J. Lieberman

Provocative tests with psychostimulant drugs in schizophrenia.

The psychotogenic effects of psychostimulant drugs have provided a major line of evidence in support of the DA hypothesis of schizophrenia. To evaluate the effects of psychostimulant (PS) drugs inschizophrenia and the clinical variables which may influence their expression, we reviewed 36 studies of PS drugs in patients with schizophrenia. Approximately 40% evidence a psychotogenic response to PS administration in doses that are subpsychotogenic in normals. Specific clinical variables appear to modify this response, including diagnosis, degree and type of psychopathology, stage of illness and pharmacologic status at the time of testing. Non-amphetamine-like PS drugs, e.g., methylphenidate, appear to have greater psychotogenic potency than amphetamine-like PS drugs. These results suggest the presence of a subgroup of schizophrenic patients who exhibit psychotic symptom activation with PS in a state dependent or independent fashion. This biologic phenomenon may be clinically exploitable and should be investigated further.

Clozapine response in treatment-refractory first-episode schizophrenia

We examined the response to clozapine in 10 schizophrenic patients who had been followed prospectively from the time of their first hospitalization and who were refractory to multiple clinical trials with typical neuroleptics

The dopamine-serotonin relationship in clozapine response

The effects of clozapine on the dopamine and serotonin systems may underlie its atypical pharmacologic and clinical profile. To examine this hypothesis, we measured dopamine and serotonin plasma and cerebrospinal (CSF) metabolites and the relationship of these values to treatment response in 19 neuroleptic refractory and intolerant schizophrenic patients. Only a small change in the CSF and plasma homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) levels was found. However, the pretreatment CSF HVA/5HIAA ratio and, to a lesser extent, the CSF HVA level predicted treatment response. These results suggest that the modest relationship between HVA and 5-HIAA and treatment response supports the involvement of both neurotransmitters in the pathophysiology of schizophrenia.

Incidence and correlates of tardive dyskinesia in first episode 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.

Brain morphometric comparison of first episode schizophrenia and temporal lobe epilepsy

BACKGROUND Converging evidence has suggested that the abnormalities in brain morphology observed in schizophrenia are similar to those seen in temporal lobe epilepsy (TLE). The purpose of this study was to compare the features of these groups directly with measures of the brain using magnetic resonance (MR) morphometry. METHOD Morphometric measures of ventricular and hippocampal volumes obtained from FLASH MR images were studied in 32 patients with first-episode schizophrenia (FES), 39 patients with TLE (21 left, 18 right), and 42 healthy controls. RESULTS Ventricular volumes in the FES and TLE groups were both significantly larger that those seen in controls and did not differ from each other. The FES group showed significantly larger temporal horns, while the TLE group had relatively larger frontal horns. Analyses of hippocampal volumes revealed a significant group by hemisphere effect. The FES group showed relative reductions in left hippocampal volume that were comparable only to TLE patients with seizures originating from the left hemisphere. CONCLUSION The results indicate that FES and TLE groups both show evidence of ventricular enlargement. Lateralised morphological abnormalities of the hippocampal formation in FES and left TLE are comparable, and may be specific to temporolimbic regions.

35. Neuropsychological prediction of functional outcome in first-episode schizophrenia

clinicalsymptomsof scbizophn-mia spectmmillness.The identificationof psychophysiologicrd measuresthatare moresensitiveto the subtlepsychopathologyof schizophrenia spectrumsubjectscouldprovide“target”intermediatephenotypesand thus add power to genetic linkageanalyses. Prepulaeinhibition(PPI)of thestartlereflex(SR)is anoperational rneaame of Serrsorim otorgating.Sehiz.ophmrric patientaaswell as individualswitb dizotypal personalitydisordershowreducedinhibitionof the SR when startlestimuliare precededby weakprestinndi.In addition,schizophrenic patientashow impairedhabituationof the SR, with a less than normal reductionof SRmagnitudeoverrepeatedpresentations of startlingstimuli. We hypothesizedthat relativesof schir.ophrerric patientswouldalso abow PPIdeficitsreflectingtrait-linkeddeficitsin centralinhibition. Weassessed 7 Wrizophrcnicprobands,21 of theirrelativesand 10normalcomparison subjectsin a startleparadigmthatprovidedmeasuresofPPIandhabituation of theSR.BoththeprobandsandtheirrelativeshadreducedPMat 30maw (effectsize = 2.0)and 120rnaec(effectsim = 0.8)interstimulus intervals. HabituationoftheSRbetweenthelirstandsecondblockofsfirnuli wasalso reducedin probands(15%,effect size=l.4) and relatives(33%,effect size=O.6)comparedtonormalswhohada47%reductioninSRmagnitude. ThesedatasuggestthatPPIandhabituationareusefulintermedr “atephen~ @s of schizophreniaspectrumillness with potentialutilityin genetic linkageanalyses.

Incidence and correlates of acute extrapyramidal symptoms in first episode schizophrenia

The incidence and correlates of extrapyramidal symptoms (EPS) in neuroleptic treatment of schizophrenic patients have been reported for chronic patients but not for first-episode patients. We examined the incidence and correlates of extrapyramidal symptoms in a cohort of 70 treatment-naive patients who received fluphenazine at 20-40 mg/day for the first 10 weeks of treatment. Thirty-four percent of our sample developed parkinsonism, 18 percent developed akathisia, and 36 percent developed dystonia. Acute EPS were associated with greater baseline psychopathology. Acute EPS were also associated with better treatment outcome in terms of time to and level of remission. These findings suggest that the EPS response of neuroleptic-naive patients may differ from that of chronically ill patients and that acute EPS status may be an indicator of pharmacologic responsivity in this group.

Delayed matching to sample in first episode schizophrenia

neurons in the rostral raphe cultures, but this was not statistically significant (maximal effect 15 %, p ~ 0.15). Preliminary studies of IL-6 reveal an enhancement of TH-positive neuron survival and no effect on 5-HT-positive neuronal survival. The opposing effects of IL-113 on the survival of fetal dopamine and serotonin neurons provide evidence that cytokines can influence neuronal development in a neuron-specific manner. These results also provide preliminary support for the hypothesis that cytokines may contribute to the altered neuronal development found in some forms of schizophrenia.