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H1-histamine receptor affinity predicts weight gain with antidepressants
European Neuropsychopharmacology (2016) 26, 1673–1677
www.elsevier.com/locate/euroneuro
H1-histamine receptor affinity predicts weight gain with antidepressants Virginio Salvia,n, Claudio Mencaccia, Francesco Barone-Adesib a
Department of Neuroscience, ASST Fatebenefratelli-Sacco, Milan, Italy Department of Pharmaceutical Sciences, University of Eastern Piedmont, Novara, Italy
b
Received 17 May 2016; received in revised form 23 July 2016; accepted 22 August 2016
KEYWORDS
Abstract
Weight gain; Antidepressants; Receptor affinity; Histamine
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: H1histamine, 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: o0.001). 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 cardiometabolic disturbances. & 2016 Elsevier B.V. and ECNP. All rights reserved.
n
Corresponding author.
http://dx.doi.org/10.1016/j.euroneuro.2016.08.012 0924-977X/& 2016 Elsevier B.V. and ECNP. All rights reserved.
1674
1.
V. Salvi et al.
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 antidepressantinduced 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.
2.
Experimental procedures
To determine which receptor(s) are most likely responsible for antidepressant-induced weight gain, we retrieved weight change data from the abovementioned meta-analysis (Serretti and Mandelli, 2010); therefore, our analysis included all publications available to January 2009. To date, this is the only study that systematically assessed weight variations with different antidepressants. The authors identified 116 studies where weight was measured before and after the start of antidepressant therapy. When reported in the article, mean and standard deviation of weight change were simply recorded. If they were not reported, missing means and standard deviations were calculated by using other information available in the papers. Studied were grouped by the authors accordingly to their length of follow as acute studies (4–12 weeks) and maintenance studies (43 months). We decided to carry out our main analysis on acute studies as this was the group with the largest number of antidepressants evaluated (16 vs 11 different drugs). However, we carried out also a secondary analysis on maintenance studies to evaluate the robustness of the results. We obtained data on the receptor affinities of the different antidepressants from Derijks and coworkers (Derijks et al., 2008a), and from the Psychoactive Drug Screening Program (PDSP) Ki database (http://pdsp.med.unc.edu/kidb.php). We searched data on affinities of the receptors acknowledged to be linked with weight gain, namely histamine H1, 5HT2c, muscarinic M3, and adrenergic α1A (Kroeze et al., 2003; Roerig et al., 2011) for all the antidepressant medica tions evaluated in the meta-analysis: amitriptyline, bupropion, citalopram, clomipramine, desipramine, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, mirtazapine, moclobemide,
nortriptyline, paroxetine, sertraline, trazodone, venlafaxine; data on moclobemide were not available, thus this drug was excluded from the analysis. Receptor affinity was expressed using the inhibition constant (Ki), a measure of the binding affinity of the ligand (antidepressant) for its receptor. Ki is the concentration of the ligand in which the receptor is occupied for 50% by the ligand, thus the lower the value of Ki the higher is the affinity of the ligand for the receptor. For the present analysis we employed only Ki values estimated using human receptors. Consistently with the approach proposed by Kroeze, values of Ki were natural log-transformed before being used in the statistical analysis and a maximum Ki of 10,000 nM was used for low-affinity interactions (Kroeze et al., 2003). The association between weight change and the receptor affinities was estimated using random-effects meta-regression (Thompson and Higgins, 2002). Each study was weighted for the inverse of its total variance (s2 +τ2), where τ2 is the between-study variance and s2 is the standard error of the estimated effect of the study. We first carried out four crude analyses evaluating the role of the affinity of antidepressants to each receptor (H1, 5HT2c, M3, and α1A). We then evaluated whether the crude estimates changed when the affinity of a second receptor was included in the model. We thus run 6 different models including all the possible pairs of the studied receptors. We decided not to include all the receptors in the same model to avoid problems of multi-collinearity. Analyses were performed using Stata 12 Software (Stata Corp, College Station, TX, USA).
