Subjective Experience and D2 Receptor Occupancy in Patients With Recent-Onset Schizophrenia Treated With Low-Dose Olanzapine or Haloperidol: A Randomized, Double-Blind Study
de Haan L, van Bruggen M, Lavalaye J, Booij J, Dingemans PMAJ and Linszen D;
Commented by , 24 Feb 2003
Aim of the study
The debate about optimal dosing of antipsychotic medication is still ongoing. The German psychiatrist Haase introduced the concept of the "neuroleptic threshold dose" already in the 1950s.
He postulated that a dose at which patients develop minimal extrapyramidal side effects is effective and that exceeding this dose would result in more extrapyramidal side effects but not in a better response.
According to functional brain imaging studies using PET and SPECT an optimal response to antipsychotic drugs can be achieved by a dopamine receptor occupancy level of approximately 70%.
The authors tested the hypothesis that there is a therapeutic window and that a dopamine D2 receptor occupancy level between 60% and 70% in patients with recent-onset schizophrenia would result in optimal subjective experience. In addition, they sought preliminary evidence on whether subjective experience is better with low-dose olanzapine than with low-dose haloperidol.
Method
24 subjects with recent onset schizophrenia according to DSM-IV criteria were included in the randomised, double-blind study and received either fixed doses of olanzapine, 7.5 mg/day, or haloperidol, 2.5 mg/day for six weeks.
The primary outcome parameter was the patients’ subjective experience as measured by the “Subjective Well-Being Under Neuroleptics Scale”. In addition psychopathology and extrapyramidal symptoms were assessed. D2 receptor occupancy was measured with [123I] iodobenzamide single photon emission computed tomography after 6 weeks.
Results
The baseline characteristics of the two studies were similar. After 6 weeks, patients receiving olanzapine had a significantly lower mean dopamine D2 receptor occupancy (51.0%, range=36%–67%) than those given haloperidol (65.5%, range=45%–75%).
A receptor occupancy between 60% and 70% was associated with optimal subjective experience, and subjective experience improved significantly in the haloperidol group. In terms of psychopathology, the Clinical Global Impression Scale improved significantly in both groups, but the PANSS did not.
Discussion
This study suggests that a level of D2 receptor occupancy between 60% and 70% is optimal for subjective experience of patients with recent-onset schizophrenia. Olanzapine, 7.5 mg/day, showed no superior subjective response over haloperidol, 2.5 mg/day.
The work from deHaan and colleagues is important for our understanding of the dosing of antipsychotic drugs. It suggests that if haloperidol is individually titrated in the very low dose range, it is possible to reach optimal receptor occupancy and effects similar to those of atypical antipsychotics.
However, there are several limitations: The olanzapine dose of 7.5 mg/day was on average too low to reach the optimum D2 receptor occupancy between 60% and 70%. Thus, using higher olanzapine doses the patients’ subjective experience might have been better. Furthermore, only the CGI, but not the PANSS improved significantly in both groups.
Since this might have been caused by the very small sample sizes and thus a lack of statistical power, the results require replication in larger groups of patients.