Michael Sanfilipo

Impaired prepulse inhibition of acoustic startle in schizophrenia

BACKGROUND Schizophrenics show deficits in sensorimotor gating, as measured by prepulse inhibition of acoustic startle (PPI). The goal of this investigation is to further characterize PPI and habituation deficits in schizophrenia, and to examine whether differing subgroups of schizophrenics would show comparable PPI deficits. METHODS PPI was measured in 24 male schizophrenic subjects (9 acutely decompensated inpatients and 15 stable outpatients) and in 20 age-matched normal control subjects. Schizophrenic subjects were rated for positive and negative symptoms at the time of testing. RESULTS Schizophrenic subjects showed deficits in prepulse inhibition and habituation as compared to normal subjects. Similar latency facilitation was produced by the prepulse in both groups. Acutely decompensated inpatients and stable outpatients did not differ in percent PPI. PPI did not correlate with severity of positive or negative symptoms. CONCLUSIONS These results suggest that schizophrenic subjects have impaired central inhibitory mechanisms as measured by PPI, and support the hypothesis that periods of relative clinical remission are not accompanied by normalization of sensorimotor gating.

Importance of pharmacologic control in PET studies: Effects of thiothixene and haloperidol on cerebral glucose utilization in chronic schizophrenia

This study compares the effects of two neuroleptic drugs with different pharmacologic characteristics (thiothixene and haloperidol) on cerebral glucose utilization in chronic schizophrenic inpatients. Positron emission tomographic (PET) scans were obtained from all subjects in a neuroleptic-free condition and again after 4-6 weeks of neuroleptic treatment. Eight subjects were treated with thiothixene and 12 with haloperidol. Thiothixene and haloperidol had different metabolic effects. For example, all thiothixene-treated subjects showed increased whole brain glucose utilization; all but one haloperidol-treated subject showed decreased utilization. Different patterns of relative prefrontal and striatal metabolism were also observed. These results highlight the importance of controlling for the effects of neuroleptic treatment and indicate the difficulty of interpreting data from studies with complex or poorly defined drug regimens.

Sociotropy and autonomy: Relationship to antidepressant drug treatment response and endogenous-nonendogenous dichotomy.

This study evaluated the relationship of sociotropic and autonomous personality traits with response to pharmacotherapy for 217 depressed outpatients using the Sociotropy-Autonomy Scale. Sociotropy was related to nonendogenous depression, whereas autonomy was related to endogenous depression. Subjects who had high autonomous-low sociotropic traits showed greater response to antidepressants (and greater drug-placebo differences) than those who had high sociotropic-low autonomous traits (who showed no drug-placebo differences). Hierarchical multiple regression analysis showed that the sociotropy-autonomy, but not the endogenous-nonendogenous, distinction was a predictor of drug treatment response. The combination of endogeneity and autonomy predicted response to placebo. If replicated, these findings may enable better matching of patient traits to various treatment modalities for depression.

Acute d-amphetamine challenge in schizophrenia: Effects on cerebral glucose utilization and clinical symptomatology

The effects of d-amphetamine (0.5 mg/kg orally) on regional cerebral glucose utilization were measured with positron emission tomography (PET) in 17 schizophrenics (along with a placebo-control group of an additional six schizophrenic patients). The acute d-amphetamine challenge tended to decrease glucose utilization throughout much of the brain, with a regional effect that was statistically significant in the left temporal cortex. There was no apparent relationship between the effects of amphetamine-induced changes in regional cerebral metabolism and psychotic symptom exacerbation. An exploratory analysis suggested that features characteristic of Crows type II syndrome were significant predictors of cerebral hyporesponsivity to stimulant challenge, however.

