Predicting response to atypical antipsychotics based on early response in the treatment of schizophrenia

OBJECTIVE: To test whether early onset of response to antipsychotic medications accurately predicts subsequent response in the treatment of patients with schizophrenia. METHODS: We used data from 5 randomized, double-blind clinical trials comparing olanzapine with other atypical antipsychotic drugs in the treatment of patients with schizophrenia and related disorders, who were at least moderately ill at baseline and who were treated for a minimum of 2 weeks (N=1077). Early response was defined as >or=20% improvement on the PANSS total score at 2 weeks. Conditional probabilities (sensitivity, specificity, positive and negative predictive values) were used to characterize the likelihood of "subsequent response" to treatment (i.e., >or=40% improvement on the PANSS total score with treatment up to 3 months). Subsequent analyses focused on varying thresholds of subsequent response, and at different time points. RESULTS: Most (80%) of subsequent non-responders by 3 months were correctly classified as early non-responders at 2 weeks (high specificity), and 84% of early non-responders at 2 weeks were subsequent non-responders by 3 months (high negative predictive value). For early responders, prediction of subsequent response was substantially lower. A higher threshold (e.g., >or=40% improvement) had greater predictive accuracy at all time points measured. Early non-responders attained less symptom improvement overall, and were more likely to discontinue from treatment. CONCLUSIONS: Early non-response to antipsychotic medications was a robust predictor of subsequent lack of response in the treatment of patients with schizophrenia. Evaluating patients as early as 2 weeks in treatment can help identify non-responders who may benefit from an alternative therapeutic approach.     

Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia.

BACKGROUND: Lamotrigine, a novel anticonvulsant drug having modulatory effects on glutamatergic neurotransmission, improves mood and cognition parameters in bipolar disorder. Recent studies suggest that when added to clozapine, lamotrigine treatment may result in significant positive symptoms reductions in schizophrenia. Similar effects were not observed in an open trial in which lamotrigine was used as adjuvant to nonclozapine antipsychotics. METHODS: Thirty-eight treatment-resistant schizophrenia inpatients receiving conventional and atypical antipsychotics enrolled in a 10-week, double-blind, placebo-controlled study, in which they were randomized in a 2:1 ratio to receive adjuvant treatment with lamotrigine, gradually titrated to a 400 mg/day dose, or placebo. Of these, 31 completed the trial. Measures of clinical efficacy and side effects were determined every other week. Serum levels of amino acids were assessed at the beginning and end of the study. RESULTS: In primary last observation carried forward analysis, no statistically significant between-group differences were observed; however, the completers' analyses revealed that lamotrigine treatment resulted in significant (p < or = .05) reductions in positive and general psychopathology symptoms, as measured by the Positive and Negative Syndrome Scale. No significant differences in lamotrigine effects were noted between conventional versus atypical antipsychotics. Lamotrigine treatment was well tolerated, and glutamate serum levels remained stable throughout the study. CONCLUSIONS: These preliminary findings 1) support the hypothesis that lamotrigine adjuvant treatment may improve positive symptoms and general psychopathology in schizophrenia, 2) suggest that beneficial effects may be achieved when lamotrigine is added to both conventional and atypical antipsychotics, and 3) warrant additional, larger scale trials.     

Management of aggression, agitation, and psychosis in dementia: focus on atypical antipsychotics

The behavioral and psychological symptoms of dementia (BPSD), such as psychosis, agitation, or aggression have a considerable negative impact on the quality of life of both patients and their caregivers. Multiple studies have demonstrated that atypical antipsychotics are efficacious in the treatment of the aggressive and psychotic symptom clusters, and here we review their use in this indication. Because of the safety concerns associated with the use of atypical antipsychotics in this population, these drugs must be used judiciously. For patients with severe BPSD such as psychosis, agitation, or aggression, for whom there are few options, atypical antipsychotics, particularly risperidone and olanzapine, should be considered.     

Duration of psychosis and outcome in first-episode schizophrenia.

OBJECTIVE: This study was undertaken to assess the potential effect of duration of untreated illness on outcome in a group of first-episode schizophrenic patients. METHOD: Seventy patients with schizophrenia diagnosed according to the Research Diagnostic Criteria entered the study and were followed for up to 3 years. All patients received standardized treatment and uniform assessments both during the acute phase of their illness and throughout the follow-up period. Outcome was measured in terms of time to remission of acute psychotic symptoms as well as degree of symptom remission. RESULTS: The mean duration of psychotic symptoms before initial treatment was 52 weeks, preceded by a substantial prepsychotic period. According to survival analysis, duration of illness before treatment was found to be significantly associated with time to remission as well as with level of remission. The effect of duration of illness on outcome remained significant when diagnosis and gender variables, themselves associated with outcome, were controlled in a regression analysis. Duration of illness was not correlated with age at onset, mode of onset, premorbid adjustment, or severity of illness at entry into the study. CONCLUSIONS: Duration of psychosis before treatment may be an important predictor of outcome in first-episode schizophrenia. Acute psychotic symptoms could reflect an active morbid process which, if not ameliorated by neuroleptic drug treatment, may result in lasting morbidity. Further implications of these findings are discussed.     

Oxidative damage and schizophrenia: the potential benefit by atypical antipsychotics

There is evidence to suggest the derangement of the oxidant and antioxidant defense system in schizophrenia. The present study examined the effect of atypical antipsychotics on lipid peroxidation, superoxide dismutase (SOD) and ascorbic acid. For this purpose, a prospective, open-label, 8-week study design was utilized. Serum SOD, serum malondialdehyde (MDA) and plasma ascorbic acid were estimated. Schizophrenic patients (n = 48) were compared with age- and sex-matched healthy volunteers (n = 40). There was a significant increase in serum SOD, serum MDA and a decrease in plasma ascorbic acid in schizophrenic patients as compared to control subjects. The trend altered significantly after the treatment with atypical antipsychotics. The results of the Brief Psychiatric Rating Scale for schizophrenia also improved with the treatment. The findings indicate an involvement of free radicals in schizophrenia and its modification by treatment with atypical antipsychotics. This study can also be used as a predictor of drug response by atypical antipsychotics in schizophrenia.     

