Running Heading: Antidepressants Antagonizing M3 Muscarinic Receptors & Incident T2DM

Running heading: Antidepressants antagonizing M3 muscarinic receptors & incident T2DM

Impact of muscarinic M3 receptor antagonism on the risk of type 2 diabetes in antidepressant-treated patients: a case-controlled study

Yen-Hao Tran1,*, Catharina C. M. Schuiling-Veninga1, Jorieke E H Bergman2, Henk Groen3, Bob Wilffert1,4

1 Unit of PharmacoTherapy, -Epidemiology & -Economics, Department of Pharmacy, University of Groningen, the Netherlands

2 Eurocat Registration Northern Netherlands, Department of Genetics, University of Groningen, University Medical Center Groningen, the Netherlands

3 Department of Epidemiology, University of Groningen, University Medical Center Groningen, the Netherlands

4 Department of Clinical Pharmacy & Pharmacology, University of Groningen, University Medical Center Groningen, the Netherlands

Supplementary information

-Supplementary Table S1. The binding affinity of antidepressants at M3 muscarinic receptors.

-Supplementary Table S2. Risk of type 2 diabetes in patients with recent use of individual antidepressants and with no concurrent use of antipsychotics.

-Supplementary Table S3. Risk of type 2 diabetes in patients with recent and former use of antidepressants.

Supplementary Table S1.Thebinding affinity of antidepressants at M3 muscarinic receptors

Antidepressants / Ki (nM) / References
AD_antaM3
amitriptyline / 12.8 / [1]
desipramine / 210 / [1]
imipramine / 60 / [1]
nortriptyline / 50 / [1]
doxepin / 52 / [1]
dosulepin / 38 / [1]
maprotiline / 570 / [2]
paroxetine / 80 / [1]
AD_nonantaM3
fluoxetine / 1000 / [1]
sertraline / 1,300 / [1]
trazodone / 10,000 / [1]
bupropion / 10,000 / [1]
venlafaxine / 10,000 / [1]
AD_antaM3 Antidepressants that antagonize M3 muscarinic receptors, AD_nonantaM3 Antidepressants that do not antagonize M3 muscarinic receptors.
Ki determinations were provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, which is directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA.
The selection of AD_antaM3 was based on the available lists from DrugBank ( and The IUPHAR/BPS Guide to PHARMACOLOGY (
The Ki values of otherAD_nonantaM3 (clomipramine, opipramol, trimipramine, citalopram, fluvoxamine, escitalopram, phenelzine, tranylcypromine, moclobemide, mianserin, nefazodone, mirtazapine, duloxetine and agomelatine) have not been reported yet.
The references used by National Institute of Mental Health’s Psychoactive Drug Screening Program and Drugbank are listed below:
1. Stanton T, Bolden-Watson C, Cusack B, Richelson E. Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. BiochemPharmacol. 1993;45(11):2352-4
2. Cusack B, Nelson A, Richelson E. Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology 1994;114:559-65.

Supplementary Table S2. Risk of type 2 diabetes in patients with recent use of individual antidepressants and with no concurrent use of antipsychotics

Types of antidepressants / Therapeutic class / Population without antipsychotics
Cases
(N=444) / Controls
(N=4,980) / Adjusted OR
(95% CI)
n (%) / n (%)
Past use / 193 (43.5) / 2,474 (49,7)
Recent use of AD_antaM3a
imipramine / TCA / 1 (0.2) / 3 (0.1) / – d
amitriptyline/nortriptylineb / TCA / 40 (9.0) / 238 (4.8) / 1.76 (1.08-2.86)
doxepin / TCA / 1 (0.2) / 2 (0.0) / – d
dosulepin / TCA / 0 (0.0) / 1 (0.0) / – d
maprotiline / TCA / 1 (0.2) / 0 (0.0) / – d
paroxetine / SSRI / 57 (12.8) / 545 (10.9) / 1.27 (0.87-1.85)
Recent use of AD_nonantaM3a
clomipramine / TCA / 3 (0.7) / 57 (1.1) / – d
fluoxetine / SSRI / 9 (2.0) / 119 (2.4) / 1.33 (0.56-3.17)
citalopram/escitalopramc / SSRI / 22 (5.0) / 232 (4.7) / 1.58 (0.90-2.74)
sertraline / SSRI / 10 (2.3) / 63 (1.3) / 1.99 (0.82-4.82)
fluvoxamine / SSRI / 3 (0.7) / 61 (1.2) / – d
moclobemide / others / 0 (0.0) / 2 (0.0) / – d
mianserin / TCA / 0 (0.0) / 1 (0.0) / – d
trazodone / SARI / 1 (0.2) / 3 (0.1) / – d
nefazodone / SARI / 0 (0.0) / 1 (0.0) / – d
mirtazapine / TCA / 9 (2.0) / 94 (1.9) / 0.97 (0.39-2.54)
bupropion / others / 4 (0.9) / 27 (0.5) / – d
venlafaxine / SNRI / 10 (2.3) / 196 (3.9) / 0.65 (0.32-1.31)
duloxetine / SNRI / 3 (0.7) / 22 (0.4) / – d
agomelatine / others / 0 (0.0) / 10 (0.2) / – d
AD_antaM3 Antidepressants that antagonize M3 muscarinic receptors, AD_nonantaM3 Antidepressants that do not antagonize M3 muscarinic receptors, TCA tricyclic and tetracyclic antidepressant, SSRI selective serotonin reuptake inhibitor, SNRI serotonin–norepinephrine reuptake inhibitor, SARI serotonin antagonist and reuptake inhibitors, OR odds ratio, CI confidence interval.
a Excluding patients who received more than one type of antidepressants (except for the combined categories: amitriptyline/nortriptyline and citalopram/escitalopram)
bAmitriptyline and nortriptyline were combined into one exposure category because nortriptyline is the metabolite of amitriptyline. This category included 40 cases and 223 controls with amitriptyline, 16 controls with nortriptyline, and 1 control with both.
cCitalopram and escitalopram were combined into one exposure category because escitalopram is the S-enantiomer of citalopram. This category included 19 cases and 195 controls with citalopram, 3 cases and40 controls with escitalopram, and 3 controls with both.
d Not computed because there were less than 5 exposed cases or controls.
Odds ratios were adjusted for the following covariates: uses ofbenzodiazepines, beta-blockers, thiazide diuretics, and systemic corticosteroids within 6 recent months.