3.
Results
Table 1 shows values of weight change associated with the use of different antidepressants and the Ki values that were used for the analysis. Results of the meta-regression are reported in Figure 1 and Table 2. We found a statistically significant inverse association between Ki of H1 receptor (H1-R) and weight gain (p value: o0.001) (Table 2 and Figure 1). Results did not change after adjustment for the affinity of each of the other receptors (Table 2). An association between weight gain and Ki was also observed in the crude models for 5HT2c, M3, and α1A receptors. However, the association disappeared when H1-R was included in the models (Table 2). When we carried out a secondary analysis using data from maintenance studies instead of those from acute studies, results did not substantially change. The regression coefficients for H1-R affinity estimated from the two sets of studies were 0.23 and 0.24, respectively.
4.
Discussion
Patients treated with psychotropic medications are at risk of weight gain and metabolic abnormalities, and, although only antipsychotic medications were previously considered likely to induce these adverse effects, further studies have underlined that this is not a “class effect”, since other medications such as the antidepressants also exert weight gain and metabolic disturbances. For instance, in a previous study conducted on 138 patients with OCD followed for 2.5 years, we had showed that albeit clomipramine use was associated with the highest weight gain at the end of follow-up, with a 34.9% of patients displaying an increase Z7% body weight, also SSRIs had different likelihood in inducing weight gain, with paroxetine and fluvoxamine inducing more weight gain, and fluoxetine and sertraline the least (Maina et al., 2004). In a more recent study conducted
H1-histamine receptor affinity
1675
Table 1 Weight gain and inhibitory constants (Ki) associated with different antidepressants. Data modified from Serretti and Mandelli, 2010 and Derijks et al., 2008a. Drug
Ki H1
Ki M3
Ki Alpha 1a
Ki 5HT2c
Weight gain, Kg (95% CI)
Amitriptyline Bupropion Citalopram Clomipramine Desipramine Duloxetine Escitalopram Fluoxetine Fluvoxamine Imipramine Mirtazapine Nortriptiline Paroxetine Sertraline Trazodone Venlafaxine
0.81 10,000 283 47 64 2300 1973 2683 10,000 26.5 1.6 7.35 10,000 10,000 1100 10,000
25.9 10,000 1430 – 210 3000 1242 1000 – 60 800 50 80 1300 10,000 10,000
14 4200 5600 3.2 23 8300 3870 2775 1288 32 – 55 2779 201 27 10,000
4 10,000 617 43.3 748 916 – 194 – 120 39 – 10,000 1000 223 7300
1.52 (1.08 to 1.95) 1.13 ( 1.41 to 0.84) 0.64 ( 0.89 to 0.38) 1.00 ( 0.44 to 2.43) 0.82 ( 0.77 to 2.42) 0.55 ( 0.77 to 0.33) 0.33 ( 0.58 to 0.07) 0.94 ( 1.24 to 0.65) 0.02 ( 0.49 to 0.45) 0.20 ( 0.77 to 0.38) 1.74 (1.28 to 2.20) 2.00 (0.74 to 3.25) 0.28 ( 0.46 to 0.09) 0.87 ( 1.04 to 0.70) 0.20 ( 0.94 to 0.54) 0.50 ( 0.74 to 0.27)
Figure 1 Association between H1 receptor affinity of antidepressants and weight gain. Bubble plot with fitted meta-regression line. The size of the circles is proportional to the precision of each estimate.