Correlation between plasma homovanillic acid levels and the response to atypical antipsychotics in male patients with schizophrenia

OBJECTIVE: The authors investigated the effects of atypical antipsychotic drugs-olanzapine, perospirone, and quetiapine-on plasma homovanillic acid (pHVA) in male patients with chronic schizophrenia. METHODS: In this prospective, open-label study, the subjects were 30 inpatients who were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria for schizophrenia. The authors switched patients from typical antipsychotic drugs to olanzapine, perospirone, or quetiapine. Each patient gave informed consent for the research. pHVA was assessed before and after switching medications. RESULTS: After the switch, the authors found a significant improvement in psychotic symptoms, nonsignificant improvement in extrapyramidal symptoms, and a nonsignificant reduction in pHVA. In addition, the baseline pHVA correlated positively with the score changes from baseline in the Brief Psychiatric Rating Scale (BPRS) total, positive, and negative symptoms in the group with a whole sample and in the olanzapine-treated group, and with the score changes in the BPRS total and positive symptoms in the quetiapine-treated group. CONCLUSION: Our findings indicated that the preswitching pHVA levels could be used to predict changes in the psychotic symptoms of male patients with chronic schizophrenia when switching to atypical antipsychotic drugs.     

Service use and costs of treating schizophrenia with atypical antipsychotics

BACKGROUND: The high acquisition cost of the atypical antipsychotics has prompted their closer clinical and economic evaluation. This study aims to examine the financial implications of using atypical antipsychotics in a defined catchment area sample of patients with schizophrenia. METHOD: Service costs over a 10-month period were compared between groups of patients fulfilling DSM-IV criteria for schizophrenia who were taking different atypical antipsychotic agents. RESULTS: All patients studied were taking clozapine (N = 31). risperidone (N = 19), or olanzapine (N = 41). Clozapine was used in more chronic patients, while risperidone and olanzapine were prescribed in both chronic and recently diagnosed cases. After background group differences were controlled for, patients on risperidone treatment incurred the lowest costs. The monthly costs for the clozapine and olanzapine groups were higher than for risperidone by US $246 and US $566, respectively. CONCLUSION: Clozapine was reserved for more severe forms of schizophrenia, but its cost impact was relatively low. Risperidone, as prescribed in ordinary practice, may be more cost-effective than olanzapine.     

Early subjective response and prediction of outcome to neuroleptic drug therapy in schizophrenia

Events that occur early in the course of neuroleptic treatment, and which may have utility in predicting short-term clinical outcome, were investigated. Such events include the patient's subjective response to drug, early clinical response, and the emergence of side effects. From all the variables examined, early subjective response and symptom change at 24 and 48 hours following initiation of neuroleptic drug therapy were found to be significantly related to short-term outcome. These findings are assessed with respect to their predictive utility and relative contribution to the development of a strategy for individualized drug treatment approaches in schizophrenia.     

Defining treatment-resistant schizophrenia and response to antipsychotics: a review and recommendation

Treatment-resistant schizophrenia (TRS) has been defined mainly by severity of (positive) symptoms and response to antipsychotics derived from a relative change in the representative scales (most frequently ≥ 20% decrease in the Positive and Negative Syndrome Scale: PANSS), but these definitions have not necessarily been consistent. Integrating past evidence and real-world practicability, we propose that TRS be defined by at least two failed adequate trials with different antipsychotics (at chlorpromazine-equivalent doses of ≥ 600mg/day for ≥ 6 consecutive weeks) that could be retrospective or preferably include prospective failure to respond to one or more antipsychotic trials. In addition, our proposed criteria require both a score of ≥ 4 on the Clinical Global Impression (CGI)-Severity and a score of ≤ 49 on the Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz) or ≤ 50 on the Global Assessment of Functioning (GAF) scales to define TRS. Once TRS is established, we propose that subsequent treatment response be defined based on a CGI-Change score of ≤ 2, a ≥ 20% decrease on the total PANSS or Brief Psychiatric Rating Scale (BPRS) scores, and an increase of ≥ 20 points on the FACT-Sz or GAF. While these suggestions provide a pragmatic framework for TRS classification, they need to be tested in future trials.     

Clinical predictors of therapeutic response to antipsychotics in schizophrenia

The search for clinical outcome predictors for schizophrenia is as old as the field of psychiatry. However, despite a wealth of large, longitudinal studies into prognostic factors, only very few clinically useful outcome predictors have been identified. The goal of future treatment is to either affect modifiable risk factors, or use nonmodifiable factors to parse patients into therapeutically meaningful subgroups. Most clinical outcome predictors are nonspecific and/or nonmodifiable. Nonmodifiable predictors for poor odds of remission include male sex, younger age at disease onset, poor premorbid adjustment, and severe baseline psychopathology. Modifiable risk factors for poor therapeutic outcomes that clinicians can act upon include longer duration of untreated illness, nonadherence to antipsychotics, comorbidities (especially substance-use disorders), lack of early antipsychotic response, and lack of improvement with non-clozapine antipsychotics, predicting clozapine response. It is hoped that this limited capacity for prediction will improve as pathophysiological understanding increases and/or new treatments for specific aspects of schizophrenia become available.