Safety of psychotropic medicines: contribution from observational evidence

The risks associated with psychotropic drugs use should be accurately documented at the population level in view of the growing number of persons exposed to these drugs. The strengths of observational studies regarding the identification of drug-related harms mirror the limitations of randomised controlled trials and vice-versa. Observational studies can be carried out in large samples of unselected participants treated in real-life conditions and who may be followed up over long periods. Serious adverse effects undetected during pre-marketing clinical trials may be observed only in post-marketing use, such as metabolic effects of second-generation antipsychotics. Observational studies play a key role in the identification of teratogenic risks, such as those induced by prenatal exposure to anticonvulsants. These studies are the main source of information to investigate the long-term effects of drugs, such as the possible increased risk of dementia in benzodiazepine users. They may also contribute to the accurate assessment at population level of risks overestimated by studies carried out in non-representative samples, such as the risk of congenital heart diseases in babies prenatally exposed to lithium. Owing to the lack of random allocation of drugs, confounding by indication or by disease severity are the major sources of biases in observational studies exploring drug safety. An adverse outcome may be wrongly imputed to drug exposure while it is a symptom/outcome of the disease motivating the decision to prescribe. Such a bias may occur in studies investigating the link between exposure to antidepressants and suicidality. As several methods have been developed to lessen the impact of such biases, pharmaco-epidemiological studies based upon stringent methodological designs should be regarded as a valid approach for assessing psychotropic drug safety.