Time (Days)

Time (Days)

Drug Interactions. Fig. 2. Pharmacokinetic behavior of a drug before and after addition of an inhibitor and before and after dose reduction.

Clinical Evaluation of Drug Interactions

Information on the pharmacodynamic and pharmacokinetic profile of the combined drugs suggests possible interactions. Because of the understanding of the relevance of pharmacokinetic drug interactions during the last 15 years, it is today necessary that preclinical drug development include not only characterization of the phar-macodynamic profile of the drugs and its metabolites but also identification of the enzymes involved in the metabolism. Substrate and inhibitor properties of the drugs and the major metabolites must be clarified in the preclinical phase of drug development. Based on this knowledge, risks of concomitant use of co-medication can be defined. Because of possible risks due to pharmacodynamic or pharmacokinetic interactions, relevant co-medications are normally not allowed during the phases of clinical evaluation. Therefore, systematic clinical testing of drug combinations is rare or even lacking, and it is difficult or even impossible to evaluate the clinical relevance of combination treatments, especially the consideration of safety aspects. This information is normally raised when the drugs are used under naturalistic conditions. For this purpose, pharmacovigilance programs are most important (Grohmann et al. 2004). In the past, many interactions of psychoactive drugs were observed accidentally, especially pharmacokinetic interactions of TDM controls. An increasingly important help is the use of computer-based drug interaction programs (e.g., current/login.htm, druginterchecker,, http://www.mediq. ch/). Their quality has improved during the last years. However, only a few systems provide adequate information about the clinical effects of drug interactions or use medical advice.

Practical Issues

Combination treatment should be used as a last resort. One must be aware of drug-drug interactions. Computerized systems have shown that drug-drug interactions are among the most frequent alerts presented to clinicians writing medication orders (Paterno et al. 2009). The choice of particular drugs for individual patients requires a balancing of efficacy and side effects. This holds true for monotherapies and even more for polypharmacy. Risks of adverse effects increase under polypharmacy, and valid data on safety and efficiency of combinations are mostly lacking. Polypharmacy can be a validated or an empirical strategy. Whenever available, validated combinations should be used. When an empirical treatment lacking research-based evidence is used, objective symptom ratings should be applied to evaluate the result of the treatment.

Whenever a combination treatment is required, the following should be considered to make polypharmacy as effective and safe as possible:

• Combination therapies should be used only when preceding therapeutic trials with a single agent were of sufficient length, sufficient dose, and sufficient drug concentrations in blood.

• For most combination therapies, effectiveness or efficacy data are rare or even lacking.

• Combination therapies increase the risk of morbidity and mortality.

• Combination treatments must consider possible phar-macodynamic and pharmacokinetic interactions.

• Ineffective or minimally effective medications should be discontinued.

• Pharmacodynamic drug interactions require careful clinical supervision.

• Pharmacokinetic drug interactions should be controlled by determining drug concentrations in blood plasma or serum (TDM), especially for drugs with a narrow therapeutic range.

• To evaluate the results of a combination treatment, objective symptom ratings should be used.

• Computer programs should be used to check the medication orders to control for possible drug-drug interactions.


► Anticonvulsants


► Antipsychotic Drugs


► Monoamine Oxidase Inhibitors

► Pharmacokinetics

► SSRIs and Related Compounds


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