Tricyclic antidepressants updated on 07-01-2025

ASD (Autism spectrum disorder): Diagnosis/Risk

R analysis
id Study   Lib. in paper Exposition period    Study type  Control type 
 
Tags OR 95%CI x1/n1 x0/n0 no cases no exposed ROB Ref.
S18373
R77507
Heuvelman, 2023 Autism spectrum disorder - Validated Read code list among primary care clinical and referral records - Mean age at end of follow-up 10.04 years, range 4–22 years during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed, sick Adjustment: Yes Monotherapy: no or not specified Partial overlapping Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy) 1.58 [1.12;2.24] -/2,148   -/16,330 - 2,148
ref
S18247
R76893
Suarez (Controls unexposed, discontinuers), 2022 Autism Spectrum Disorder - ≥ 2 dates with ICD-9 Dx 299.xx (except 299.1x) - At ≥ 1 year of age 2nd and/or 3rd trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes Monotherapy: no or not specified Unexposed sick: recent illness/treatment (during or juste before pregnancy or treatment stopped in view of pregnancy) 1.14 [0.65;1.98] 30/4,307   34/5,710 64 4,307
ref
S18248
R76894
Suarez (Controls unexposed, general pop), 2022 Autism Spectrum Disorder - ≥ 2 dates with ICD-9 Dx 299.xx (except 299.1x) - At ≥ 1 year of age 2nd and/or 3rd trimester retrospective cohort (claims database) unexposed (general population or NOS) excluded Adjustment: Yes Monotherapy: no or not specified 0.84 [0.58;1.23]
excluded (control group)
30/4,357   11,394/2,965,988 11,424 4,357
ref
S10949
R46868
Hagberg (Controls exposed to SSRIs), 2018 Autism spectrum disorder (diagnostic code including codes for autism, Asperger’s syndrome, and pervasive developmental disorder (PDD)) - Median diagnosis 5.8 years during pregnancy (anytime or not specified) retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Monotherapy: TCA only Partial overlapping 1.20 [0.96;1.52] C
excluded (control group)
98/4,856   292/17,362 390 4,856
ref
S10950
R46869
Hagberg (Controls unexposed, disease free), 2018 Autism spectrum disorder (diagnostic code including codes for autism, Asperger’s syndrome, and pervasive developmental disorder (PDD)) - Median diagnosis 5.8 years during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed, disease free excluded Adjustment: Yes Matched Monotherapy: TCA only Partial overlapping 1.95 [1.58;2.40]
excluded (control group)
98/4,856   1,500/154,107 1,598 4,856
ref
S10951
R46870
Hagberg (Controls unexposed, sick), 2018 Autism spectrum disorder (diagnostic code including codes for autism, Asperger’s syndrome, and pervasive developmental disorder (PDD)) - Median diagnosis 5.8 years during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed, sick Adjustment: No Monotherapy: TCA only Partial overlapping Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy) 1.34 [1.05;1.72] C 98/4,856   196/12,994 294 4,856
ref
S11335
R46871
Rai - Clomipramine only (Controls exposed to SSRIs), 2017 Autism spectrum disorder (ICD-9 (299), ICD-10 (F84), or DSM-IV (299) codes) - At 4-17 years during pregnancy (anytime or not specified) prospective cohort exposed to other treatment, sick excluded Adjustment: No Monotherapy: TCA only 1.81 [1.05;3.12] C
