Seth Apter

Empirical assessment of the factorial structure of clinical symptoms in schizophrenia: Negative symptoms

The factor structure of the Scale for the Assessment of Negative Symptoms (SANS) was examined in a confirmatory factor analysis that used the LISREL procedure. Four models of negative symptom factors were tested in 130 hospitalized schizophrenic patients. A three-factor model of diminished expression, social dysfunction, and disorganization generated by the authors yielded a superior fit to the data relative to the two-factor model of Liddle (1987b) and a unifactorial severity model. A four-factor model based on the original subscale formulation of the SANS failed to fit the data.

Neuropsychological correlates of central monoamine function in chronic schizophrenia: relationship between CSF metabolites and cognitive function

Schizophrenia is associated with multiple cognitive deficits which in turn may be related to abnormal dopamine (DA) function. To examine possible associations between cognitive dysfunction and central DA activity in schizophrenia, neuropsychological measures (visuospatial and verbal recall; performance on the Wisconsin Card Sort Test (WCST); visuospatial perception) were examined in 17 drug-free male schizophrenic patients and related to cerebrospinal fluid concentrations of the metabolites of dopamine (homovanillic acid (HVA)), serotonin, and norepinephrine. CSF HVA concentrations were correlated with the ability to recall visuospatial information, with attention to verbal tasks, and with WCST performance (low CSF HVA concentrations predicting poor performance on these tests) but not with the ability to recall verbally presented material and visuospatial perception. These data are consistent with earlier results suggesting that (cortical) DA function is associated with recall and retrieval of visuospatial information and with WCST performance.

Serotonin function in schizophrenia: Effects of meta- chlorophenylpiperazine in schizophrenia patients and healthy subjects

This study examined serotonin (5-hydroxytryptamine; 5HT) receptor responsivity in 22 chronic schizophrenic patients and 17 healthy control subjects. The 5HT agonist meta-chlorophenylpiperazine (MCPP) was used as a probe of serotonergic function. MCPP (0.35 mg/kg) or placebo was administered orally after a 3-week drug-free period in a randomized double-blind design. Hormonal (adrenocorticotropic hormone and prolactin), temperature, and behavioral responses and MCPP blood levels were assessed for 210 minutes after administration of the capsules. The schizophrenic patients had blunted temperature responses compared with those of the healthy control subjects: MCPP raised body temperature in the control subjects, but not in the patients. Behavioral responses also differed in the two groups: MCPP increased the total Brief Psychiatric Rating Scale (BPRS) score in the control subjects and tended to decrease it in the patients. In patients, MCPP decreased the BPRS psychosis subscore. Hormonal responses did not differ significantly in the two groups. These findings suggest that further exploration of 5HT function in schizophrenia is warranted.

Treatment with clozapine and its effect on plasma homovanillic acid and norepinephrine concentrations in schizophrenia

Measurement of plasma concentrations of the dopamine metabolite, homovanillic acid (pHVA), is an indirect tool to assess changes in dopamine turnover. Levels of pHVA have been reported to decrease during treatment with conventional antidopaminergic, neuroleptics, with the decrement correlating with symptomatic improvement in schizophrenic symptoms. Clozapine, an atypical neuroleptic, is the only drug proved to be effective in treatment-refractory patients. However, the mechanism mediating this unique efficacy has not been fully elucidated. This study examined the effect of clozapine on pHVA concentrations in schizophrenic patients. Since clozapine potently binds to alpha 2-adrenergic receptors, plasma norepinephrine (pNE) concentrations were also measured. Twenty-eight treatment-refractory schizophrenic patients (24 men, 4 women) were treated with clozapine (up to 600 mg/day) for 5 weeks, after a minimum 1-week drug-free period. Symptomatology and pHVA and pNE concentrations were measured at the last drug-free day and weekly for 5 weeks. Fourteen patients responded to clozapine treatment, while an equal number did not. Mean pHVA concentrations did not significantly change during treatment with clozapine. Although clozapine tended to lower pHVA concentrations in treatment responders, the effect was small and not significant. Clozapine treatment significantly raised pNE concentrations, but this did not differentiate responders from nonresponders to clozapine. These findings suggest that clozapines effect on DA turnover is small and that clozapine may be effective in treatment-refractory schizophrenia by mechanisms other than, or in addition to, dopamine receptor blockade. However, since about one-third of NE is metabolized into HVA, the clozapine-induced increase in pNE may have overshadowed a possible lowering effect of clozapine on pHVA.

Early response to haloperidol treatment in chronic schizophrenia.

This study examined the time-course of treatment response to haloperidol in chronic schizophrenia. Furthermore the predictive value of baseline psychopathology and early therapeutic changes for the identification of the eventual treatment outcome was examined. After a two-week drug-free period forty-three chronic schizophrenic patients were treated with haloperidol for five weeks. Psychopathology was assessed on the last drug-free day and on the third and eighth day from the initiation of treatment, and then at weekly intervals. At the end of the study based on a priori criteria patients were classified as responders or non-responders to haloperidol. Seventeen patients met criteria for treatment response at the end of five weeks of treatment, while 26 did not. Already by the third day of treatment, in the responders there was a significant decrease in total BPRS and in the subscales scores for psychosis, tension and anergia, but not for hostility-suspiciousness and depression. These decreases represented approximately half of the eventual improvement obtained by the end of the study. Discriminant function analysis showed that severity of symptoms at baseline and improvement by day 3 correctly classified overall outcome in 72% of the cases.

