A. Koreen

Incidence and correlates of tardive dyskinesia in first episode schizophrenia

BACKGROUNDnThere 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.nnnMETHODSnWe 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.nnnRESULTSnThe 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).nnnCONCLUSIONnPoor 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.

Biological Predictors of Antipsychotic Treatment Response

Schizophrenia is a heterogeneous disorder with variable symptomatology, course, treatment response, and outcome. Widely variable responses to antipsychotic medication in turn influence patients’ course of illness and outcome. Despite substantial research efforts attempting to separate patients into meaningful phenomenologic or biological subtypes that correspond to illness course and outcome, no such subtypes have been firmly established. So far, we have no reliable biological markers or predictors of treatment response. Clearly, given the recent pressure to decrease inpatient lengths of stay, any predictors of outcome are not only of clinical but also of economic importance. Clinically, such predictors might afford clinicians with the knowledge of which antipsychotics to use (i.e., typical vs atypical), which dose may be most beneficial, and which patient may be the one who may be withdrawn successfully from medication.

Differential effects of typical and atypical antipsychotic medication on plasma prolactin levels

100. DIFFERENTIAL EFFECTS OF TYPICAL AND ATYPICAL ANTIPSYCHOTIC MEDICATION ON PLASMA PROLACTIN LEVELS H. LeeI, lA. Lieberman I, B. Sheitman I, A.R. Koreen, M. Kroenig, A. Mendelowitz, D. Umbricht, J.M.J. Alvir, & T. Cooper DlOL rSYCIIIATRY 1996:39:500-666 102. THE RELATIONSHIP BETWEEN CLOZAPINE DOSE AND PLASMA LEVEL AND SIDE EFFECTS A.H. Kalali I , R. Bera, B. Gulasekararrr, S. Hayes, Y. Jin, J. Costa, J. Oldroyd, T. Cooper, & S.G. Potkin l 529 Hillside Hospital. Long Island Jewish Medical Center, 75-59 263rd St. Glen Oaks. NY 11004; 2Nathan Klein Research Facility. Orangeburg. NY Previous studies have found that prolactin levels are elevated following treatment with typical antipsychotic rncdlcation (Meltzer et al 1978). but are not significanlly elevated witb clozapine (l.leberman ct al 1986). Animal studies suggest that the putative atypical agent rispcrldone produces u more marked increase in prolactin level than an equivalent dosase of a typlcal agent (Bowden ct al 1992). Thepurpose of thisstudy was to examine the differences in prolactin response following treatment with fluphenazine, rispcridone and clozaplne in a group of treatment naive patients in theirfirsl episode of psychosis. Forty-nine patients who mel DSM-IIl-R criteria for schizophrenia (n=30) or schlzosffective disorder (n= 19)were entered intothestudy. Twenty-four patients (15M. 9F) were treated with nllphenazine (5-20 mglday}, 14 patients (GM, SF) with clozapine (titrated to ISO mglday by day 9) and [I (SM.6F) with rispcridone (6 mslday by dlly 3). Blood wasdrawn for plasma prolactin assay at baseline, weeks I, 2,3, 4.5. 6, and 8 of treatment. Results will be presented and the relevance of risperldones S-HT2Idopamine D2 antagonist profile will be discussed, 101. Pl3EDICTING CLINICAL RESPONSE TO CLOZAPINE TREATMENT BY PLASMA LEVEL R. BeraI, A.H. Kalali l , B. Gulasekaram, S. Hnyes, Y. Jin, J. Costa, J. Oldroyd, T. Cooper, & S.O. Perkin lDepartmenl of Psychiatry and Human Behavior, University of California Irvine Medical Center, Orange. CA 92668; 2Melropolillln Stale Hospital. Norwalk. CA; :lThc Nathan S, Kline Institute for Psychiatric Research. Orangeburg, NY Therelationship between plasma levcl ofclozaplne lind clinical response, and whether an increase in plasma level in non-responders would enhance the response rate was examined. Fifty-eight treatment resistant schizophrenic patients completed a 12 week fixed-dose, double blind mal. Steady-state plasma clozaplne concentratlons varied more than 4S fold aner Iixed-dcsc treatment (400 mglda)·). Discriminant function analysis determined that n plasma revet of 420 nglmL optimally distinguished responders from non-responders. At week 4 only 8% of those patients witha plasma level below 420 nglmL responded compared with 60% of those who had a plasma level above 420 nglmL. When plasma levels