excluded (control group)
16/235   105/2,710 121 235
ref
S11126
R46872
Rai - Clomipramine only (Controls unexposed, disease free), 2017 Autism spectrum disorder (ICD-9 (299), ICD-10 (F84), or DSM-IV (299) codes) - At 4-17 years during pregnancy (anytime or not specified) prospective cohort unexposed, disease free excluded Adjustment: No Monotherapy: TCA only 3.50 [2.10;5.82] C
excluded (control group)
16/235   4,889/238,943 4,905 235
ref
S11127
R46873
Rai - Clomipramine only (Controls unexposed, sick), 2017 Autism spectrum disorder (ICD-9 (299), ICD-10 (F84), or DSM-IV (299) codes) - At 4-17 years during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: Yes Monotherapy: TCA only Unexposed sick: old history of illness/treatment (> 12 months before pregnancy) or not specified 1.76 [1.01;3.05] 16/235   353/12,325 369 235
ref
S10945
R46865
Boukhris (Controls exposed to SSRIs), 2016 Autism spectrum disorder (ICD-9 codes 299.0, 299.8, 299.9; ICD-10 codes F84.0, F84.1, F84.5, F84.8, F84.9) - End follow-up: mean 6.2 years (median 7.0 years) 2nd and/or 3rd trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Monotherapy: TCA only 0.63 [0.15;2.68] C
excluded (control group)
2/229   22/1,583 24 229
ref
S10947
R46866
Boukhris (Controls unexposed, NOS), 2016 Autism spectrum disorder (ICD-9 codes 299.0, 299.8, 299.9; ICD-10 codes F84.0, F84.1, F84.5, F84.8, F84.9) - End follow-up: mean 6.2 years (median 7.0 years) 2nd and/or 3rd trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: Yes Monotherapy: TCA only 1.03 [0.23;4.61] 2/229   1,023/142,924 1,025 229
ref
S10956
R46874
Sørensen (Controls exposed to SSRIs), 2013 Autism spectrum disorder (ICD-10, codes F84.0, F84.1, F84.5, F84.8, and F84.9) - At 4-14 years (mean 8.8 years) during pregnancy (anytime or not specified) population based cohort retrospective exposed to other treatment, sick excluded Adjustment: No Monotherapy: TCA only 1.16 [0.58;2.31] C
excluded (control group)
9/642   91/7,506 100 642
ref
S10957
R46875
Sørensen (Controls unexposed, NOS), 2013 Autism spectrum disorder (ICD-10, codes F84.0, F84.1, F84.5, F84.8, and F84.9) - At 4-14 years (mean 8.8 years) during pregnancy (anytime or not specified) population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Monotherapy: TCA only 1.50 [0.80;2.90] 9/642   5,333/646,782 5,342 642
ref
S11245
R46867
Croen, 2011 Autism spectrum disorder (autism (ICD-9-CM code 299.0), Asperger syndrome (ICD-9-CM code 299.8), or pervasive developmental disorder not otherwise specified (ICD-9-CM code 299.8)) - Age: median 3-4 years 3 months (or more) before pregnancy or during pregnancy excluded case control unexposed (general population or NOS) Adjustment: No Matched Monotherapy: TCA only 1.50 [0.55;4.09] C
excluded (exposition period)
5/22   293/1,783 298 22
ref
Total 6 studies 1.42 [1.20;1.68] 7,094 12,417
x1: number of endpoints among exposed, n1: number of exposed; x0: number of endpoints among non exposed, n0: number of non exposed; C: calculated odds ratio from numbers of events and effectives

