Steven B. Schwarzkopf

Cognitive impairment and cerebral structure by MRI in bipolar disorder

The distinction between bipolar disorder and schizophrenia customarily follows examination of the clinical symptomatology and course of illness. The presence of cognitive impairment has been held to be uncommon in bipolar disorder and more likely in schizophrenia. This study explored neuropsychological function in 30 ambulatory outpatients with a DSM-III-R diagnosis of bipolar affective disorder (all of whom had been psychotic during manic episodes), comparing their performance with that of controls. These bipolar patients proved to have significant levels of diffusely represented cognitive impairment when compared with controls. Further, the degree of impairment was significantly correlated with reduction in midsagittal areas of brain structures measured on magnetic resonance imaging scans. The implications of these findings in relation to bipolar disorder are discussed.

Stimulus configuration and context effects in perceptual organization in schizophrenia.

Two studies assessed perceptual organization in schizophrenia to determine (a) whether inpatient and outpatient groups with poor premorbid schizophrenia have comparable levels of perceptual organization deficit; and (b) whether the deficit could be eliminated by task manipulations. In Study 1, inpatients demonstrated clear evidence of a perceptual organization deficit, whereas outpatients performed similarly to the control groups. In Study 2, a performance pattern that operationally defined a perceptual organization deficit was eliminated by a task manipulation thought to aid in context processing. The perceptual organization deficit is most pronounced in actively symptomatic patients with poor premorbid schizophrenia, and the deficit reflects, in part, deficient top-down influences to basic perceptual processes.

Concurrent assessment of acoustic startle and auditory P50 evoked potential measures of sensory inhibition

The acoustic startle response (ASR) and midlatency auditory evoked potentials (AEP) have been utilized in the measurement of sensory inhibition. Using these different paradigms, abnormalities suggesting a lack of normal inhibition have been noted in a number of psychiatric syndromes. To date, the most commonly used sensory inhibition paradigms have not been studied in the same individuals, making generalizations across studies tenuous. In this report, reduction of ASR over multiple trials (habituation), prepulse inhibition (PPI) of ASR (decrease in ASR caused by low intensity prepulses) and P50 suppression (P50 AEP amplitude reduction in a paired-click paradigm) were measured in the same individuals. Relationships between these measures of acoustic startle and AEP inhibition were then assessed. Twenty subjects with no personal history of psychiatric disorder were tested and exhibited significant habituation and PPI of ASR as well as P50 suppression. Habituation of ASR was significantly and positively correlated with P50 suppression early, but not late, in AEP testing. Only a modest trend for a positive association between PPI and P50 suppression was noted. Habituation and PPI of startle were both highly correlated (positively) with P50 AEP amplitude. Habituation of startle remained significantly predictive of P50 suppression after controlling for P50 amplitude, whereas the modest association between PPI and P50 suppression was removed when P50 amplitude was factored out. Results indicate that habituation of acoustic startle, but not PPI, is highly associated with P50 suppression in control subjects. An unexpected finding was a robust positive correlation between P50 amplitude and both measures of startle inhibition. These findings and methodologic issues are discussed in terms of possible neural substrates involved in different measures of sensory inhibition.

The Mentally Ill in Jails and Prisons: Towards an Integrated Model of Prevention

Jails and prisons have become a final destination for persons with severe mental illness in America. Addiction, homelessness, and fragmentation of services have contributed to the problem, and have underscored the need for new models of service delivery. Project Link is a university-led consortium of five community agencies in Monroe County, New York that spans healthcare, social service and criminal justice systems. The program features a mobile treatment team with a forensic psychiatrist, a dual diagnosis treatment residence, and culturally competent staff. This paper discusses the importance of service integration in preventing jail and hospital recidivism, and describes steps that Project Link has taken towards integrating healthcare, criminal justice, and social services. Results from a preliminary evaluation suggest that Project Link may be effective in reducing recidivism and in improving community adjustment among severely mentally ill patients with histories of arrest and incarceration.

Neuropsychological deficit in schizophrenic subtypes: Paranoid, nonparanoid, and schizoaffective subgroups

Schizophrenic patients were carefully diagnosed and screened for a history of neurological disorders. Diagnosis and subtyping was based on DSM-III-R criteria, using the Structured Clinical Interview for DSM-III-R, which was administered by trained interviewers and confirmed by a research psychiatrist. The schizophrenic patients were compared with an age-matched control group on an extensive battery of neuropsychological measures. The undifferentiated/disorganized schizophrenic patients were consistently the most impaired on a broad range of tasks. When the effect of symptom severity and drug level were statistically controlled (analysis of covariance), however, the magnitude and number of differences were substantially reduced. The perseverative error score from the Wisconsin Card Sort Test showed the greatest difference between the groups. However, the strongest and most consistent effects were observed in relation to symptom ratings. These data indicate the importance of controlling for medication and symptom severity, and suggest that current diagnostic classifications may not be the most useful factors for studies of the cognitive correlates of schizophrenia.

