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Factors influencing treatment response and outcome of first episode schizophrenia: implications for understanding the pathophysiology of schizophrenia.

Lieberman JA, Koreen AR, Chakos M, Sheitman B, Woerner M, Alvir JMJ, and Bilder R (1996).

Journal of Clinical Psychiatry (Suppl) 57 (Suppl 9): 5-9.

This study indicates that, although treatment resistance may be present in a small proportion of patients suffering from their first episode of schizophrenia, it develops in other patients over the course of their illness. This suggests that, although certain aspects of the illness in terms of its severity and course are predetermined, a number of other risk and treatment factors can exert favorable and unfavorable effects on the course of illness. There may be an active pathologic process that occurs during periods of acute psychosis which, if not counteracted, can produce persisting morbidity and impair patients’ ability to respond to treatment. If so, then the early use of antipsychotic medications could be integral to preventing relapses and thus subsequent deterioration in patients with schizophrenia.

The authors’ premise is that, in schizophrenia, specific disease-related factors are either associated with or influence the course of the illness, as well as the response to antipsychotic medications. Most studies have found that first episode patients with schizophrenia differ from more chronic patients. The authors cite their recent study, conducted with Nina Schooler, which found that, with treatment, acute psychotic symptoms in first-episode patients were more likely to subside than those of more chronic patients, and that first-episode patients required lower doses of antipsychotic medications for both acute and maintenance treatment. However, it is not clear whether these differences are the result of disease progression or attrition patterns in the patient population, with the first-episode patients who have the least severe course recovering and thus not being present in analyses of more chronic populations.

In order to address the issue of what causes the difference between first-episode and chronic patients with schizophrenia, the authors analyzed the relapse pattern and recovery time for a group of 70 schizophrenic patients followed prospectively over 10 years. All patients were initially treated with fluphenazine, and most (70%) had had no prior exposure to antipsychotic medications. The authors found that 86% (n=57) of this sample recovered (either fully or partially) from their first episode of illness; however, 22 of these patients had a subsequent relapse, and another six had a second relapse (or third episode). For the group of 22 patients, the median time to remission was 8.4 weeks for the first, and 11.9 weeks for the second episode. Whereas all 22 patients remitted from the first episode, only 20 remitted from their first relapse. The median time to remission for the six patients who had three episodes were four, seven, and 24.1 weeks, respectively. Although the authors caution that their results are preliminary, the findings show a clear pattern of decreasing responsiveness to treatment over subsequent episodes of illness; however, they cannot determine to what degree this diminished response is due to the disease or because there is something about the treatment that produced it.

The authors also discuss the risk factors associated with outcome in schizophrenia. Factors thought to negatively influence the course of the illness include: longer duration of illness; more numerous episodes; duration of psychosis prior to the first episode of illness; the presence of extrapyramidal side effects (EPS) or tardive dyskinesia (either idiopathic or drug-induced); and enlargement of the lateral and third ventricles in the brain. Taken together, these suggest that there is an active pathologic process that occurs during periods of acute psychosis which, if not counteracted, can produce persisting morbidity and impair patients’ ability to respond to treatment.

Factors thought to positively influence the course of illness include: early treatment with antipsychotic medications, and higher pretreatment levels of plasma homovanillic acid, one of the major metabolites of dopamine.

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