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Objective: Neuropsychological impairments are well documented in schizophrenia and are important targets of treatment. Information about the severity and pattern of deficits after treatment for the first psychotic episode and about relationships between these deficits and syndromal characteristics remains limited., Method: Comprehensive neuropsychological assessments including 41 individual tests were given to 94 patients with first-episode schizophrenia after initial stabilization of psychosis and to a comparison group of 36 healthy volunteers. Profiles of neuropsychological deficits and the relationship of deficits to sex and handedness were examined. Correlations of neuropsychological deficit with a broad range of historical and clinical characteristics, including outcome, were explored., Results: Patients had a large generalized neuropsychological deficit (1.5 standard deviations compared to healthy volunteers). Patients also had, superimposed on the generalized deficit, subtle relative deficits (less than 0.5 standard deviation compared to their own average profile) in memory and executive functions. Learning/memory dysfunction best distinguished patients from healthy individuals; after accounting for this difference, only motor deficits further distinguished the groups. Patients with higher neuropsychological ability had only memory deficits, and patients with lower ability had both memory and executive deficits. No sex differences were observed beyond the normal advantage for men in motor speed. Dextral patients had less severe generalized deficit. Severity of residual symptoms was associated with greater generalized deficit. Executive and attentional deficits were most linked to global functional impairment and poor outcome., Conclusions: The results document a large generalized deficit, and more subtle differential deficits, in clinically stabilized first-episode patients. Learning/memory deficits were observed even in patients with less severe generalized deficit, but the pattern was unlike the amnestic syndrome and probably reflects different mechanisms. Executive and attentional deficits marked the more severely disabled patients, and may portend relatively poor outcome. Failure to develop typical patterns of cerebral dominance may increase the risk for greater generalized deficit.

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.

Objective: The purposes of this study were to investigate the rate (incidence) of tardive dyskinesia in elderly patients beginning treatment with antipsychotic medication and to identify risk factors for development of tardive dyskinesia in this age group., Method: A group of 261 neuroleptic-naive patients aged 55 or above were identified at the time they were starting antipsychotic drug treatment. This group is the complete study group; a preliminary report based on the first 160 patients was published previously. Patients were evaluated at baseline and followed up at 3-month intervals for periods ranging from 3 to 393 weeks. Assessments included abnormal involuntary movements, extrapyramidal signs, psychiatric symptoms, and medical and drug treatment histories., Results: The cumulative rates of tardive dyskinesia were 25%, 34%, and 53% after 1, 2, and 3 years of cumulative antipsychotic treatment. A greater risk of tardive dyskinesia was associated with history of ECT treatment, higher mean daily and cumulative antipsychotic doses, and presence of extrapyramidal signs early in treatment. Differences in tardive dyskinesia rates between diagnostic groups found in univariate analyses were attenuated when the authors controlled for these variables., Conclusions: Tardive dyskinesia rates for patients beginning treatment with conventional antipsychotics in their fifth decade or later are three to five times what has been found for younger patients, despite treatment with lower doses. Alternative treatments need to be investigated.

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.

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.

Objective: The goal of this study was to determine whether patients experiencing their first episode of schizophrenia differ from healthy subjects in regional cerebral hemispheric volumes or asymmetries., Method: Regional volumes corresponding to prefrontal, premotor, sensorimotor, occipitoparietal, and temporal lobes in each hemisphere were measured on contiguous coronal magnetic resonance images in 70 patients experiencing their first episode of schizophrenia and in 51 healthy comparison subjects., Results: Patients did not differ from the comparison subjects in regional or total hemispheric volumes, but they had abnormal hemispheric asymmetries. Subjects in the comparison group had significant lateral asymmetries in each region: their occipitoparietal and sensorimotor regions were larger on the left, and their premotor, prefrontal, and temporal regions were larger on the right. Patients lacked lateral asymmetries and showed significantly less asymmetry than healthy subjects in occipitoparietal, premotor, and prefrontal regions. Absence of the normal asymmetry was more common among patients initially diagnosed with the undifferentiated than with the paranoid subtype of schizophrenia and was associated with more severe negative symptoms among men. Asymmetries were related to sex and handedness regardless of diagnosis; specifically, dextral men showed more asymmetry than nondextral men or dextral women., Conclusions: The absence of normal hemispheric asymmetries suggests an anomaly in the development of laterally specialized cerebral systems in schizophrenia, and this may be associated with an initial presentation of nonparanoid psychosis.

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.

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.

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.

Diabetes mellitus has been identified as a possible risk factor for tardive dyskinesia. The authors examined 160 elderly individuals who were beginning neuroleptic treatment; 24 had diabetes and 136 did not. After 43 weeks of neuroleptic exposure, the cumulative incidence rates of tardive dyskinesia were 54.1% (SE = 5.6%) for the diabetics and 25.6% (SE = 16.1%) for the nondiabetics.

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.

Objective: Neuroimaging studies of brain morphology in schizophrenia have used predominantly morphometric techniques to assess brain scans. However, as currently implemented, such methods are not particularly helpful in the routine assessment of individual patients. The purpose of this study was to evaluate brain morphology seen with magnetic resonance imaging (MRI) by qualitative assessment, the most frequently used method in clinical practice for evaluating brain scans., Method: First-episode (N = 62) and chronic, multi-episode (N = 24) schizophrenic patients and healthy comparison subjects (N = 42) underwent MRI of the whole head in a sequence that provided 63 contiguous brain slice images. Each subject received a rating of normal, questionably abnormal, or definitely abnormal for four brain regions (lateral ventricles, third ventricle, medial temporal lobe structures, and frontal/parietal cortex) and a global rating., Results: The schizophrenic patients had significantly higher global rates of abnormal morphology (first-episode group, 31%; chronic group, 42%) than the normal subjects (5%). The highest regional rates of abnormalities were seen in the lateral ventricles and the lowest in the frontal/parietal cortex. Although the chronic patients had generally higher abnormal rates than the first-episode patients, these differences were not statistically significant. The qualitative ratings of brain morphology were significantly correlated with quantitative assessments performed in separate studies., Conclusions: Despite its limits in sensitivity (and until quantitative morphometric techniques are made practical and more widely available), qualitative evaluation of MRI scans can be a useful technique in research and clinical evaluation of patients with schizophrenia.

The authors evaluated 24 outpatients with panic disorder by means of the afternoon continuous test for cortisol and the 1-mg dexamethasone suppression test (DST) and compared the results with those of 38 outpatients with major depressive disorder and 61 healthy control subjects. The mean basal cortisol level of the patients with panic disorder was significantly higher than that of the normal control subjects but almost identical to that of the depressed patients. Only three of the patients with panic disorder had abnormal DST results. These results indicate that patients with panic disorder have an abnormality of at least one function of the hypothalamic-pituitary-adrenal system which overlaps the abnormality in major depressive disorder.