Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder.

OBJECTIVE: This study examined the treatment response of patients with first-episode schizophrenia and schizoaffective disorder and potential predictors of response. METHOD: First-episode patients were assessed on measures of psychopathology, cognition, social functioning, and biological parameters and treated according to a standardized algorithm. RESULTS: One hundred eighteen patients (52% male, mean age 25.2 years) entered the study. The cumulative percentage of patients responding by 1 year was 87%; the median time to response was 9 weeks. The following variables were significantly associated with less likelihood of response to treatment: male sex, obstetric complications, more severe hallucinations and delusions, poorer attention at baseline, and the development of parkinsonism during antipsychotic treatment. Variables not significantly related to treatment response were diagnosis (schizophrenia versus schizoaffective disorder), premorbid functioning, duration of psychotic symptoms prior to study entry, baseline disorganization, negative and depressive symptoms, baseline motor function, akathisia and dystonia during treatment, growth hormone and homovanillic acid measures, psychotic symptom activation to methylphenidate, and magnetic resonance measures. CONCLUSIONS: Patients with first-episode schizophrenia and schizoaffective disorder have high rates of response to antipsychotic treatment; there are specific clinical and pathobiologic predictors of response.

Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder.

BACKGROUND: We examined relapse after response to a first episode of schizophrenia or schizoaffective disorder. METHODS: Patients with first-episode schizophrenia were assessed on measures of psychopathologic variables, cognition, social functioning, and biological variables and treated according to a standardized algorithm. The sample for the relapse analyses consisted of 104 patients who responded to treatment of their index episode and were at risk for relapse. RESULTS: Five years after initial recovery, the cumulative first relapse rate was 81.9% (95% confidence interval [CI], 70.6%-93.2%); the second relapse rate was 78.0% (95% CI, 46.5%-100.0%). By 4 years after recovery from a second relapse, the cumulative third relapse rate was 86.2% (95% CI, 61.5%-100.0%). Discontinuing antipsychotic drug therapy increased the risk of relapse by almost 5 times (hazard ratio for an initial relapse, 4.89 [99% CI, 2.49-9.60]; hazard ratio for a second relapse, 4.57 [99% CI, 1.49-14.02]). Subsequent analyses controlling for antipsychotic drug use showed that patients with poor premorbid adaptation to school and premorbid social withdrawal relapsed earlier. Sex, diagnosis, obstetric complications, duration of psychotic illness before treatment, baseline symptoms, neuroendocrine measures, methylphenidate hydrochloride challenge response, neuropsychologic and magnetic resonance imaging measures, time to response of the initial episode, adverse effects during treatment, and presence of residual symptoms after the initial episode were not significantly related to time to relapse. CONCLUSIONS: There is a high rate of relapse within 5 years of recovery from a first episode of schizophrenia and schizoaffective disorder. This risk is diminished by maintenance antipsychotic drug treatment.

Incidence and correlates of tardive dyskinesia in first episode of schizophrenia.

BACKGROUND: There is controversy over whether tardive dyskinesia (TD) is solely a consequence of antipsychotic drug treatment or in part may reflect an intrinsic aspect of the disease process. Pathophysiologic factors could, independently or in concert with drug effects, lead to the development of dyskinetic signs. METHODS: We studied prospectively 118 patients in their first episode of psychosis who were treatment-naive or had less than 12 weeks of antipsychotic drug exposure at study entry. Patients received standardized antipsychotic drug treatment and were evaluated for up to 8 1/2 years with regular assessments of psychopathologic signs and symptoms and side effects. RESULTS: The cumulative incidence of presumptive TD was 6.3% after 1 year of follow-up, 11.5% after 2 years, 13.7% after 3 years, and 17.5% after 4 years. Persistent TD had a cumulative incidence of 4.8% after 1 year, 7.2% after 2 years, and 15.6% after 4 years. Taken individually, both antipsychotic drug dose, entered as a time-dependent covariate, and poor response to treatment of the first psychotic episode were significant predicters of time to TD. When antipsychotic drug dose and treatment response were examined together, treatment responders had significantly lower hazards for presumptive TD than nonresponders (hazard ratio, 0.29; 95% confidence interval, 0.09 to 0.97). Dose was a trend-level predicter, with each 100-mg chlorpromazine equivalent unit increase in dose associated with a 5% increase in the hazard of presumptive TD (hazard ratio, 1.05; 95% confidence interval, 0.99 to 1.11). CONCLUSION: Poor response to the treatment of a first episode of psychosis and, to a lesser extent, antipsychotic drug dose are important factors in the development of TD. This suggests that there may be a disease-related vulnerability to TD manifest with antipsychotic drug exposure. Potential pathophysiologic factors might include neurodevelopmentally induced structural neuropathologic characteristics, sensitization of nigrostriatal dopamine neurons, and the induction of glutamatergically mediated neurotoxic effects.

