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.

The behavioral effect of m-chlorophenylpiperazine (mCPP) and methylphenidate in first-episode schizophrenia and normal controls.

Although there has been renewed interest in the serotonin (5-HT) system in schizophrenia, direct evidence for 5-HT dysfunction is limited. This study compares the responses of m-chlorophenyl-piperazine (mCPP), a 5-HT agonist, in first-episode schizophrenia and a known psychotogenic dopamine agonist, methylphenidate. Eighteen patients experiencing their first episode of psychosis and eight healthy controls received methylphenidate (0.5 mg/kg) and mCPP (0.1 mg/kg) intravenously. Behavioral assessments were done before and after the procedure, and a peak response to each agent was rated. Methylphenidate, but not mCPP, produced psychotic symptoms in patients. mCPP did decrease anxiety, hallucinations, and anger and increased agitation, somatic concern, and impaired understandability. Both agents had limited effects on controls. In conclusion, unlike methylphenidate, mCPP did not produce psychotic symptom activation in schizophrenic patients in, and its effects appeared to be nonspecific.

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.

Psychobiologic correlates of treatment response in schizophrenia.

In studies conducted on largely treatment naive patients in their first episode of psychosis, we have found that treatment outcome is quite good and that most patients recover or at least achieve a substantial degree of symptom remission. However, over the course of their illness and in the context of subsequent psychotic episodes, they may experience some decrease in their treatment response from illness progression. In addition, the heterogeneity of treatment outcome is associated with specific clinical (gender, primary negative symptoms of the deficit state, duration of psychosis) and biological variables (pHVA, ventricular volume). It is unclear whether these variables represent aspects of discrete subtypes of schizophrenia or dimensional measures of pathology within the broad context of a unitary disease entity.

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

For the majority of patients, schizophrenia is a chronic recurrent disease that leads to significant residual morbidity which occurs through a process of behavioral deterioration. The factors that influence the course of schizophrenia after its onset and the ability of treatment to modify the effects of the patient's illness are not well understood. This article examines specific clinical and biological variables that are associated with treatment response and outcome. These variables, which are both trait and state dependent, include premorbid adjustment, age and mode of onset of illness, gender, duration of psychosis, schizophrenia subtype, primary negative symptoms, and extrapyramidal signs including tardive dyskinesia and plasma HVA and brain pathomorphology. In addition, the chronic effects of antipsychotic drug treatment may influence illness course both favorably and adversely as well as potentially altering the neurobiological substrates that mediate expression of the illness and treatment response. Finally, the question of whether the active phase of the illness involves a pathologic process that leads to illness progression is discussed. In light of this discussion, we can speculate that although certain aspects of the illness in terms of its severity and course may be, to an extent, predetermined, a number of factors can exert favorable and unfavorable effects on the course of the illness and its ultimate outcome. One question for the field is to develop therapeutic strategies that minimize the morbidity of the illness in a way that does not introduce iatrogenic consequences to the patient.

Prevalence and clinical correlates of extrapyramidal signs and spontaneous dyskinesia in never-medicated schizophrenic patients.

OBJECTIVE: This study assessed the prevalence of extrapyramidal signs and spontaneous dyskinesia in neuroleptic-naive, first-episode schizophrenic patients and examined the clinical correlates. METHOD: In a prospective study of the psychobiology of schizophrenia, the authors examined 89 neuroleptic-naive patients for the presence of extrapyramidal signs by using the Simpson-Angus Rating Scale and for dyskinesia by using the Tardive Dyskinesia Rating Scale. RESULTS: Fifteen patients (16.9%) had extrapyramidal signs, but only one had spontaneous dyskinesia at baseline. Presence of extrapyramidal signs was correlated with more negative symptoms and poorer treatment outcome that was reflected in a longer time to and lower level of remission. There was no correlation of spontaneous extrapyramidal signs with age of patient, age at onset of psychotic symptoms, or baseline psychopathology. There was no difference between patients with and without spontaneous extrapyramidal signs in terms of the subsequent development of persistent tardive dyskinesia, but the patients with spontaneous extrapyramidal signs were more likely to develop parkinsonian side effects after 8 weeks of antipsychotic treatment. CONCLUSIONS: Extrapyramidal signs are present in a proportion of neuroleptic-naive, first-episode schizophrenic patients, which suggests an involvement of these signs in the schizophrenic process that probably reflects basal ganglia pathology. The presence of spontaneous extrapyramidal signs seems to have prognostic significance insofar as it is linked to a poorer outcome and longer time to remission. Spontaneous dyskinesia appears to be a relatively rare finding.

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.

Reduced caudate nucleus volume in obsessive-compulsive disorder.