were Increased above 420 nglmL (by II double-blind random assignment procedure), non-responders increased their response rate to 73% if theirplasma levelexceeded 420 nglmL ttt week 12. compared to 29% if week 12 levels remained below 420 nglmL (p<O,04). Dcpanment of Psychiatry and Human Behavior. University of California Irvine Medical Center. Orange, CA 92668: ~Metropolilan Stale Hospital, Norwalk, CA; Jorhe Nathan S. Kline lnsthute for Psychiatric Research. Orangeburg. NY Previous work has shown that monitoring clozaplne plasma levels may help predict clinical response in treatment resistant schizophrenics, and thai a threshold level exists above which clinical response rate increases, However there have beenConcerns that increasing lbe clozaplne dose to achieve a higher plasma level may lead to higher rates of motor symptoms, or olher side effects associated wilh neuroleptic use. In our study, 58 treatment resistant schizophrenic patients wereentered into a fixed-dose, double blind trial. Al week 4 halfof ihepatients were treated with 400 mg and half with800 mg. Therewas tlO difference in motor or othersideeffects between thetwogroups at week4 and<It week 12. Two patients developed seizures during tile initlnl tltnuion at oraldoses of 200 mg a day. Furthermore, there was no relationship between side effecls and clozaplne plasma concentration, 103. DOSE~RELATED EFFECTS OF CLOZAPINE ON TARDIVE DYSKINESIA AMONG TREATMENT~REFRACTORY PATIENTS WITH SCHIZOPHRENIA C. Nair, G. Abraham, J. de Leon, J.K. Stanilla, R.C. Josiassen, & G. Simpson Medical College or Pennsylvania/Norristown Stnte Hospital Ctlnlcal kesearch Center, Norristown, PA 19401 Clczaplne has been reported to improve tardive dyskinesia (Simpson 1978). 23 OSM-IIIR ueannent-refractory schizophrenics (mean age 46:8.5 years) received 100,300.and600 mgsofclozaplnc (ClZ) for 16 weeks each in a double-blind randomized cross-over design. Patients were evaluated on il weekly basis across II naturalistic baseline (Bt) of 4 weeks; haloperidol (HLP) IOmg for4 weeks and3 eLZ phasd: Arter 16 weeks on the initial elZ dose. palienls were randomly crossed over 10 theother two doses for 4 months each. Abbreviated Dyskinesia Rating Scale (ADRS) ralings were done weekly during naturalistic baseline, HLP, and the first CLZ dose phase, Thcrenrter, monthly ratlngs were dam: in the Iwo subsequent crossover phases, Mean ADRS Total Scores were: BL= 23.2±S.4; HLP= 26.2±6.7; loomg ClZ 26)::!: 10.5; 300mg CLZ= 23.4±8.8; 600mg CLZ= 21.7±6.5. Thc Total ADRS scores at 600mg elZ dose was slgnificantly lower when compared to HLP (p<0.03) and loomgeLZ (p<O,OO4). Patients werecategorized at baseline into those with TO (14123) and without TD (9/23) (Kline lind Schooler criteria). Across the study phasespatients with TO, did best on 600mgCLZ, MeanADRS Total SCOfcS in those withTD were: Bt.;;;; 26.4::4.3; HLP 29.1 ::6.4; lOOmgClZ= 29,6± 11 .7: 300mg CLZ;::z 26.4±9.9 aml600mgelZ 23.7::!:7.4. This subgroup. when on 600mg eLZ differed signilicilnlly from BL (p<.OJ) nnd 100 mg elZ

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.

Behavioural effects of IV MCPP in schizophrenia

The effect of the serotonergic system on psychotic behaviour and sehizophrenia has been recently studied. Meta-chlorophenylpiperazine (MCPP) is a direct-acting 5HT receptor agonist which has been shown to have both neurochemical and behavioural effects in schizophrenic subjects. In this study, we report the behavioural effect of I.V. MCPP administration in a cohort of new-onset and chronic schizophrenics. clozapine trial. Patients were rated for the presence of psychopathological and tardive dyskinesia at regular intervals. Plasma and cerebrospinal fluid homovanillic acid (pHVA, CSF HVA) and cerebrospinal 5hydroxyindoleacetic acid (CSF SHIAA) levels were collected at baseline and treatment week 3. Data from 19 DSM III schizophrenic and schizoaffective disorder patients were examined. The sample was 68% male, 88% treatment refractory, 53% had tardive dyskinesia and the mean age was 29.5k6.3 years. Dividing the sample into clozapine responders vs nonresponders showed that the responders had both a lower baseline CSF HVA levels (pc.08) and a CSF HVA/SHIAA ratio (pi.04). Plasma HVA levels were not associated with CSF HVA values but with CSF SHIAA levels.