Forest plot

StudyTE95% CIn casesn exposedweightROBABCDEF Heuvelman, 2023Heuvelman, 2023 1.58[1.12; 2.24]-2,14824%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: criticalROB mesure: criticalROB reporting: low Suarez (Controls unexposed, discontinuers), 2022Suarez, 2022 1 1.14[0.65; 1.98]644,3079%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Hagberg (Controls unexposed, sick), 2018Hagberg, 2018 2 1.34[1.05; 1.72]2944,85649%ROB confusion: unclearROB selection: lowROB classification: lowROB missing: moderateROB mesure: moderateROB reporting: moderate Rai - Clomipramine only (Controls unexposed, sick), 2017Rai - Clomipramine only, 2017 3 1.76[1.01; 3.05]36923510%ROB confusion: unclearROB selection: lowROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Boukhris (Controls unexposed, NOS), 2016Boukhris, 2016 4 1.03[0.23; 4.61]1,0252291%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Sørensen (Controls unexposed, NOS), 2013Sørensen, 2013 5 1.50[0.80; 2.90]5,3426427%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Total (6 studies) I2 = 0% 1.42[1.20; 1.68]7,09412,4170.55.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, discontinuers; 2: Controls unexposed, sick; 3: Controls unexposed, sick; 4: Controls unexposed, NOS; 5: Controls unexposed, NOS;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.42[1.20; 1.68]7,09412,4170%NAHeuvelman, 2023 Suarez (Controls unexposed, discontinuers), 2022 Hagberg (Controls unexposed, sick), 2018 Rai - Clomipramine only (Controls unexposed, sick), 2017 Boukhris (Controls unexposed, NOS), 2016 Sørensen (Controls unexposed, NOS), 2013 6 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.41[0.78; 2.56]6,3678710%NABoukhris (Controls unexposed, NOS), 2016 Sørensen (Controls unexposed, NOS), 2013 2 unexposed, sickunexposed, sick 1.42[1.19; 1.70]72711,5460%NAHeuvelman, 2023 Suarez (Controls unexposed, discontinuers), 2022 Hagberg (Controls unexposed, sick), 2018 Rai - Clomipramine only (Controls unexposed, sick), 2017 4 Tags Adjustment   - No  - No 1.34[1.05; 1.72]2944,856 -NAHagberg (Controls unexposed, sick), 2018 1   - Yes  - Yes 1.49[1.18; 1.89]6,8007,5610%NAHeuvelman, 2023 Suarez (Controls unexposed, discontinuers), 2022 Rai - Clomipramine only (Controls unexposed, sick), 2017 Boukhris (Controls unexposed, NOS), 2016 Sørensen (Controls unexposed, NOS), 2013 5 Monotherapy   - no or not specified  - no or not specified 1.44[1.07; 1.94]646,4550%NAHeuvelman, 2023 Suarez (Controls unexposed, discontinuers), 2022 2   - TCA only  - TCA only 1.41[1.14; 1.73]7,0305,9620%NAHagberg (Controls unexposed, sick), 2018 Rai - Clomipramine only (Controls unexposed, sick), 2017 Boukhris (Controls unexposed, NOS), 2016 Sørensen (Controls unexposed, NOS), 2013 4 Partial overlappingPartial overlapping 1.42[1.16; 1.73]2947,0040%NAHeuvelman, 2023 Hagberg (Controls unexposed, sick), 2018 2 Unexposed sick   - intermediate history of illness/tre ...  - intermediate history of illness/treatment (3-12 months before pregnancy) 1.42[1.16; 1.73]2947,0040%NAHeuvelman, 2023 Hagberg (Controls unexposed, sick), 2018 2   - old history of illness/treatment (> ...  - old history of illness/treatment (> 12 months before pregnancy) or not specified 1.76[1.01; 3.06]369235 -NARai - Clomipramine only (Controls unexposed, sick), 2017 1   - recent illness/treatment (during o ...  - recent illness/treatment (during or juste before pregnancy or treatment stopped in view of pregnancy) 1.14[0.65; 1.99]644,307 -NASuarez (Controls unexposed, discontinuers), 2022 1 All studiesAll studies 1.42[1.20; 1.68]7,09412,4170%NAHeuvelman, 2023 Suarez (Controls unexposed, discontinuers), 2022 Hagberg (Controls unexposed, sick), 2018 Rai - Clomipramine only (Controls unexposed, sick), 2017 Boukhris (Controls unexposed, NOS), 2016 Sørensen (Controls unexposed, NOS), 2013 60.55.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-1.82.10.9180.000Heuvelman, 2023Suarez (Controls unexposed, discontinuers), 2022Hagberg (Controls unexposed, sick), 2018Rai - Clomipramine only (Controls unexposed, sick), 2017Boukhris (Controls unexposed, NOS), 2016Sørensen (Controls unexposed, NOS), 2013

Asymetry test p-value = 0.9311 (by Egger's regression)

slope=0.3606 (0.1332); intercept=-0.0575 (0.6249); t=0.0920; p=0.9311

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 10956, 10945, 11335, 11126, 10949, 10950, 18248

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.63[0.98; 2.72]24,29410,31983%NASuarez (Controls unexposed, general pop), 2022 Hagberg (Controls unexposed, disease free), 2018 Rai - Clomipramine only (Controls unexposed, disease free), 2017 Boukhris (Controls unexposed, NOS), 2016 Sørensen (Controls unexposed, NOS), 2013 5 unexposed, sick controlsunexposed, sick controls 1.42[1.19; 1.70]72711,5460%NAHeuvelman, 2023 Suarez (Controls unexposed, discontinuers), 2022 Hagberg (Controls unexposed, sick), 2018 Rai - Clomipramine only (Controls unexposed, sick), 2017 4 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.25[1.02; 1.53]6355,9620%NAHagberg (Controls exposed to SSRIs), 2018 Rai - Clomipramine only (Controls exposed to SSRIs), 2017 Boukhris (Controls exposed to SSRIs), 2016 Sørensen (Controls exposed to SSRIs), 2013 40.510.01.0