on around 3000 Canadian women, obesity was consistently associated with use of TCA but not SSRI (Grundy et al., 2014): the authors concluded that “the increased risk of obesity among depressed women taking antidepressants supports a role for these medications as an intermediate between depression and obesity”. Our reanalysis of the data from Serretti and Mandelli metaanalysis highlights the leading role of histamine H1 receptor antagonism in delivering antidepressant-induced weight gain. Affinity to H1-R was strongly related to weight change, and the association remained after adjustment for the affinity to the other studied receptors. Interestingly their meta-analysis shows, at least for SSRIs, an early weight reduction that disappears in the long-term (Serretti and Mandelli, 2010). Indeed, although serotonin effects on food intake are complex,
higher serotonin levels may deliver an initial weight-reducing effect through the activation of melanocortin system (Lam et al., 2010). The observed effect might also be due to the timing of improvement of depressive symptoms, with appetite loss resolving later on leading to physiological return to previous weight. On the other hand, the fact that mirtazapine and tricyclics are able to induce weight gain even in the short term, further strengthens a direct pharmacological effect of anti-histaminergic compounds on appetite and weight, not mediated by depression improvement. Our findings replicate the results of Kroeze et al. study, which indicated that weight gain with antipsychotics could be well explained with their H1 receptor antagonism. The authors, likewise, reanalyzing data from a meta-analysis assessing antipsychotic-induced weight gain, showed that
0.12 [ 0.33 to 0.09]
–
0.13 [ 0.37 to 0.11]
0.24 [ 0.47 to 0.00]
0.19 [ 0.41 to 0.03] 0.13]
0.03]
0.10]
0.24 [ 0.35 to
0.17 [ 0.31 to
0.30 [ 0.49 to
–
0.10 [ 0.37 to 0.17]
–
0.13 [ 0.32 to 0.05]
0.29 [ 0.48 to 0.11] 0.09 [ 0.19 to 0.37] 0.22 [ 0.36 to 0.08] 0.07 [ 0.24 to 0.09] 0.29 [ 0.54 to 0.04] 0.04 [ 0.22 to 0.15] 0.24 [ 0.33 to –
Crude model adjusted by H1 adjusted by M3 adjusted by Alpha 1a adjusted by 5HT2c
H1
Parameters
0.15]
M3
Alpha 1a
5HT2c
V. Salvi et al.
Model
Table 2 Meta-regression analysis. Association between H1 affinity (expressed as Ki) and weight gain. Results from different models. Figures in bold are statistically significant at the 95% level.
1676
H1, 5HT2C, 5HT6 and α1A antagonism receptor affinities were associated with weight increase; however after further analysis only H1 receptor affinity was found to be a significant predictor of the propensity of antipsychotics to induce weight gain (Kroeze et al., 2003). Similar results were achieved by Matsui-Sakata and colleagues (Matsui-Sakata et al., 2005). Together with these reports, our results suggest that H1-R affinity plays a major role in psychotropic drug-induced weight change. Strong experimental evidence points to the blockade of histamine H1 receptors as the most relevant mechanism of weight gain and metabolic abnormalities induced by psychotropic medications. For instance, an experimental study found that 4 weeks of treatment with amitryptiline and mirtazapine led to an increase in leptin plasma levels and weight gain, while treatment with paroxetine and venlafaxine did not (Schilling et al., 2013); according to the authors, leptin resistance (shown by increase in leptin levels ineffective in controlling weight) could be explained by the antihistaminergic effect of such compounds, interfering on hypothalamic nuclei integrating signals relevant for energy balance. More recently, an experimental study found that olanzapine induced hyperphagia and weight-gain in rats by up-regulating mRNA expression and protein level of hypothalamic H1 receptor (He et al., 2014). Further evidence to the leading role of histamine in delivering weight gain has been provided by recent trials conducted on healthy subjects and patients with schizophrenia demonstrating the effect of betahistine – an agonist at H1 receptors – in reducing antipsychotic-induced weight gain (Lian et al., 2016). Beyond weight gain, H1 receptor antagonism has also been linked with other metabolic abnormalities: Derijks and colleagues found higher fasting glucose levels in patients taking antidepressants with high anti-histaminergic activity (Derijks et al., 2008b). In a study conducted on a clinical sample of patients with bipolar disorder exposed to antidepressants, we further showed a strong, linear correlation between the histamine H1 receptor affinity of the antidepressants and the prevalence of metabolic syndrome, demonstrating an effect of histaminergic blockade on metabolism beyond weight gain (Salvi et al., 2016). Although the blockade of H1 receptors plays a clear role in antidepressant-induced weight gain, there probably are other mechanisms involved. Indeed, in a recent study conducted on a representative sample from a health insurance plan, bupropion was associated with significant weight loss while sertraline, which equally displays a lack of H1-R affinity, was associated with significant weight gain after two years of follow-up (Arterburn et al., 2016). Therefore, although findings coming from single uncontrolled studies may not be generalised, there might be other reasons accounting for medications-induced weight gain. In conclusion, the present reanalysis of data adds further evidence to the causative role of H1 receptor blockade in weight gain induced by psychopharmacologic medications. All these results suggest that H1-R affinity of antidepressants can have important implication in clinical practice, particularly when dealing with overweight patients or patients at risk with cardiovascular and metabolic disease; in these patients, these medications should possibly be avoided.