Gender differences in onset of illness, treatment response, course, and biologic indexes in first-episode schizophrenic patients.

OBJECTIVE: Gender differences in onset of illness, response to treatment, course, and biologic measures have been consistently reported in patients with chronic schizophrenia. Patients with first-episode schizophrenia were examined to determine whether gender differences also occur in these patients. METHOD: Fifty-four neuroleptic-naive schizophrenic patients (29 men and 25 women) were studied beginning in an initial stage of the first hospitalization for psychosis while undergoing treatment with a standardized medication regimen. Before antipsychotic drug treatment and during 1 year of follow-up each patient was rated on the Schedule for Affective Disorders and Schizophrenia--Change Version (psychosis and disorganization items), Scale for the Assessment of Negative Symptoms, Clinical Global Impression, modified Simpson Tardive Dyskinesia Scale, and Simpson-Angus Rating Scale for extrapyramidal side effects. Methylphenidate challenge testing was done at study entry. Plasma neuroleptic, homovanillic acid (HVA), and prolactin levels were determined weekly for the first 6 weeks. RESULTS: The female schizophrenic patients had a later onset and better treatment response than the men. Plasma HVA levels at baseline and week 1 and changes in prolactin levels from baseline to weeks 1 through 6 were greater among the women. CONCLUSIONS: Gender differences in onset and degree of treatment response in first-episode schizophrenic patients are similar to those of chronic patients and are apparent at early stages of the illness. The greater pharmacologic responsivity of the female patients, as indicated by the neuroendocrine results, is consistent with the gender difference in degree of symptom improvement with medication.

The deficit state in first-episode schizophrenia.

OBJECTIVE: The prevalence, clinical correlates, and outcome of the deficit syndrome were determined for 70 patients ascertained in their first episode of schizophrenia and then followed through their recovery. METHODS: Patients were treated in a standardized manner and underwent baseline assessments of symptoms and adverse effects that were repeated at intervals throughout their inpatient and subsequent outpatient course. Forty-seven patients were followed for a minimum of 6 months after remission of their positive symptoms, allowing for an assessment of their deficit syndrome status. RESULTS: Using modified criteria of Carpenter et al. for the deficit syndrome, the authors found that two patients (4%) met all criteria for the deficit syndrome, nine (19%) had deficit symptoms (questionable deficit state), and 36 (77%) had no deficit symptoms. When patients who had not fully remitted or had remitted for less than 6 months were included, seven (10%) met deficit syndrome criteria, 11 (16%) had deficit symptoms, and 52 (74%) had no deficit symptoms. CONCLUSIONS: The prevalence of the deficit syndrome in first-episode schizophrenia varies depending on the criteria used and is lower than that previously described in more chronic patient samples. Patients without deficit symptoms had better premorbid functioning and a better global outcome than patients with deficit symptoms.

Plasma homovanillic acid levels in first-episode schizophrenia. Psychopathology and treatment response.

