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, with genotypes associated with deviant CYP450 metabolizer status are randomized over two strategies: dosing based both on CYP450-genotype and blood level measurements and dosing as usual (standard doses plus blood levels). A third arm of 100 patients with normal CYP450-activity serves as a reference group (standard dosing and blood levels). We hypothesize that for patients with genotypes reflecting deviant CYP450 enzyme activity, 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.