H1-histamine receptor affinity
Role of the funding source None.
Contributors Dr. Salvi designed the study and wrote the manuscript; Dr. Mencacci added significant comments and improvements to the manuscript, Dr. Barone-Adesi designed the study and performed the statistical analyses. All authors contributed to and have approved the final manuscript.
Conflict of interests We report no conflict of interest to disclose for the present article.
Acknowledgements We thank the colleagues at ASST-Fatebenefratelli-Sacco and at University of Eastern Piedmont for their support.
References Arterburn, D., Sofer, T., Boudreau, D.M., Bogart, A., Westbrook, E. O., Theis, M.K., Simon, G., Haneuse, S., 2016. Long-term weight change after initiating second-generation antidepressants. J. Clin. Med. 5 (4) pii: E48. Correll, C.U., Detraux, J., De Lepeleire, J., De Hert, M., 2015. Effects of antipsychotics, antidepressants and mood stabilizers on risk for physical diseases in people with schizophrenia, depression and bipolar disorder. World Psychiatry 14 (2), 119–136. De Hert, M., Dekker, J.M., Wood, D., Kahl, K.G., Holt, R.I., Möller, H.J., 2009. Cardiovascular disease and diabetes in people with severe mental illness position statement from the European Psychiatric Association (EPA), supported by the European Association for the Study of Diabetes (EASD) and the European Society of Cardiology (ESC). Eur. Psychiatry, 24; , 412–424. Derijks, H.J., Heerdink, E.R., Janknegt, R., De Koning, F.H., Olivier, B., Loonen, A.J.M., Egberts, A.C., 2008a. Visualizing pharmacological activities of antidepressants: a novel approach. Open Pharmacol. J. 2, 54–62. Derijks, H.J., Meyboom, R.H.B., Heerdink, E.R., De Koning, F.H., Janknegt, R., Lindquist, M., Egberts, A.C., 2008b. The association between antidepressant use and disturbances in glucose homeostasis: evidence from spontaneous reports. Eur. J. Clin. Pharmacol. 64, 531–538. Grundy, A., Cotterchio, M., Kirsh, V.A., Kreiger, N., 2014. Associations between anxiety, depression, antidepressant medication, obesity and weight gain among Canadian women. PLoS One 9 (6), e99780. Hasnain, M., Vieweg, W.V., Hollett, B., 2012. Weight gain and glucose dysregulation with second-generation antipsychotics
1677 and antidepressants: a review for primary care physicians. Postgrad. Med. 124 (4), 154–167. He, M., Zhang, Q., Deng, C., Wang, H., Lian, J., Huang, X.F., 2014. Hypothalamic histamine H1 receptor-AMPK signaling timedependently mediates olanzapine-induced hyperphagia and weight gain in female rats. Psychoneuroendocrinol 42, 153–164. Lam, D.D., Garfield, A.S., Marston, O.J., Shaw, J., Heisler, L.K., 2010. Brain serotonin system in the coordination of food intake and body weight. Pharmacol. Biochem. Behav. 97 (1), 84–91. Kroeze, W.K., Hufeisen, S.J., Popadak, B.A., Renock, S.M., Steinberg, S., Ernsberger, P., Jayathilake, K., Meltzer, H.Y., Roth, B. L., 2003. