H1-histamine receptor affinity predicts weight gain with antidepressants

Abstract

Weight gain and metabolic abnormalities are extensively found in patients taking psychotropic medications. Although mainly antipsychotics have been implicated, also antidepressants carry the potential to induce weight gain, with tricyclics and mirtazapine being associated with the greatest weight gain. It has been suggested that this could be due to the different ability of antidepressants to block adrenergic, cholinergic, and histaminergic postsynaptic receptors. To date, however, the link between antidepressant-induced weight gain and their receptor affinity profile has not been established. We reanalysed data from a previous meta-analysis to evaluate whether weight change is associated with specific receptor affinity of antidepressants.

We retrieved data from the only meta-analysis that assessed weight change with antidepressants. We searched in the Psychoactive Drug Screening Program (PDSP) Ki database data on the affinities of antidepressants to receptors hypothetically linked with weight change: H1-histamine, 5HT2c, M3-muscarinic, and α1A-adrenergic receptors. The association between weight change and receptor affinities was estimated using meta-regression.

We found a significant association between the affinity of antidepressants to H1-receptor and weight gain (p value: <0.001). An association between weight gain and receptor affinity was also observed in the models for 5HT2c, M3, and α1A receptors. However, the association disappeared when H1-receptor was included in the models.

This reanalysis of data demonstrates that anti-histaminergic activity is the strongest predictor of weight gain with antidepressants. These results further stress a reclassification of antidepressants according to their pharmacodynamic properties, and suggest avoiding prescribing antidepressants with an anti-histaminergic profile to patients at risk for cardio-metabolic disturbances.

Introduction

Weight gain and metabolic abnormalities have been extensively found in patients suffering from psychiatric disorders, due to several causes such as unhealthy diet and inactivity, and to the use of several common psychotropic medications (De Hert et al., 2009; McElroy et al., 2009).

Although the use of antipsychotics has been mostly associated with weight gain, in recent years growing evidence indicates that also antidepressants carry the potential to induce weight gain and diabetes (Hasnain et al., 2012, Correll et al., 2015).

Antidepressants however are not equal in the capacity to induce weight gain. A meta-analysis based on 116 studies employing most marketed antidepressants, highlighted that different antidepressant medications greatly differ in their ability to affect body weight (Serretti and Mandelli, 2010). The authors found that tricyclics and mirtazapine were associated with the maximum weight gain, where most SSRIs, SNRIs and bupropion induced very little, if anything, weight gain (Serretti and Mandelli, 2010). They speculated that this could be due to the different ability of antidepressants to block adrenergic, cholinergic, and histaminergic postsynaptic receptors. In a recent review that discussed the relation between obesity and exposure to antidepressant medications, pharmacodynamic mechanisms such as adrenergic, muscarinic, and serotonergic receptor blockade were also called upon to explain weight gain with antidepressants (Lee et al., 2016).

To date, however, the link between antidepressant-induced weight gain and their receptor affinity profile has not been established. In the present study we reanalysed data from the meta-analysis from Serretti and Mandelli to evaluate whether the observed weight change could be explained with the receptor affinity of antidepressants.