Antidepressants and the developing nervous system


For anyone interested in the philosophy of risk–benefit analysis, a two-part paper in this issue makes stimulating reading [1, 2]. The authors describe an effect of antidepressants on fetal neuronal development. Maternal exposure to both tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) during pregnancy was associated with a 10-fold increase in laxative use in children. The findings illustrate how safety issues can remain undetected late in the life cycle of a drug, despite millions of patients being exposed for decades.

Clinical pharmacology research, as with any science, needs to define questions that summarize the hypotheses to be tested. The efficacy of medicines can be defined by questions that are easy to formulate and are addressed by clinical trials. Even so, the efficacy of antidepressant medication is contentious, given the high placebo response, failure to prevent suicide and selective reporting of results [3, 4].

For safety issues, the key questions are usually not known until the data are collected. With myriad potential safety questions, it is important that all the available basic pharmacology is reviewed and that this knowledge is used to direct a search for specific clinical safety signals. The Groningen group have adopted this approach with a detailed literature review to form a hypothesis that maternal antidepressant use might influence fetal enteric nervous system development [1]. In a second study, they use epidemiology to assess paediatric laxative use as a potential marker of a specific teratogenic signal associated with the maternal use of antidepressants [2]. The starting point for this work was the linking of a small signal of infantile hypertrophic pyloric stenosis cases to the maternal use of fluoxetine in a northern Netherlands birth defect registry. This association is rational, because fluoxetine crosses the blood–brain barrier and serotonin contributes to the development of enteric neurons. A serotonin-based mechanism could also explain an increased use of laxatives by the children of mothers who had taken an SSRI.

When a drug first comes to market, the assessment of the risk-to-benefit ratio is an educated guess. Efficacy can be defined by objective clinical trials, where predefined end-points are quantified. That the efficacy data are invariably adequate at the time of marketing is supported by the rarity of withdrawals of medicines because of later proof of a lack of efficacy. But safety cannot usually be quantified objectively; thus, many parameters might show a signal which can neither be confirmed or ignored [5]. To define fully the safety profile of a medicine at the time of marketing would be so expensive that new drug development would halt if this were a requirement. As a compromise, the subjective assessment of safety data is based on international guidance on minimal requirements, summarized by the International Conference on Harmonisation's guideline, ICHE1 [6]. This sets a reasonable minimal exposure for medicines for non-life-threatening diseases of about 1500 people, of whom some 300–600 should be exposed for 6 months and at least 100 are exposed for 1 year. Though a reasonable requirement for drug development, the limitations of ICHE1 and the importance of postmarketing data are highlighted by the number of drugs that are withdrawn from the market for previously undetected safety problems.

The ICHE1 safety population may prove inadequate to detect major concerns. Sometimes major safety concerns are only evident with larger and longer population exposure, for example, clofibrate. Here an early data set, considerably larger than the ICHE1 requirement, initially showed a favourable risk–benefit ratio [7]. But eventually, a clinical trial of some 200 000 patient-years showed a significant increase in mortality [8]. But not all important safety signals require large numbers of patients treated for many years.

A safety signal might occur in only a small subpopulation, which at the time of licensing has either not been studied or has been studied in limited numbers. Ever since the thalidomide disaster revolutionized medicines regulation, the prime subpopulation of concern has been the fetus. The number of pregnancies exposed to a new drug at the time of licensing is invariably small or zero. When the drug is likely to be worth the risk of prescribing in pregnancy, it may take decades before the risks are quantified, for example, with anti-epileptic therapy [9]. With the increasing use of antidepressants during pregnancy in recent years, now about 2% of all pregnant women in some countries, it is time to consider how safe such prescribing might be. The labelling information of antidepressants has numerous safety warnings and always recommends caution in pregnancy, but statements that ‘neonates should be observed’ raises the question of what form this observation should take. Without control groups, it is often impossible to separate the risk of the disease, the risk of the therapy and the background incidence of developmental abnormality.

Some adverse events only become apparent indirectly through the presence of a cofactor, a proxy or a challenge test. Supressing eosinophils may seem safe until a parasitic infection is encountered; grapefruit juice seems innocuous until a drug solely metabolized by CYP3A4 is co-administered. In the present study, the group used a pharmacy prescription database to detect the use of diarrhoea and constipation medication as a marker of enteric nervous system development. What is commendable in this approach is that basic pharmacology has been reviewed to develop a hypothesis that is then tested with epidemiology.

Antidepressants can modify monoamine synaptic transmission of serotonin, noradrenaline or dopamine. The pharmacology of noradrenaline and dopamine is well established. Serotonin may affect anger, aggression, arousal, body temperature, mood, sleep, vomiting, sexuality and appetite and may even modify social decision making [10]. The pharmacology of serotonin has been sufficiently studied that it is possible to define safety questions that need to be answered in clinical studies of a new molecule that affects serotoninergic pathways. These include whether there is an effect on the following parameters: pulmonary hypertension; pulmonary hypertension in the fetus; heart valve abnormalities; chronotropic/inotropic effects via receptors in atria or ventricles; mood changes or suicidality; platelet aggregation; vasoconstriction; QT effects similar to cisapride; the incidence of serotonin syndrome alone or in combination; and bone resorption [11]. But there is more to the monoamines than neurotransmission. Knockout mouse models show the importance of the serotonin re-uptake transporter (SERT) and the noradrenaline transporter (NET) in neuronal development. SERT-deficient mice are susceptible to both diarrhoea and constipation in adult life. A careful review of the literature by the Groningen authors discusses evidence that modification of 5-HT2B receptors, SERT and NET may each adversely affect enteric nervous system development [1].

The safety analysis of medicines is more complex than the assessment of efficacy. Though antidepressants are taken by about 10% of Americans (they are the most commonly used prescription drug class in the USA), they continue to come up with surprises. If proved, the current findings are a major concern. Antidepressants have to cross the blood–brain barrier and affect neuronal function in order to work. This makes them likely to cross the placenta and access the neural crest and neural tube. If these commonly used drugs affect enteric nervous system development, then it is difficult to guarantee the safe development of other tissues. We cannot yet be reassured about potential central nervous system effects on children who have been exposed in utero, nor is there much certainty about long-term effects on the increasing number of children and adolescents exposed to antidepressants during their youth [12, 13]. The approach by the Groningen group, of using pharmacology to define an appropriate safety question, is exemplary. Only when such questions are formulated can sense be made of much of the mass of postmarketing pharmacovigilance data. Finding signals in these huge databases is like searching for a needle in a haystack. Defining a question based on the pharmacology to probe the data and using co-medication usage as a marker is analogous to using a magnet to search for such a valuable needle.

Competing Interests

The author is a pharmaceutical industry consultant and advises a range of companies on pharmaceutical development. The content of this article does not promote a particular commercial interest.