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 28 (3), 519–526. Lee, S.H., Paz-Filho, G., Mastronardi, C., Licinio, J., Wong, M.L., 2016. Is increased antidepressant exposure a contributory factor to the obesity pandemic. Transl. Psychiatry 6, e759. Lian, J., Huang, X.F., Pai, N., Deng, C., 2016. Ameliorating antipsychotic-induced weight gain by betahistine: mechanisms and clinical implications. Pharmacol. Res. 106, 51–63. Maina, G., Albert, U., Salvi, V., Bogetto, F., 2004. Weight gain during long-term treatment of obsessive-compulsive disorder: a prospective comparison between serotonin reuptake inhibitors. J. Clin. Psychiatry 65 (10), 1365–1371. Matsui-Sakata, A., Ohtani, H., Sawada, Y., 2005. Receptor occupancy-based analysis of the contributions of various receptors to antipsychotics-induced weight gain and diabetes mellitus. Drug Metab. Pharmacokinet. 20 (5), 368–378. McElroy, S.L., 2009. Obesity in patients with severe mental illness: overview and management. J. Clin. Psychiatry 70 (Suppl 3), 12–21. PDSP-database. 〈http://pdsp.med.unc.edu/kidb.php〉. Ki determinations were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract # HHSN-271-2013-00017-C (NIMH PDSP). Roerig, J.L., Steffen, K.J., Mitchell, J.E., 2011. Atypical antipsychotic-induced weight gain: insights into mechanisms of action. CNS Drugs 25 (12), 1035–1059. Salvi, V., Barone-Adesi, F., D'Ambrosio, V., Albert, U., Maina, G., 2016. High H1-affinity antidepressants and risk of metabolic syndrome in bipolar disorder. Psychopharmacol. (Berl.) 233 (1), 49–56. Schilling, C., Gilles, M., Blum, W.F., Daseking, E., Colla, M., WeberHamann, B., Lederbogen, F., Krumm, B., Heuser, I., Wudy, S.A., Kopf, D., Deuschle, M., 2013. Leptin plasma concentrations increase during antidepressant treatment with amitriptyline and mirtazapine, but not paroxetine and venlafaxine: leptin resistance mediated by antihistaminergic activity? J. Clin. Psychopharmacol. 33, 99–103. Serretti, A., Mandelli, L., 2010. Antidepressants and body weight: a comprehensive review and meta-analysis. J. Clin. Psychiatry 71 (10), 1259–1272. Thompson, S.G., Higgins, J.P., 2002. How should meta-regression analyses be undertaken and interpreted? Stat. Med. 21 (11), 1559–1573.
www.elsevier.com/locate/euroneuro
H1-histamine receptor affinity predicts weight gain with antidepressants Virginio Salvia,n, Claudio Mencaccia, Francesco Barone-Adesib a
Department of Neuroscience, ASST Fatebenefratelli-Sacco, Milan, Italy Department of Pharmaceutical Sciences, University of Eastern Piedmont, Novara, Italy
b
Received 17 May 2016; received in revised form 23 July 2016; accepted 22 August 2016
KEYWORDS
Abstract
Weight gain; Antidepressants; Receptor affinity; Histamine
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: H1histamine, 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: o0.001). 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 cardiometabolic disturbances. & 2016 Elsevier B.V. and ECNP. All rights reserved.
n
Corresponding author.
http://dx.doi.org/10.1016/j.euroneuro.2016.08.012 0924-977X/& 2016 Elsevier B.V. and ECNP. All rights reserved.
1674
1.
V. Salvi et al.
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 antidepressantinduced 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.
2.
