Tricyclic Antidepressants (TCA's) are the cornerstone of treatment for patients with severe
Major Depressive Disorder (sMDD). Current dosing is guided by repeated measurements of blood
levels. Compared to patients with a normal metabolization function, for those with increased
CYP450 enzyme activity it takes longer to reach a therapeutic drug level. The consequent
delay of drug efficacy is associated with a prolonged treatment period, increased risk of
suicidal behaviour and eventually lower remission rates. For those with reduced CYP450
activity higher rates of side effects are expected. An innovative TCA dosing strategy, taking
the genetic variants of CYP2D6 and CYP2C19 into account may help to reduce the above
mentioned problems. Up till now, the current guidelines for CYP450 pharmacogenetics based TCA
dosing have not been systematically evaluated for effectiveness and cost-effectiveness in
larger groups of patients. Such evaluation is necessary before broad implementation of these
guidelines can be advocated. In the present study 200 patients with sMDD who are treated with
nortriptyline, clomipramine or imipramine are randomized over two strategies: dosing based
both on CYP450-genotype and blood level measurements and dosing as usual (standard doses plus
blood levels). We hypothesize that genotype informed dosing results in faster attainment of
therapeutic drug levels, lower rates of side effects, earlier symptom relief and lower levels
of health- and working related costs.
Phase:
Phase 4
Details
Lead Sponsor:
Radboud University
Collaborator:
ZonMw: The Netherlands Organisation for Health Research and Development