Levomepromazine versus chlorpromazine in treatment-resistant schizophrenia: a double-blind randomized trial

Objective: We compared the effect of levomepromazine (LMP) with chlorpromazine (CPZ) in treatment-resistant schizophrenia (TRS). Methods: We carried out a double-blind, parallel group study (n = 19/arm) with balanced randomization in blocks of 4 and stratification by sex. Subjects entered a 30-week trial, of which phases I-III were open: phase I (wk 0-6) baseline; phase II (wk 7-9) stepwise transition to haloperidol (HAL), 30 mg/d, plus benztropine (BT), 4 mg/d; phase III (wk 10-15) HAL, 40-60 mg/d, plus BT, 4-6 mg/d; phase IV (wk 16-20) stepwise transition to LMP or CPZ (500 mg/d) following randomization; phase V (wk 21-28) stepwise increase of LMP or CPZ (600-1000 mg/d, dose reduction permitted) to establish optimum dose; and phase VI (wk 29-30) optimized dose maintained. Criteria for TRS were based on those established by Kane et al in 1988. The criterion for a response to treatment was a reduction of 25% or more in total Brief Psychiatric Rating Scale score. Results: Both LMP (p = 0.007) and CPZ (p = 0.030) improved TRS relative to baseline. Although there was no significant difference between the 2 groups in treatment response at study end point, hierarchical linear modelling of longitudinal outcome revealed a significant (p = 0.006) advantage of LMP over CPZ for the BPRS total score. Ten of 19 participants on LMP and 8 of 19 on CPZ met the criterion for treatment response, and 9 of the 18 responders did so on 200-700 mg/d phenothiazine. The mean dose of responders was 710 (standard deviation [SD] 265) mg/d (LMP) and 722 (SD 272) mg/d (CPZ). Akathisia was associated with a nonresponse to phenothiazines ( p= 0.010). BPRS scores increased significantly on HAL (p = 0.006). Two of 19 participants on LMP and 5 of 19 on CPZ withdrew early from the study. Conclusion: LMP and CPZ may be useful in the management of TRS. A modest advantage of LMP compared with CPZ was seen in longitudinal analysis. High doses of neuroleptics may contribute to TRS; reduction of neuroleptics to modest or moderate doses should be considered before categorizing a patient as treatment resistant.