Experimental procedures
To determine which receptor(s) are most likely responsible for antidepressant-induced weight gain, we retrieved weight change data from the abovementioned meta-analysis (Serretti and Mandelli, 2010); therefore, our analysis included all publications available to January 2009. To date, this is the only study that systematically assessed weight variations with different antidepressants. The authors identified 116 studies where weight was measured before and after the start of antidepressant therapy. When reported in the article, mean and standard deviation of weight change were simply recorded. If they were not reported, missing means and standard deviations were calculated by using other information available in the papers. Studied were grouped by the authors accordingly to their length of follow as acute studies (4–12 weeks) and maintenance studies (43 months). We decided to carry out our main analysis on acute studies as this was the group with the largest number of antidepressants evaluated (16 vs 11 different drugs). However, we carried out also a secondary analysis on maintenance studies to evaluate the robustness of the results. We obtained data on the receptor affinities of the different antidepressants from Derijks and coworkers (Derijks et al., 2008a), and from the Psychoactive Drug Screening Program (PDSP) Ki database (http://pdsp.med.unc.edu/kidb.php). We searched data on affinities of the receptors acknowledged to be linked with weight gain, namely histamine H1, 5HT2c, muscarinic M3, and adrenergic α1A (Kroeze et al., 2003; Roerig et al., 2011) for all the antidepressant medica tions evaluated in the meta-analysis: amitriptyline, bupropion, citalopram, clomipramine, desipramine, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, mirtazapine, moclobemide,
nortriptyline, paroxetine, sertraline, trazodone, venlafaxine; data on moclobemide were not available, thus this drug was excluded from the analysis. Receptor affinity was expressed using the inhibition constant (Ki), a measure of the binding affinity of the ligand (antidepressant) for its receptor. Ki is the concentration of the ligand in which the receptor is occupied for 50% by the ligand, thus the lower the value of Ki the higher is the affinity of the ligand for the receptor. For the present analysis we employed only Ki values estimated using human receptors. Consistently with the approach proposed by Kroeze, values of Ki were natural log-transformed before being used in the statistical analysis and a maximum Ki of 10,000 nM was used for low-affinity interactions (Kroeze et al., 2003). The association between weight change and the receptor affinities was estimated using random-effects meta-regression (Thompson and Higgins, 2002). Each study was weighted for the inverse of its total variance (s2 +τ2), where τ2 is the between-study variance and s2 is the standard error of the estimated effect of the study. We first carried out four crude analyses evaluating the role of the affinity of antidepressants to each receptor (H1, 5HT2c, M3, and α1A). We then evaluated whether the crude estimates changed when the affinity of a second receptor was included in the model. We thus run 6 different models including all the possible pairs of the studied receptors. We decided not to include all the receptors in the same model to avoid problems of multi-collinearity. Analyses were performed using Stata 12 Software (Stata Corp, College Station, TX, USA).
3.
Results
Table 1 shows values of weight change associated with the use of different antidepressants and the Ki values that were used for the analysis. Results of the meta-regression are reported in Figure 1 and Table 2. We found a statistically significant inverse association between Ki of H1 receptor (H1-R) and weight gain (p value: o0.001) (Table 2 and Figure 1). Results did not change after adjustment for the affinity of each of the other receptors (Table 2). An association between weight gain and Ki was also observed in the crude models for 5HT2c, M3, and α1A receptors. However, the association disappeared when H1-R was included in the models (Table 2). When we carried out a secondary analysis using data from maintenance studies instead of those from acute studies, results did not substantially change. The regression coefficients for H1-R affinity estimated from the two sets of studies were 0.23 and 0.24, respectively.
4.