Lateral ventricular enlargement in schizotypal personality disorder

Although an increase in the ratio of ventricular space to brain (ventricle-brain ratio), VBR) on computed tomography (CT) has been among the most robust findings in chronic schizophrenia, VBR has not been investigated in a large, well-characterized clinical population of patients with schizotypal personality disorder (SPD), a clinical entity with a phenomenologic, gentle biological, and treatment response relationship to chronic schizophrenia. Accordingly, CT scans were obtained in 36 male SPD patients, 23 males with other personality disorders, 133 male schizophrenic patients, and 42 male normal volunteers. The mean body of the lateral VBR was significantly greater in the SPD patients than in the patients with other personality disorders. The VBR of the SPD patients did not differ significantly from either that of the normal volunteers or the schizophrenic patients but was intermediate between the two groups. There were no correlations with either psychotic-like or deficit-related symptoms of SPD in either the SPD or total personality disorder cohorts. SPD patients, like schizophrenic patients, may have increased VBRs compared wit patients with other personality disorders; their VBRs fall between the means of schizophrenic patients and normal control subjects.

Increments in plasma homovanillic acid concentrations after neuroleptic discontinuation are associated with worsening of schizophrenic symptoms

1. Thirty-two male schizophrenic patients participated in this study. 2. Plasma concentrations of the dopamine metabolite, homovanillic acid (pHVA) were assessed once on neuroleptic medication and twice a week for a maximum of six weeks after its discontinuation. 3. Psychiatric symptomatology was assessed once on neuroleptic medication and once a week for a maximum of six weeks after its discontinuation, using the brief psychiatric rating scale (BPRS). 4. pHVA and total BPRS score increased significantly after discontinuation of neuroleptic as compared to baseline. 5. The magnitude of pHVA and BPRS increments after discontinuation of neuroleptic correlated significantly. 6. Results of this study suggest that worsening of schizophrenic symptoms after discontinuation of neuroleptic treatment is associated with increased pHVA concentrations.

Kraepelinian schizophrenia: A replication in an independent sample

Chronic, unremitting schizophrenic patients, who for the past 5 years had been either continuously hospitalized or completely dependent on others for their survival are designated Kraepelinians according to Emil Kraepelin’s description of dementia praecox. Previous studies from our center have demonstrated that Kraepelinian patients more consistently received a diagnosis of schizophrenia across a variety of cross-sectional and longitudinal diagnostic criteria and had more severe negative symptoms and formal thought disorder compared to a group of age-matched non-Kraepelinian chronic schizophrenic patients. In addition, Kraepelinian schizophrenics had a greater morbid risk for schizophrenia spectrum disorders in their first-degree relatives, had a greater left-to-right asymmetry of their lateral cerebral ventricles, and had less of a prospective response to a standard dose of haloperidol. On the other hand, the severity of positive symptoms did not distinguish Kraepelinian schizophrenics from other chronic schizophrenic patients. This study presents data on a completely independent sample of 22 Kraepelinian and 86 non-Kraepelinian schizophrenic patients. Initial data analyses suggest a replication of the findings reported on the original cohort. Kraepelinian patients had more severe negative symptoms (p < 0.002) and formal thought disorder (p c 0.001) than non-Kraepelinian chronic schizophrenic patients. The first degree relatives of Kraepelinian patients had a greater morbid risk for schizophrenia spectrum disorders than the relatives of other chronic schizophrenic patients (z = 3.3 1, p < 0.001). CT ventricular measures indicated a left frontal horn enlargement in Kraepelinian patients relative to nonKraepelinians (p < 0.05). These analyses provide independent confirmation that Kraepelinian schizophrenic patients, who require institutionalization or institution-like care, differ from other schizophrenic patients on measures of clinical presentation and family history, suggesting that these patients are a relatively homogenous subgroup of schizophrenics with very severe symptoms and uniformly poor outcomes.

Longitudinal classification in schizophrenia: The relationship between kraepelinian and deficit syndrome subtypologies

Kraepelinian schizophrenics are defined as a subgroup of schizophrenic patients who display at least five continuous years of complete dependence on others for food, shelter, and clothing. These patients have been empirically distinguished from nonkmepelinian schizophrenics in several areas of diagnostic validation. Kraepelinians demonstrate an absence of treatment response, greater CT vencicular abnormalities, more severe formal thought disorder and negative symptoms, less severe symptoms of mood disorder, and greater morbid risk for schizophrenia spectrum disorders in their first degree relatives. The deficit syndrome, as described by Carpenter et al (1987), is defined as the presence of enduring negative symptoms considered to be primary (ie., not secondary to such factors as depression, medication, etc.) and stable (i.e., present both during and between exacerbations of positive symptomatology for at least one year), it was the aim of the present study to assess the relationship between Kraepelinian status and the deficit syndrome, two longitudinal subtypologies of schizophrenia. The Schedule for the Deficit Syndrome was completed by 16 Kraepelinian and 31 nonkmepelinian schizophrenic patients, similar in terms of age, education, and duration of illness. Kraepelinian patients were significantly more likely to present with the deficit syndrome than were nonkraepelinian patients (chi-square 18.0, dfi, p -.0001). Every Kraepelinian patient met criteria for the deficit syndrome while only 35% of the nonkraepelinian patients (I I out of 31) exhibited the deficit syndrome. Of 27 total deficit patients, only 16 were Kraepelinian. Thus, there is substantial overlap between the Kraepelinian and the deficit syndrome subtypes, with the Kraepelinian subtype identifying a more restricted group of patients. 290. EMPIRICAL EVALUATION OF THE FACTORIAL STRUCTURE OF CLINICAL SYMPTOMS IN SCHIZOPHRENIA: IS THE PANSS A VALID SCALE?