Dose-effect relationships for antidepressants

Abstract

Dose-effect studies provide, for groups of patients, information on the probability of therapeutic response and tolerability problems (non tolerability) for different doses and varying duration of therapy.

By such studies it thus may be possible to describe the inter-patient variability in intended and unintended effects and therapeutic range or index of the compound examined.

In several reviews and studies on different types of antidepressants it has been concluded that a dose with optimal balance between intended and unintended effects cannot be indicated, since the dose-effect curves for antidepressant effect and adverse reactions are flat and overlapping. (Gram, NEJM, 1994, 331: 1354, Bollini & al. BJP,1999, 174: 297, DUAG-4, CPT 1999, 66: 152).

For TCA such as clomipramine dose-dependant kinetics and genetic polymorphisms are important. However, for clomipramine the concentration-effect relationship was not better than the dose-effect relationship, suggesting that the variation in dose-effect is as much related to other factors than kinetic variability.

Data on clomipramine (DUAG-4, 1999) suggested that higher doses, not only are more effective, but also is associated with faster response. Indeed higher doses are also associated with more frequent tolerability problems causing drop-out. Clinical dosing should be based on a judgment of the patient's need for rapid effective cure, against the importance of good tolerability.