Relation of neurological soft signs to psychiatric symptoms in schizophrenia

INTRODUCTION Although several studies have identified abnormal rates of neurological soft signs (NSS) as a manifestation of CNS dysfunction in schizophrenia, differences in sample populations have contributed to a discrepancy in empirical findings. Furthermore, little is known about the potential of NSS to predict a clinical response to antipsychotic medications. The present study tests the associations between NSS and schizophrenia symptomatology and examines NSS as a potential marker for predicting treatment response. METHODS Nineteen unmedicated male schizophrenia patients were treated prospectively with haloperidol for six weeks. The subjects were assessed for pre and post-treatment NSS and schizophrenia symptomatology (Brief Psychiatric Rating Scale, BPRS). RESULTS NSS at baseline were significantly associated with baseline symptoms on the Positive, Negative, and Psychological Discomfort BPRS subscales. NSS showed a strong trend toward improvement during six weeks of a prospective haloperidol trial. Hierarchical linear regression analyses indicated that more severe baseline NSS predicted poorer response to haloperidol treatment as measured by post-treatment BPRS Total subscale scores. DISCUSSION NSS at untreated baseline are associated with baseline symptom severity, and elevated NSS are predictive of a smaller degree of improvement in symptoms after antipsychotic treatment. These findings are consistent with the hypothesis that NSS are linked to the neuropathology that underlies schizophrenia symptomatology and course.

Akathisia and exacerbation of psychopathology: a preliminary report.

Akathisia has previously been reported to exacerbate psychopathology and to be associated with noncompliance, suicidality, and violence. One previous study found brisk decrements in psychopathology after acute treatment of akathisia with intramuscular biperiden. This study assessed changes in akathisia and psychopathology in 19 patients after separate one-day treatments with intramuscular benztropine and oral propranolol. Benztropine and propranolol led to clinically meaningful and statistically significant decrements in ratings of subjective and objective measures of akathisia and in psychopathology scores. Changes in psychopathology correlated significantly with changes in subjective measures of akathisia after benztropine and with subjective and objective measures of akathisia after propranolol. Changes in akathisia accounted for 9%–42% of the variance in changes in psychopathology. After treatment, statistically significant decrements in Brief Psychiatric Rating Scale (BPRS) positive symptoms were noted, and individual items not directly related to the akathisia syndrome, such as conceptual disorganization, hallucinatory behavior, and unusual thought content declined, although not significantly. These findings, taken together with the results of a similar previous study, indicate that the effect of akathisia in exacerbating psychopathology is large. If suspected, akathisia should be treated promptly.

Cardiovascular effects of 0.5 milligrams per kilogram oral d-amphetamine and possible attenuation by haloperidol.

In a series of earlier studies, an oral dose of 0.5 mg/kg d-amphetamine was administered to 81 patients with schizophrenia and eight normal control subjects. Seven more subjects with schizophrenia received placebo. Blood pressure and pulse rate were monitored before and 3 hours after drug administration. Blood pressure increased in both amphetamine groups, whereas placebo had no effect. However, pulse rate did not change in the schizophrenic group and only increased after 3 hours in normal control subjects as blood pressure began to decrease. Significant negative correlations between systolic blood pressure and pulse rate occurred at 2 and 3 hours, suggesting that the early cardiovascular response to amphetamine is an increase in blood pressure that recruits reflex control of heart rate. Eighteen of these subjects had hypertensive responses. Six subjects received 5 mg haloperidol intramuscularly, and 12 others had their blood pressure monitored until normalization. Haloperidol led to a more rapid decline of some but not all indices of blood pressure, suggesting that amphetamine-induced hypertension may have a dopaminergic component.

Intersubject coregistration of brain images: a phantom study

Inter-subject coregistration is a powerful neuroimaging technique that enables comparison and detection of morphological differences across groups of subjects. The present study uses digital phantoms to evaluate errors in two widely employed approaches to inter-subject coregistration of structural MR images of the brain: the manual step-wise approach and the automated method provided with the software package SPM96. Phantoms were constructed by deforming a high resolution T1-weighted MR image in which we have embedded 12 landmarks. For the manual method the accuracy ranged from 0.8 mm in quadrigeminal plate to 2.4 mm in superior central sulcus and occipital lobe. The average error was 1.5 mm. For the automated SPM96 method and the 9 parameter model, the accuracy ranged from 0.8 mm to 2.1 mm and averaged 1.1 mm. Error of the manual method correlated strongly with the distance from the center of the image (r equals 0.77, slope equals .020, p equals .003). The linear correlation of the error obtained with the automated method with the distance was poor (r equals 0.39, slope equals .008, p > 0.2). The results suggest that the inferior performance of the manual method is due to its step-wise approach and to a relatively large rotational error.