Discussion
Patients treated with psychotropic medications are at risk of weight gain and metabolic abnormalities, and, although only antipsychotic medications were previously considered likely to induce these adverse effects, further studies have underlined that this is not a “class effect”, since other medications such as the antidepressants also exert weight gain and metabolic disturbances. For instance, in a previous study conducted on 138 patients with OCD followed for 2.5 years, we had showed that albeit clomipramine use was associated with the highest weight gain at the end of follow-up, with a 34.9% of patients displaying an increase Z7% body weight, also SSRIs had different likelihood in inducing weight gain, with paroxetine and fluvoxamine inducing more weight gain, and fluoxetine and sertraline the least (Maina et al., 2004). In a more recent study conducted
H1-histamine receptor affinity
1675
Table 1 Weight gain and inhibitory constants (Ki) associated with different antidepressants. Data modified from Serretti and Mandelli, 2010 and Derijks et al., 2008a. Drug
Ki H1
Ki M3
Ki Alpha 1a
Ki 5HT2c
Weight gain, Kg (95% CI)
Amitriptyline Bupropion Citalopram Clomipramine Desipramine Duloxetine Escitalopram Fluoxetine Fluvoxamine Imipramine Mirtazapine Nortriptiline Paroxetine Sertraline Trazodone Venlafaxine
0.81 10,000 283 47 64 2300 1973 2683 10,000 26.5 1.6 7.35 10,000 10,000 1100 10,000
25.9 10,000 1430 – 210 3000 1242 1000 – 60 800 50 80 1300 10,000 10,000
14 4200 5600 3.2 23 8300 3870 2775 1288 32 – 55 2779 201 27 10,000
4 10,000 617 43.3 748 916 – 194 – 120 39 – 10,000 1000 223 7300
1.52 (1.08 to 1.95) 1.13 ( 1.41 to 0.84) 0.64 ( 0.89 to 0.38) 1.00 ( 0.44 to 2.43) 0.82 ( 0.77 to 2.42) 0.55 ( 0.77 to 0.33) 0.33 ( 0.58 to 0.07) 0.94 ( 1.24 to 0.65) 0.02 ( 0.49 to 0.45) 0.20 ( 0.77 to 0.38) 1.74 (1.28 to 2.20) 2.00 (0.74 to 3.25) 0.28 ( 0.46 to 0.09) 0.87 ( 1.04 to 0.70) 0.20 ( 0.94 to 0.54) 0.50 ( 0.74 to 0.27)
Figure 1 Association between H1 receptor affinity of antidepressants and weight gain. Bubble plot with fitted meta-regression line. The size of the circles is proportional to the precision of each estimate.
on around 3000 Canadian women, obesity was consistently associated with use of TCA but not SSRI (Grundy et al., 2014): the authors concluded that “the increased risk of obesity among depressed women taking antidepressants supports a role for these medications as an intermediate between depression and obesity”. Our reanalysis of the data from Serretti and Mandelli metaanalysis highlights the leading role of histamine H1 receptor antagonism in delivering antidepressant-induced weight gain. Affinity to H1-R was strongly related to weight change, and the association remained after adjustment for the affinity to the other studied receptors. Interestingly their meta-analysis shows, at least for SSRIs, an early weight reduction that disappears in the long-term (Serretti and Mandelli, 2010). Indeed, although serotonin effects on food intake are complex,
higher serotonin levels may deliver an initial weight-reducing effect through the activation of melanocortin system (Lam et al., 2010). The observed effect might also be due to the timing of improvement of depressive symptoms, with appetite loss resolving later on leading to physiological return to previous weight. On the other hand, the fact that mirtazapine and tricyclics are able to induce weight gain even in the short term, further strengthens a direct pharmacological effect of anti-histaminergic compounds on appetite and weight, not mediated by depression improvement. Our findings replicate the results of Kroeze et al. study, which indicated that weight gain with antipsychotics could be well explained with their H1 receptor antagonism. The authors, likewise, reanalyzing data from a meta-analysis assessing antipsychotic-induced weight gain, showed that
0.12 [ 0.33 to 0.09]
–
0.13 [ 0.37 to 0.11]
0.24 [ 0.47 to 0.00]
0.19 [ 0.41 to 0.03] 0.13]
0.03]
0.10]
0.24 [ 0.35 to
0.17 [ 0.31 to
0.30 [ 0.49 to
–
0.10 [ 0.37 to 0.17]
–
0.13 [ 0.32 to 0.05]
0.29 [ 0.48 to 0.11] 0.09 [ 0.19 to 0.37] 0.22 [ 0.36 to 0.08] 0.07 [ 0.24 to 0.09] 0.29 [ 0.54 to 0.04] 0.04 [ 0.22 to 0.15] 0.24 [ 0.33 to –
Crude model adjusted by H1 adjusted by M3 adjusted by Alpha 1a adjusted by 5HT2c
H1
Parameters
0.15]
