schizophrenia and schizoaffective disorder at high risk for suicide. Use of clozapine in this population should lead to a significant reduction in suicidal behavior.
Previously, we have shown that in vitro antidepressants modulate glucocorticoid receptor (GR) function and expression, and have suggested that these effects could be relevant for the mechanism of action of antidepressants. To further clarify the interaction between antidepressants and glucocorticoids, we evaluated the in vitro effect of the tricyclic antidepressant, clomipramine (CMI), on the GR function in 15 treatment-resistant depressed inpatients and 28 healthy controls. Diluted whole-blood cells were incubated for 24 h in the presence or absence of CMI (10 mM). Glucocorticoid function was measured by glucocorticoid inhibition of lypopolysaccharide (LPS)-stimulated interleukin-6 (IL-6) levels. The results show that glucocorticoids (dexamethasone, prednisolone, cortisol and corticosterone) caused a concentration-dependent inhibition of LPS-stimulated IL-6 levels. In healthy controls, CMI decreased glucocorticoid inhibition of LPS-stimulated IL-6 levels, while this effect was not present in depressed patients. Therefore, depressed patients, who were clinically treatment resistant, also showed a lack of effect of the antidepressant in vitro. Upcoming studies shall test whether assessing the effects of antidepressants in vitro on GR function could predict future treatment response in a clinical setting.
Suicidal behavior in patients with psychotic disorders represents a seriously undertreated life-threatening condition. The International Suicide Prevention Trial (InterSePT) is the first large-scale, prospective study designed to evaluate the potential of antipsychotic medications to reduce suicidal behaviors in patients with schizophrenia or schizoaffective disorder who are known to be at high risk for suicide. The unique challenges to study design and the solutions identified for the InterSePT study are described. These challenges included defining suicidal behavior in patients with psychosis, endpoint selection, determination of analytic strategy, and development of scales to assess suicidal behavior. Given the life-threatening nature of suicidal behavior, ethical considerations required that the design minimize suicide attempts and deaths. While the study focused primarily on treatment of suicide, opportunities were used to collect data in related areas of interest, including suicide risk factors, other efficacy measures (e.g., Positive and Negative Syndrome Scale, Covi Anxiety Scale, Calgary Depression Scale), adverse events, pharmacoeconomics, and pharmacogenetics. Because of the complexity of the design issues, a steering committee, suicide monitoring board, and publication committee were established to assist with their management.
The incidence of treatment resistance in schizophrenia (failure to respond to antipsychotic therapy) is about 20%. Factors that may contribute to it include non-adherence (non-compliance) to treatment, comorbid conditions and medication side-effects. The National Institute for Clinical Excellence recommends that clozapine be used for schizophrenia resistant to another atypical antipsychotic. Here we focus on patients who are also resistant to clozapine given in adequate dosage for sufficient duration. Switching from clozapine to a previously untried atypical (e.g. olanzapine, risperidone, quetiapine) might be of benefit in partial treatment resistance. In more difficult cases, augmentation of clozapine with benzamides (sulpiride, amisulpride) and anti-epileptics (lamotrigine) shows some success. In extreme treatment resistance, a strategy is recommended that combines the proven best drug for the particular patient and psychosocial treatments.
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