Supplementary Table S3.Risk of type 2 diabetes in patients with recent and former use of antidepressants

Period of use / Total population / Population without antipsychotics
Cases
(N=530) / Controls
(N=5,300) / Adjusted ORb
(95% CI) / Cases
(N=444) / Controls
(N=4,980) / Adjusted ORc
(95% CI)
n (%) / n (%) / n (%) / n (%)
Past usea / 210 (39.6) / 2,568 (48.5) / 1 / 193 (43.5) / 2,474 (49,7) / 1
Former use / 65 (12.3) / 748 (14.1) / 1.04 (0.76-1.44) / 59 (13,3) / 721 (14.5) / 1.01 (0.72-1.43)
Recent use
Within 6 recent months / 255 (48.1) / 1,984 (37.4) / 1.35 (1.09-1.67) / 192 (43.2) / 1,785 (35.8) / 1.32 (1.05-1.66)
combination / 19 (3.6) / 61 (1.2) / 2.29 (1.26-4.17) / 11 (2.5) / 47 (0.9) / 2.61 (1.22-5.58)
AD_antaM3 / 115 (21.7) / 831 (15.7) / 1.55 (1.18-2.02) / 101 (22.7) / 795 (16.0) / 1.49 (1.12-1.99)
AD_nonantaM3_ser / 117 (22.1) / 1,049 (19.8) / 1.11 (0.85-1.44) / 76 (17.1) / 906 (18.2) / 1.05 (0.78-1.41)
agomelatine_bupropion / 4 (0.8) / 43 (0.8) / – d / 4 (0.9) / 37 (0.7) / – d
Within 3 recent months / 234 (44.2) / 1,827 (34.0) / 1.35 (1.08-1.67) / 175 (39.4) / 1,641 (33.0) / 1.30 (1.03-1.65)
combination / 14 (2.6) / 40 (0.8) / 2.69 (1.32-5.46) / 9 (2.0) / 33 (0.7) / 2.79 (1.20-6.49)
AD_antaM3 / 106 (20.0) / 761 (14.4) / 1.54 (1.17-2.03) / 93 (20.9) / 727 (14.6) / 1.49 (1.11-2.01)
AD_nonantaM3_ser / 111 (20.9) / 990 (18.7) / 1.11 (0.85-1.46) / 70 (15.8) / 851 (17.1) / 1.03 (0.76-1.40)
agomelatine_bupropion / 3 (0.6) / 36 (0.7) / – d / 3 (0.7) / 30 (0.6) / – d
Within 1 recent month / 210 (39.6) / 1,653 (31.2) / 1.30 (1.03-1.62) / 154 (34.7) / 1,489 (29.9) / 1.25 (0.98-1.60)
combination / 12 (2.3) / 23 (0.4) / 4.15 (1.82-9.50) / 8 (1.8) / 17 (0.3) / 6.51 (2.30-18.38)
AD_antaM3 / 99 (18.7) / 684 (12.9) / 1.56 (1.17-2.07) / 87 (19.6) / 655 (13.2) / 1.50 (1.11-2.05)
AD_nonantaM3_ser / 97 (18.3) / 908 (17.1) / 1.02 (0.77-1.36) / 57 (12.8) / 785 (15.8) / 0.91 (0.66-1.27)
agomelatine_bupropion / 2 (0.4) / 38 (0.7) / – d / 2 (0.5) / 32 (0.6) / – d
Currently treated / 179 (33.8) / 1,380 (26.0) / 1.29 (1.02-1.63) / 132 (29.7) / 1,238 (24.9) / 1.27 (0.98-1.65)
combination / 7 (1.3) / 13 (0.2) / 4.38 (1.46-13.16) / 6 (1.4) / 8 (0.2) / 9.64 (2.7-34.01)
AD_antaM3 / 87 (16.4) / 558 (10.5) / 1.56 (1.15-2.12) / 75 (16.9) / 533 (10.7) / 1.55 (1.11-2.16)
AD_nonantaM3_ser / 84 (15.8) / 781 (14.7) / 1.02 (0.75-1.38) / 50 (11.3) / 675 (13.6) / 0.92 (0.65-1.31)
agomelatine_bupropion / 1 (0.2) / 28 (0.5) / – d / 1 (0.2) / 22 (0.4) / – d
AD_antaM3 Antidepressants that antagonize M3 muscarinic receptors and have serotonin effect, AD_nonantaM3_ser Antidepressants that do not antagonize M3 muscarinic receptors and have serotonin effect, Combination is either the combination of AD_antaM3 and AD_nonantaM3_ser or the combination of AD_antaM3 and agomelatine/bupropion, OR odds ratio, CI confidence interval.
aReference category.
bOdds ratios were adjusted for the following covariates: uses ofbenzodiazepines, beta-blockers, thiazide diuretics, systemic corticosteroids, and antipsychotics within 6 recent months.
cOdds ratios were adjusted for the following covariates: uses ofbenzodiazepines, beta-blockers, thiazide diuretics, and systemic corticosteroidswithin 6 recent months.
d Not computed because there were less than 5 exposed cases or controls.