M3
Alpha 1a
5HT2c
V. Salvi et al.
Model
Table 2 Meta-regression analysis. Association between H1 affinity (expressed as Ki) and weight gain. Results from different models. Figures in bold are statistically significant at the 95% level.
1676
H1, 5HT2C, 5HT6 and α1A antagonism receptor affinities were associated with weight increase; however after further analysis only H1 receptor affinity was found to be a significant predictor of the propensity of antipsychotics to induce weight gain (Kroeze et al., 2003). Similar results were achieved by Matsui-Sakata and colleagues (Matsui-Sakata et al., 2005). Together with these reports, our results suggest that H1-R affinity plays a major role in psychotropic drug-induced weight change. Strong experimental evidence points to the blockade of histamine H1 receptors as the most relevant mechanism of weight gain and metabolic abnormalities induced by psychotropic medications. For instance, an experimental study found that 4 weeks of treatment with amitryptiline and mirtazapine led to an increase in leptin plasma levels and weight gain, while treatment with paroxetine and venlafaxine did not (Schilling et al., 2013); according to the authors, leptin resistance (shown by increase in leptin levels ineffective in controlling weight) could be explained by the antihistaminergic effect of such compounds, interfering on hypothalamic nuclei integrating signals relevant for energy balance. More recently, an experimental study found that olanzapine induced hyperphagia and weight-gain in rats by up-regulating mRNA expression and protein level of hypothalamic H1 receptor (He et al., 2014). Further evidence to the leading role of histamine in delivering weight gain has been provided by recent trials conducted on healthy subjects and patients with schizophrenia demonstrating the effect of betahistine – an agonist at H1 receptors – in reducing antipsychotic-induced weight gain (Lian et al., 2016). Beyond weight gain, H1 receptor antagonism has also been linked with other metabolic abnormalities: Derijks and colleagues found higher fasting glucose levels in patients taking antidepressants with high anti-histaminergic activity (Derijks et al., 2008b). In a study conducted on a clinical sample of patients with bipolar disorder exposed to antidepressants, we further showed a strong, linear correlation between the histamine H1 receptor affinity of the antidepressants and the prevalence of metabolic syndrome, demonstrating an effect of histaminergic blockade on metabolism beyond weight gain (Salvi et al., 2016). Although the blockade of H1 receptors plays a clear role in antidepressant-induced weight gain, there probably are other mechanisms involved. Indeed, in a recent study conducted on a representative sample from a health insurance plan, bupropion was associated with significant weight loss while sertraline, which equally displays a lack of H1-R affinity, was associated with significant weight gain after two years of follow-up (Arterburn et al., 2016). Therefore, although findings coming from single uncontrolled studies may not be generalised, there might be other reasons accounting for medications-induced weight gain. In conclusion, the present reanalysis of data adds further evidence to the causative role of H1 receptor blockade in weight gain induced by psychopharmacologic medications. All these results suggest that H1-R affinity of antidepressants can have important implication in clinical practice, particularly when dealing with overweight patients or patients at risk with cardiovascular and metabolic disease; in these patients, these medications should possibly be avoided.
H1-histamine receptor affinity
Role of the funding source None.
Contributors Dr. Salvi designed the study and wrote the manuscript; Dr. Mencacci added significant comments and improvements to the manuscript, Dr. Barone-Adesi designed the study and performed the statistical analyses. All authors contributed to and have approved the final manuscript.
Conflict of interests We report no conflict of interest to disclose for the present article.
Acknowledgements We thank the colleagues at ASST-Fatebenefratelli-Sacco and at University of Eastern Piedmont for their support.
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