Concentration-Effect Relationships of Psychoactive Drugs and the Problem to Calculate Therapeutic Reference Ranges

Despite the obvious potential of Therapeutic Drug Monitoring (TDM) as a tool to optimize psychopharmacotherapy, especially treatment with mood-stabilizing, antidepressant and antipsychotic drugs, acceptance of TDM as a routine tool is still limited. A serious scientific argument against the regular use of TDM is the lack of evidence for a concentration-dependent clinical effect. The aim of this review was to highlight methodological problems leading to poor or even negative concentration-effect relationships and to show how therapeutically effective concentrations of psychoactive drugs can be determined using routine TDM databases.

Reports on concentration-effect relationships of psychoactive drugs were analyzed with regard to applied methods. From routine TDM databases of patients who had been treated with antidepressant or antipsychotic drugs and whose improvement was measured by the clinical global impressions scale, mean and median drug concentrations were calculated and compared with reference ranges recommended by TDM guidelines.

Few fixed-dose studies with adequate design and data analysis demonstrated a correlation between drug concentration and clinical effect for psychoactive drugs. Most studies, however, mostly retrospective analyses of TDM databases, failed to find significant concentration-effect relationships because of flexible dosing. They were not suitable for the determination of therapeutically effective drug concentrations. Using TDM databases of antidepressant and antipsychotic drug concentrations in blood of patients who were categorized as responders by the clinical global impressions score, the interquartile ranges of drug concentrations (25th-75th percent range) can be shown to be very close to the therapeutic reference ranges recommended in guidelines for TDM in psychiatry.

This review provides a discussion on why simple correlation analyses of psychoactive drug concentrations in blood and clinical effects are obsolete for flexible-dose studies or TDM databases. TDM databases, however, can and should be used to calculate drug concentrations in blood of patients who had responded to the drugs. Interquartile ranges can be regarded and used as preliminary therapeutic reference ranges.