OBJECTIVES: To examine plasma homovanillic acid (pHVA) levels in first-episode schizophrenia, to compare pHVA levels in patients and controls, and to assess the association of pHVA levels with psychopathology and treatment response. METHODS: Forty-one patients entered the study, and pHVA levels were measured at baseline and on a weekly basis for up to 6 weeks of open standardized neuroleptic treatment. Psychopathology was evaluated with the Schedule for Affective Disorders and Schizophrenia, the Scale for Assessment of Negative Symptoms, and the Clinical Global Impressions scale. Ten healthy controls were used for comparison of baseline pHVA levels. RESULTS: No differences were observed between patients and controls. Baseline pHVA level was not associated with psychopathology but was associated with time to reach remission. Baseline pHVA levels and week-1 pHVA levels were higher in responders than nonresponders. Regardless of responsiveness, female participants had higher pHVA levels than male participants throughout the study. The pattern of pHVA levels with treatment was similar in all patients with a short-term rise initially and then a decrease toward baseline values. CONCLUSIONS: These findings suggest that pHVA levels have prognostic significance for response and time to reach remission. Qualitative and quantitative differences between first-episode patients' pHVA levels and studies using a long-term, neuroleptic-exposed population suggest that changes occur with neuroleptic treatment or the progression of the illness.

Depression in first-episode schizophrenia.

OBJECTIVE: Because findings regarding the prognostic significance of depressive symptoms in schizophrenia and their effect on the course and treatment of schizophrenia have been limited by the effects of previous treatment, retrospective evaluations, and differing definitions and criteria, the authors sought to determine the prevalence and prognostic significance of depressive symptoms in first-episode schizophrenia. METHOD: Thirty-nine men and 31 women experiencing their first episode of schizophrenia were evaluated with behavioral and extra-pyramidal symptom scales before treatment (baseline), biweekly during acute treatment, and then monthly. Extracted scores on the Hamilton Rating Scale for Depression and a "syndromal" definition of depression based on Research Diagnostic Criteria were obtained. Patients were followed prospectively for up to 5 years and received open standardized treatment. RESULTS: The prevalence of depressive symptoms at baseline ranged from 75% (patients who met extracted Hamilton and/or syndromal criteria) to 22% (patients who met both criteria). Of 808 psychotic ratings given to the 70 patients over a 5-year follow-up period, 210 (26%) were concurrently rated as depressed; of the 1,754 nonpsychotic ratings, only 70 (4%) were concurrently rated as depressed. Of the 210 depressive symptoms that occurred concurrently with psychosis, 206 (98%) resolved as the psychosis remitted. Depressive symptoms were prodromal to a psychotic relapse in only two (7%) of 27 patients who relapsed. Depressive symptoms correlated more with positive and negative symptoms than with extrapyramidal symptoms. CONCLUSIONS: These findings suggest that depressive symptoms in patients experiencing their first episode of schizophrenia may represent a core part of the acute illness or may occur as a subjective reaction to the experience of psychotic decompensation. Since most of the depressive symptoms resolved as the psychosis remitted, antidepressant therapy should be limited to patients in whom the depression persists.

Methylphenidate increases thought disorder in recent onset schizophrenics, but not in normal controls.

The effects of apomorphine and methylphenidate on thought disorder, as measured by the Thought Disorder Index, in schizophrenic patients and in normal controls were evaluated. Methylphenidate, but not apomorphine, increased thought disorder in patients. Neither drug significantly increased thought disorder in controls.

Brain morphology, dopamine, and eye-tracking abnormalities in first-episode schizophrenia. Prevalence and clinical correlates.

OBJECTIVE: To characterize the pathophysiology of schizophrenia and to identify biologic markers in first-episode patients with no or little prior treatment exposure. DESIGN: Prospective study of an inception cohort. SETTING: Psychiatric division of an academic medical center with a suburban metropolitan catchment area. PATIENTS: 70 patients in their first episode of schizophrenia (77%) or schizoaffective disorder (23%) with no (70%) or limited prior neuroleptic exposure (30%), and 50 healthy volunteer control subjects. ASSESSMENT MEASURES: Demographic and clinical evaluations of natural history and psychopathology; methylphenidate hydrochloride and apomorphine hydrochloride stimulation tests as measures of central nervous system dopamine activity; brain magnetic resonance imaging; eye-tracking examinations. RESULTS: Preliminary analyses demonstrate that pathobiologic features previously identified in heterogeneous and primarily chronically ill patients are also present in subgroups during their first episode. These include psychotogenic response to methylphenidate (59%), abnormal growth hormone (GH) secretion (50%), abnormal brain morphology (31%), and eye-tracking dysfunction (51%). An association of pathobiologic variables with increased symptom severity and earlier age of onset was observed but not statistically significant. The strongest associations among biologic variables were for the following: GH secretion and psychotogenic response to methylphenidate, which may reflect increased dopamine agonist neural activity; decreased GH response to apomorphine and third-ventricle enlargement, which may represent a neuropathologic correlate of anterior pituitary abnormalities; and morphologic abnormalities of the medial temporal lobe and third ventricle were associated with normal eye tracking, suggesting that these pathobiologic features are mediated by distinct processes. CONCLUSIONS: These phenomena appear to be a consequence of the disease rather than the effects of chronicity, drug treatment, or institutionalization. It remains to be determined if these biologic phenomena will remain stable over time or change with disease progression. A companion article examines the clinical significance of these findings.

