The Impact of Hormonal Contraceptive Use on Serotonergic Neurotransmission and Antidepressant Treatment Response: Results From the NeuroPharm 1 Study

Abstract

Background: Hormonal contraceptive (HC) use has been associated with an increased risk of developing a depressive episode. This might be related to HC's effect on the serotonergic brain system as suggested by recent cross-sectional data from our group, which show that healthy oral contraceptive (OC) users relative to non-users have lower cerebral serotonin 4 receptor (5-HT4R) levels. Here, we determine if cerebral 5-HT4R binding differs between HC non-users, OC users, and hormonal intrauterine device (HIUD) users among women with an untreated depressive episode. Also, we test if antidepressant drug treatment response and its association with pre-treatment 5-HT4R binding depends on HC status.

Methods: [¹¹C]-SB207145 Positron Emission Tomography imaging data from the NeuroPharm-NP1 Study (NCT02869035) were available from 59 depressed premenopausal women, of which 26 used OCs and 10 used HIUDs. The participants were treated with escitalopram. Treatment response was measured as the relative change in the Hamilton Depression Rating Scale 6 items (rΔHAMD₆) from baseline to week eight. Latent variable models were used to evaluate the association between global 5-HT4R binding and OC and HIUD use as well as rΔHAMD₆.

Results: We found no evidence of a difference in global 5-HT4R binding between depressed HC users and non-users (p≥0.51). A significant crossover interaction (p=0.02) was observed between non-users and OC users in the association between baseline global 5-HT4R binding and week eight rΔHAMD₆; OC users had 3-4% lower binding compared to non-users for every 10% percent less improvement in HAMD₆. Within the groups, we observed a trend towards a positive association in non-users (p_adj=0.10) and a negative association in OC users (p_adj=0.07). We found no strong evidence of a difference in treatment response between the groups (p=0.13).

Conclusions: We found no difference in 5-HT4R binding between HC users vs. non-users in depressed women, however, it seemed that 5-HT4R settings differed qualitatively in their relation to antidepressant drug treatment response between OC users and non-users. From this we speculate that depressed OC users constitutes a special serotonin subtype of depression, which might have implications for antidepressant drug treatment response.

Keywords: [11C]SB207145; hormonal contraception; hormonal intrauterine device; major depressive disorder; oral contraception; serotonin; serotonin 4 receptor; sex steroid hormones.

Figure 1

The estimated latent variable model for the effect of oral contraceptive (OC) and hormonal intrauterine device (HIUD) use on baseline 5-HT4R BP_ND in women with an untreated depressive episode. γ is the effect on the global latent variable interpreted as global (log-transformed) 5-HT4R BP_ND effects. λ is the loading on each region. The boxes beneath the loadings indicate the percentage difference in 5-HT4R binding for each brain region in OC- and HIUD users compared to non-users. Regional bindings were adjusted for Age, BMI, 5-HTTLPR genotype and injected tracer mass per kg bodyweight (not shown). P-values and confidence intervals are adjusted for 3 comparisons by use of the Dunnett’s test.

Figure 2

Antidepressant drug treatment response at week eight across hormonal contraceptive user status. Difference in relative change in Hamilton Depression Rating Scale 6 items (HAMD6) from baseline between the HC non-users, the hormonal intrauterine device (HIUD) users and the oral contraceptive (OC) users. A larger negative change corresponds to a better improvement of depressive symptoms. P-values are computed with Mann-Whitney tests with no correction for multiple comparisons.

Figure 3

Estimated global 5-HT4R latent variable summarizing the association between baseline global 5-HT4R brain binding and week eight antidepressant drug treatment response across the groups. The slopes are the association between baseline (un-medicated) 5-HT4R binding and change in Hamilton Depression Rating Scale 6 items (HAMD₆) in each group, respectively. A negative change in HAMD₆ mirrors an improvement of depressive symptoms. The slopes are 1.33x10^-2 (p_adj=0.10) for the non-users, -3.34x10^-3 (p_adj=0.75) for the hormonal intrauterine device (HIUD) users, and -1.27x10^-2 (p_adj=0.07) for the oral contraceptive (OC) users.

Figure 4

The estimated latent variable model for the association between baseline 5-HT4R binding and week eight antidepressant treatment response as a function of hormonal contraceptive status shown in three layers (A–C). (A) The association between baseline 5-HT4R binding and treatment response in non-users. (B) The difference in the association between baseline 5-HT4R binding and treatment response between the non-users and the oral contraceptive (OC) and the hormonal intrauterine device (HIUD) users, respectively. (C) The estimated effect of OC and HIUD use on 5-HT4R binding when no change in Hamilton Depression Rating Scale 6 items (HAMD6). γ is the estimates of the association with the global latent variable interpreted as global (log-transformed) 5-HT4R BP_ND estimates. λ is the loading on each region. The boxes beneath the loadings indicate the percentage difference in 5-HT4R binding for each brain region. Regional bindings were adjusted for Age, BMI, 5-HTTLPR genotype and injected tracer mass per kg bodyweight (not shown). P-values and confidence intervals are adjusted for 3 comparisons. r₁₀ΔHAMD₆: 10% relative change in Hamilton Depression Rating Scale 6 items.

Figure 5

The effect of eight weeks of SSRI/SNRI treatment on neostriatal 5-HT4R binding across the groups. p_perm: p-values based on 10,000 permutations to account for the small sample sizes in the oral contractive (OC)- and the hormonal intrauterine device (HIUD) user groups.