The utilization of drug plasma levels to effect optimal clinical response and to minimize side or toxic effects is standard practice in general medicine (e.g.. phenytoin, digoxin) and psychiatry (e.g., lithium, carbamazepine). Unfortunately, for a number of methodological and clinical reasons, we have not achieved similar success with the monitoring of neuroleptic steady state plasma concentrations. The existing data supports the possibility of either a linear or curvilinear studies keep patients on fixed doses of drug for a predetermined period after which clinical response is determined and then correlated with the concentration of the drug and/or all active metabolites in plasma. To our knowledge, there are no targeted haloperidol plasma level studies in the literature, although one with a different design is in progress. In addition, little is known about the relationship between the neuroleptic plasma level/clinical response relationship and alterations in DA function. However, there is evidence that HVA (the major DA metabolite) is a useful marker of pharmacologically induced DA turnover. Recent animal data shows that pharmacologically induced changes in brain HVA parallels changes in plasma HVA. Finally, Pickar et al (1986) and Davis et al (1985) suggest that plasma HVA is associated with psychotic symptoms less than in humans. We propose to use the existing data in the haloperidol (HPDL) literature to designate low less than ng/ml), medium (>5: less than ng/ml) plasma level categories. Patients will then be randomly assigned to one of these categories and dose adjusted to achieve the desired (or targeted) plasma level. Response will then be determined and reassignment (to alternate plasma level categories) will occur in half the non-responders for a second treatment period. It is our prediction that patients originally assigned or subsequently reassigned to the medium plasma level categories. Alternately, if there is a minimal threshold level for response (e.g., a linear response), those assigned to either the medium or high categories will show a higher response rate than those in the low group. All initial responders and half of the initial nonresponders (i.e., 80% of the entire sample) will remain in their original plasma level groups as controls for time on treatment. We will measure changes in plasma HVA concentration as they parallel changes in the HPDL plasma concentration/clinical response relationship. Since plasma HVA may parallel changes in psychotic symptoms, the concomitant measurement of this metabolite along with the plasma HPDL level and clinical response may enable us to address whether DA turnover relates to clinical improvement and HPDL plasma levels.
| Janicak, P G (1993) The relevance of clinical pharmacokinetics and therapeutic drug monitoring: anticonvulsant mood stabilizers and antipsychotics. J Clin Psychiatry 54 Suppl:35-41;discussion 55-6 |
| Javaid, J I; Janicak, P G; Hedeker, D et al. (1991) Steady-state plasma level prediction for haloperidol from a single test dose. Psychopharmacol Bull 27:83-8 |