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.

Prospective study of psychobiology in first-episode schizophrenia at Hillside Hospital.

Heterogeneity has been a consistent problem in the research and treatment of schizophrenia. Despite marked variation in the onset, phenomenology, treatment response and outcome of schizophrenic patients, our ability to identify subtypes is remarkably limited. A major problem in schizophrenia research has been the use of cross-sectional study designs and heterogeneous patient samples at different stages of the illness and who have been previously exposed to neuroleptics which have potentially confounding effects on the disease. This study intends to identify biologic correlates of the phenomenology and course of schizophrenia by using a prospective, longitudinal, repeated measures design assessing biologic and clinical parameters including measures of psychopathology, side effects, and social adjustment to examine clinical variables of treatment response, illness course, and outcome; measures of central nervous system dopamine activity and brain morphology in patients, from the onset of their illness. Patients were ascertained at hospital admission and assessed with a battery of clinical, neuropsychologic, and biologic measures before undergoing standardized treatment for the acute and maintenance phases of the illness. Upon completion, approximately 120 first-episode patients will have entered the study and will have been followed prospectively for up to 5 years and assessed at specific time intervals. Preliminary results reveal significant abnormalities in brain morphology, growth hormone secretion, eye movement function, and psychotogenic response to dopamine agonists in first-episode, treatment-naive patients which are associated with treatment response and outcome. This article describes the study's rationale, design, and methods, and a summary of the published results to date. These are discussed in terms of their significance for putative clinical subtypes and pathophysiological models of schizophrenia.

Intellectual deficits in first-episode schizophrenia: evidence for progressive deterioration.

The developmental processes leading to neuropsychological deficits in schizophrenia are poorly understood. Both early developmental defects and subsequent deterioration may occur. Intelligence test profiles are often used to estimate premorbid ability and deterioration from prior levels of functioning. These characteristics were assessed in samples of first-episode (n = 51) and chronic (n = 50) schizophrenic patients. Although the groups showed few differences on tests to estimate premorbid intellectual ability, the chronic group performed worse on measures considered sensitive to deterioration. Dextral (right-handed) patients tended to have better performance; this effect was marked in the first-episode sample, especially on verbal tests. Male patients showed more evidence of deterioration than female patients. Subgroups differing in the time course of premorbid social dysfunction also differed in intelligence test profiles, suggesting that estimates of social and cognitive deterioration may have concurrent validity. The results support the hypothesis that patients differ in the course of cognitive decline and suggest that deterioration of function may follow the onset of overt psychosis in some patients. Prospective longitudinal studies of first-episode schizophrenic patients could directly test this hypothesis.

Incidence and correlates of acute extrapyramidal symptoms in first episode of schizophrenia.

The incidence and correlates of extrapyramidal symptoms (EPS) in neuroleptic treatment of schizophrenic patients have been reported for chronic patients but not for first-episode patients. We examined the incidence and correlates of extrapyramidal symptoms in a cohort of 70 treatment-naive patients who received fluphenazine at 20-40 mg/day for the first 10 weeks of treatment. Thirty-four percent of our sample developed parkinsonism, 18 percent developed akathisia, and 36 percent developed dystonia. Acute EPS were associated with greater baseline psychopathology. Acute EPS were also associated with better treatment outcome in terms of time to and level of remission. These findings suggest that the EPS response of neuroleptic-naive patients may differ from that of chronically ill patients and that acute EPS status may be an indicator of pharmacologic responsivity in this group.