Predicting Patterns of Clozapine Response in a Group of Chronic State Hospital Schizophrenics

Abstract

Reports estimate that 30-60% of treatment refractory schizophrenics show at least a 20% decrease in BPRS when treated with clozapine. We assessed 14 schizophrenics refractory to traditional neuroleptics with MRI to determine whether brain morphology predicts the pattern of clinical response to clozapine after 2, 6 and 12 weeks. Baseline assessment revealed this sample of severely impaired schizophrenics (mean BPRS total=63, SD=10; mean preclozapine standard neuroleptic dose=2009 CPZ mg equiv./day and mean 12 week cloz dose=644 mg/day), relative to healthy controls, had reductions of cortical gray matter volume (mean head size- and age-corrected z-score=−1.55) and increases in cortical sulcal (mean z=.653) and ventricular CSF volume (mean z= 1.50); those patients with the highest BPRS total (BPRS tot) and positive symptoms (BPRS pos) tended to have less cortical gray matter volume in the frontal and temporal but not parietal regions (p≤.05), while patients with more negative symptoms (BPRS neg) tended to have smaller lateral ventricular volumes (p≤.05). Significant improvement occurred in BPRS pos at 6 weeks (p≤.05) and in BPRS tot at 12 weeks (p<. 05); paired t-tests for all other BPRS change scores were n.s.. A lower than expected % of subjects achieved a 20% improvement at each time period (0 % at 2 wks, 7 % at 6wks and 14 % at 12 weeks). A cluster analysis of BPRS tot change scores across time periods revealed 3 distinct response patterns: early responders (ER; n=5) improved by 2 weeks, delayed responders (DR, n=5) improved by 6 weeks, and non-responders (NR; n=4) did not improve after 12 weeks. To determine whether these response patterns could be predicted from baseline brain morphology and clinical status, the three groups were compared using non-parametric tests. The ER had significantly less cortical gray matter volume in anterior and temporal regions and more third ventricular CSF volume than either the DR or NR., but DR and NR did not significantly differ. The NR had significantly lower baseline BPRS pos and BPRS tot scores than the DR and the ER; the latter two groups did not statistically differ. In conclusion, the ER had the greatest brain volume deficits and the most severe clinical symptoms at baseline, whereas the NR showed the opposite pattern; the DR showed a mixed pattern, with smaller brain volume deficits but more severe symptoms.