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Although there is sufficient evidence for the benefits of therapeutic drug monitoring (TDM) in optimizing antidepressant therapy, its widespread use in routine care is far from optimal. In clinical practice, in antidepressant drug dose optimization is often guided by a trial-and-error dose titration strategy. The importance of therapeutic drug monitoring of SSRIs is the subject of controversial discussion. However, TDM offers information about drug interactions, insufficient therapeutic effect, side effects, compliance and overdose. Genetic inşuences on metabolism are most salient for antidepressants that have a low therapeutic index. TDM has been reported to increase not only efficacy and safety of antidepressant treatment, but also cost-effectiveness. Tricyclic antidepressant (TCAD) use in the treatment of depression is limited by their greater risk of overdose, potential effects on cardiac conduction. TCAD’s may lead to toxic plasma levels producing anticholinergic, cardiac, and CNS effects. The toxic levels of most TCAD’s are only two times therapeutic levels. Although the SSRI have a broad therapeutic index so that most patients are able to tolerate wide şuctuations in plasma levels due to pharmacokinetic interactions and can inşuence toxicity of co-administered drugs that are metabolized via this system. The SSRIs are the most commonly prescribed antidepressants. They are generally well tolerated but have sexual adverse effects, increase the risk of hyponatremia, bleeding, stroke, and death in the elderly. All of the SSRIs are primarily eliminated by cytochrome P450 catalyzed oxidation in the liver. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, şuvoxamine markedly inhibits CYP1A2 and CYP2C19. For this reason, clinically relevant interactions may be expected when these antidepressants are co-administered with substrates of the pertinent forms, particularly those with a narrow therapeutic index. Duloxetine and bupropion are inhibitors of CYP2D6. Both the practitioner and the patient need to be aware of the potential risks of using a combination strategy and should set up an active monitoring system, which may include service of TDM. TDM group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) has published literature-based guidelines for optimal use of TDM in psychiatry. AGNP recommends regular monitoring of plasma concentrations under maintenance therapy, at least every 3-6 months, to prevent relapses and rehospitalizations. The frequency of TDM requests may be increased if patients are known to be non-adherent to the medication or in case of changes of co-medications or of smoking (CYP1A2 substrate such as duloxetine) that affect the pharmacokinetics of the drug. Combining antidepressants is a recognized step for those failing to respond to monotherapy. Despite the limited evidence base, this strategy is widely used by clinicians in practice. Not every combination used clinically is safe, and the use of such combinations may increase the side-effect burden without any additional advantage to the patient.