BACKGROUND: Current hypotheses about the neuroanatomical structures involved in obsessive-compulsive disorder (OCD) suggest abnormalities in cortical-striatal-thalamic-cortical circuits. This study examined selected brain regions within or adjacent to these circuits. METHODS: Magnetic resonance imaging scans from 26 patients with OCD and 26 healthy controls were analyzed to determine the volumes of the following structures: prefrontal cortex (cortex anterior to the genu of the corpus callosum), caudate nucleus, lateral and third ventricles, and whole brain. RESULTS: Patients with OCD had significantly smaller caudate nucleus volumes than controls (F[1,48] = 9.4, P = .004) but did not differ in prefrontal cortex size or in volumes of the lateral or third ventricles. Structural volumes were not significantly correlated with the duration or severity of OCD symptoms. CONCLUSION: Our findings provide additional evidence for pathological involvement of the caudate in OCD.

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.

Relation of plasma fluphenazine levels to treatment response and extrapyramidal side effects in first-episode schizophrenic patients.

OBJECTIVE: The aim of this study was to determine the relation between plasma fluphenazine levels and clinical response in first-episode schizophrenic patients. METHOD: Data from 36 first-episode schizophrenic or schizoaffective inpatients diagnosed according to the Research Diagnostic Criteria were evaluated. The patients received open, standardized treatment with fluphenazine, 20 mg/day, for at least 4 weeks. Psychopathology was assessed biweekly, and plasma fluphenazine levels were ascertained weekly. Patients were classified as responders or nonresponders, and correlations between their neuroleptic levels and ratings of psychopathologic and extrapyramidal symptoms were computed. RESULTS: Plasma fluphenazine levels for weeks 1 through 4 were significantly correlated with each other but were not correlated with age, gender, diagnosis, or race. Mean neuroleptic levels (weeks 3 and 4) were not different between responders and nonresponders and were not correlated with measures of psychopathology or extrapyramidal symptoms. CONCLUSIONS: These results do not indicate an association between plasma fluphenazine levels and response to treatment or extrapyramidal side effects in first-episode schizophrenia. The disparity between the results of this study and those of previous studies may be due to methodological differences or to a biologically based difference between first-episode and chronic patients.

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.

Neurochemistry and neuroendocrinology of schizophrenia: a selective review.

Neurochemical investigation has played a major role in the search for the cause of schizophrenia. Initial research strategies involved the direct measurement of neurochemical substances in biological fluids. Subsequently, indirect measures of brain biochemistry including pituitary hormones and responses to pharmacologic probes were examined. Recent advances in in vivo functional neuroimaging, biochemical neuropathology, and molecular genetics have extended the scope of clinical neurochemical studies. The historical emphasis on the dopamine neurotransmitter system has subsided in the wake of the demonstrated limitations of the dopamine hypothesis of schizophrenia and increased evidence for the role of other neurotransmitters in the pathophysiology of schizophrenia as well as their interactions with dopamine neural systems. The neurotransmitters that have come under increasing scrutiny include serotonin, norepinephrine, glutamate, and related excitatory amino acids, and the neuropeptides cholecystokinin and neurotensin. In this article, the authors reviewed significant recently published neurochemical and neuroendocrine studies of schizophrenia in the context of previous work and found an extensive but fragmentary body of data which provides neither consistent nor conclusive evidence for any specific etiologic theory. Aspects of the disease and methodological limitations that may account for this as well as future research strategies are discussed.

Treatment of neuroleptic-resistant schizophrenic relapse.

Preliminary findings are reported for a study of the relative efficacy of conventional treatment alternatives routinely used to treat acutely relapsed schizophrenic patients who fail an initial course of standard neuroleptic therapy. A sample of 156 acutely ill schizophrenic, schizoaffective, and schizophreniform patients who had been hospitalized recently in an acute-care inpatient facility were treated openly with fluphenazine (FPZ) 20 mg/day and with prophylactic benztropine for 4 weeks. Those subjects who failed to meet a priori criteria for substantial therapeutic response at the end of Week 4 were randomized to receive double-blind treatment for an additional 4 weeks with one of the following: (1) the same dose of neuroleptic (FPZ 20 mg/day); (2) an increased dose of neuroleptic (FPZ 80 mg/day); or (3) a different class of neuroleptic (haloperidol 20 mg/day). Of the 115 subjects who completed the open phase of study, 32 percent were identified as responders. Higher negative symptom scores and increased acute extrapyramidal side effect ratings appeared to distinguish the nonresponder from the responder group. Of the nonresponders who went on to randomized treatment, only 4 of 47 subjects (9%) subsequently responded. No superior efficacy was associated with any of the specific alternative treatments studied.