Effects of haloperidol and SCH 23390 on acoustic startle and prepulse inhibition under basal and stimulated conditions

1. Adult Sprague-Dawley rats underwent startle testing for assessment of baseline startle amplitude and prepulse inhibition (PPI) of the startle reflex. 2. Animals were tested after administration of either: saline, a selective D1 dopamine (DA) receptor antagonist, a relatively selective D2 DA antagonist, or combined low dose D1 and D2 antagonists. 3. Changes due to antagonists were assessed with and without administration of the D1/D2 agonist apomorphine. 4. Testing without apomorphine stimulation showed that both D1 and D2 antagonists reduce baseline startle and enhance PPI. Further, the two antagonists exhibited a synergistic interaction. 5. Testing with apomorphine showed that D1 and D2 antagonists reduce apomorphine-induced startle enhancement. Again, the two exhibited a synergistic interaction. 6. For PPI, the D2 but not D1 antagonist reduced the apomorphine effect. However, the D1 antagonist potentiated the effect of the D2 antagonist.

Sensory gating in rats depleted of dopamine as neonates: potential relevance to findings in schizophrenic patients ☆

Based on a recent hypothesis of reduced subcortical dopaminergic tone, evidence of early neurodevelopmental deviation, and acoustic startle abnormalities in schizophrenia, we examined acoustic startle in adult animals depleted of dopamine (DA) as neonates. Male rat pups received intracerebroventricular injections of either 6-hydroxydopamine (6-OHDA, 100 micrograms) or its vehicle on postnatal day 3. At 60 days of age, baseline startle and prepulse inhibition (PPI) of startle were assessed in a no injection condition, with all other animals receiving injections of saline or the DA agonist, apomorphine. Acoustic startle was elicited using 120 db white noise bursts alone or preceded by prepulses of 75, 80, and 85 db. Animals treated with 6-OHDA exhibited a 93% depletion of striatal DA compared to vehicle-treated controls. Whereas DA depleted animals did not differ from controls in the no injection condition, they showed greater baseline startle and reduced PPI compared to controls after saline injections. Depleted animals also showed exaggerated responses to apomorphine, with greater increases in baseline startle, loss of habituation, and decreased PPI compared to controls. Findings indicate that neonatal DA depletions lead to increased baseline startle and impaired sensory gating in adulthood after saline injections and dopamine agonists compared to controls. These findings may be relevant to a subgroup of psychotic patients that exhibit similar startle abnormalities as well as signs of hypodopaminergic function.

Effects of the PCP analog dizocilpine on sensory gating : Potential relevance to clinical subtypes of schizophrenia

Prepulse inhibition (PPI) of the acoustic startle reflex, a measure of sensory gating, is reduced in schizophrenic patients. Dopamine agonists and NMDA receptor antagonists such as phencyclidine (PCP) can disrupt PPI in animals, consistent with both the dopamine and glutamate hypotheses of schizophrenia. In this study, we sought to further characterize the effects of the NMDA antagonist dizocilpine on acoustic startle modulation. Fischer 344 rats were tested after one of three doses of dizocilpine (0.05, 0.2, and 0.5 mg/kg) and assessed for PPI as well as for alterations in baseline startle and prepulse facilitation (PPF). Results showed complete disruption of PPI for each inhibitory trial type after 0.2 and 0.5 mg/kg of dizocilpine. Baseline startle and PPF were enhanced by the low dose but decreased with the moderate and high doses of dizocilpine. Although dizocilpine caused alterations in prepulse modulation of startle similar to dopamine agonists, some effects differ. Unique effects of dizocilpine on sensory gating are discussed in terms of their potential for discriminating subtypes of schizophrenic illness with different underlying pathophysiology.

Efficacy and Tolerability of Low-dose Donepezil in Schizophrenia

There have been many advancements in the pharmacologic treatment of schizophrenia; however, negative symptoms and cognitive impairment remain an intractable part of this illness. Donepezil is an anticholinesterase inhibitor with cognitive enhancing effects approved for the treatment of Alzheimer disease that has shown some benefit in the treatment of schizophrenia. In this study, 15 inpatients at a state hospital with a history of schizophrenia were administered donepezil in a randomized, double-blind, crossover design. Neurocognitive testing and psychiatric ratings were completed at baseline and at regular intervals for 18 weeks. Results indicated that donepezil treatment was associated with modest improvements in psychiatric symptoms and improved verbal learning. These results suggest that donepezil may be helpful as adjunctive therapy for the treatment of psychiatric symptoms and cognitive impairment in a subgroup of schizophrenic patients.

Family history and brain morphology in schizophrenia: An MRI study

This study examined neuroanatomical differences between male schizophrenic patients with a family history of psychosis (n = 16) and those without such a history (n = 15). Intracranial area, cerebral area, ventricular size, and cortical atrophy were assessed using magnetic resonance imaging (MRI). Third ventricular enlargement was more prevalent in patients than controls (n = 15). Familial and nonfamilial patients differed significantly. Reduced cranial and cerebral areas without ventricular enlargement characterized familial patients, whereas nonfamilial patients showed marked lateral ventricular enlargement without a reduction in cranial/cerebral size.