Delay to first antipsychotic medication in schizophrenia: impact on symptomatology and clinical course of illness

Abstract

The possible adverse clinical effects of untreated psychosis in schizophrenic patients, particularly early in the course of illness, have been a topic of considerable interest in recent years. We examined the timing of first administration of antipsychotic medication after the first onset of psychotic symptoms in 103 patients with DSM-III-R diagnoses of schizophrenia, schizophreniform or schizo-affective disorder. Patients with a delay of one or more years between the onset of the first psychotic symptom and the initiation of antipsychotic treatment demonstrated more severe negative symptomatology on admission to hospital and more severe positive symptoms and negative symptoms at discharge. These effects were present in both first-admission patients, in whom the delay to treatment immediately preceded hospitalization and chronic patients with a history of multiple hospitalizations. Patients with one or more years of untreated psychosis prior to their first antipsychotic treatment displayed a more severe poverty syndrome at the time of admission and discharge and a more severe reality distortion syndrome at discharge from the index hospitalization. These findings were not related to age, premorbid functioning, duration of illness, first- vs multiple-episode status, or dosage of antipsychotic medication at time of admission or discharge assessment. Findings from the present study suggest that failure to initiate antipsychotic treatment early in the course of the illness may be associated with a recurrent pattern of poorer treatment response and more severe and persistent positive and negative symptomatology. These findings indicate the importance of early detection of illness and early initiation of antipsychotic treatment for the first psychotic symptoms of schizophrenia.

Introduction

Although antipsychotic medications have demonstrated efficacy in minimizing psychotic symptoms and forestalling relapse in schizophrenia, little is known about the effects of delaying antipsychotic treatment during the initial phase of active psychosis. Recent research indicates considerable variation across schizophrenia patients in the timing of initiation of antipsychotic medication following the first symptoms of psychosis. Findings show that a majority of schizophrenia patients receive antipsychotic medication within 12 months from the onset of the first psychotic symptom (Crow et al., 1986; Haas and Sweeney, 1992; Loebel et al., 1993). However, as many as one-third of first-treatment cases report untreated psychotic symptoms lasting from one to twenty years (Crow et al., 1986; Haas and Sweeney, 1992).

In a study of 120 first-episode schizophrenic patients, Crow et al. (1986)linked the length of the period between onset of first psychotic symptoms and the initiation of antipsychotic medication (delay to first medication) with long-term treatment outcome and risk for subsequent relapse. Patients for whom this symptom-onset-to-first-treatment interval was one year or greater experienced significantly elevated risk for relapse over the initial two years of antipsychotic treatment. In the discussion of their findings, Crow et al. questioned whether delay in the initiation of antipsychotic medication ‘leads to abnormality, [sic] which cannot be completely reversed by subsequent treatment’ (p. 127).

In a comparative review of the clinical outcomes from the pre-antipsychotic treatment era with those obtained using conventional antipsychotic treatment, Wyatt (1991)cited evidence that the duration of early untreated psychosis may influence later antipsychotic treatment response. Early placebo-controlled trials of antipsychotic treatments for initial episodes of schizophrenia also provide support for this hypothesis (Wyatt, 1991). In one of the first random-assignment, controlled trials of initial treatment with chlorpromazine (CPZ), first-hospitalization schizophrenia patients were randomly assigned to one of three treatment conditions: a non-medication hospital treatment group, a ‘clinical judgment’ hospital treatment group in which treatment with CPZ was available but not required and an antipsychotic (CPZ) medication group (Wirt and Simon, 1959). Patients assigned to the CPZ treatment condition for the first 30 days of treatment had a better outcome at one- and eight-year follow-up evaluation when compared with patients assigned to either the clinical judgment treatment or the non-medication treatment condition. Likewise, findings from the study by May et al. (1981)indicated that patients given antipsychotic treatment during their first hospitalization had significantly better treatment outcome over the subsequent three-year follow-up period than did patients treated without medication during their first hospitalization for a first episode of psychosis. A recent re-analysis of the follow-up data from the same study by May et al. (1981)revealed that patients initially treated with medications were less likely to be hospitalized during the second year following discharge and were functioning at a higher level at 6–7 years following discharge than were patients not initially treated with antipsychotic medication (Wyatt et al., 1997).

The third random-assignment study of inpatient antipsychotic treatment for first episode schizophrenia yielded equivocal results. Schooler et al. (1967)observed better outcome for outpatients treated with placebo as compared with those treated with antipsychotic medication. They concluded that the findings ‘must be an artifact’ (p. 991), possibly related to different rates of discharge into the community, and\or different lengths of hospitalization (longer for the placebo group compared to the antipsychotic treatment group).

Prospective studies of treatment-response in first-episode schizophrenia patients also suggest that the duration of untreated psychotic symptoms predicts a longer time to remission (Loebel et al., 1992) and increased risk for rehospitalization (Crow et al., 1986). The study of Loebel et al. (1992)represents a major methodological advance in using a prospectively-evaluated subject sample and standardized rating instruments and structured diagnostic interview procedures.

The current study investigated the association between duration of untreated psychosis with both the severity of positive symptoms during an episode of symptom exacerbation (e.g. on admission to hospital) and treatment response. In addition, we posed several questions: Is longer duration of untreated psychosis prior to the first episode of schizophrenia associated with more severe symptoms and poorer treatment response exclusively during the initial treatment for the first episode of schizophrenia, or does the effect extend to subsequent episodes of hospitalization? What is the specific nature of the symptoms that appear to be more severe following extended untreated psychosis at the point of illness onset?