Table 2.
Evidence table for use of tricyclic antidepressants (TCAs) with hormonal contraception
| Author, year, funding source |
Design | Study population | Exposure psychotropic drug | Exposure contraceptive | Outcomes | Results | Strengths | Limitations | Quality |
|---|---|---|---|---|---|---|---|---|---|
| Clinical studies for TCAs | |||||||||
| Beaumont, G. 1973 Funding source not stated |
Retrospective cohort with nested case control | 114 female patients with depression taking clomipramine 30 OC users/18 completed 84 non-OC users/18 matched non-OC users completed |
Clomipramine | OCs | Response of depression to clomipramine (not otherwise defined) | No difference in drop-out rate due to side effects (22 vs. 23%) No difference in treatment response No qualitative difference in type of side effects |
Non-OC users matched by age, clomipramine dose, previous treatment, type of depression and physician | Multiple OC formulations/doses used Dose(s) of clomipramine not stated Unclear how outcomes defined or measured, no statistics reported High dropout rate (22–23% in each group) Follow-up time not reported |
II-2, poor |
| Gringras, M. 1980. Funding source not stated (PK outcomes reported in John, Seldrup and Luscombe) |
Prospective cohort | Women with depression age 18–40 suitable for treatment with clomipramine 21 COC users/15 completed 25 non-OC users/20 completed |
Clomipramine 25 mg orally at bedtime for 4 weeks | COC use (any type with either 0.015 or 0.03 mg EE) for>2 months | GPCR depression rating scale at 0,2,4 weeks |
GPCR depression scores, at baseline➔4 weeks COC users-28.1➔ 10.9 Non-OC users-22.4 ➔ 8.5 No difference in side effects. No statistics performed |
Unclear how COC use was measured with a mix of doses and formulations used Groups not similar at onset with regard to initial severity of depression. Unclear if statistics performed on differences in individual side effects. |
II-2, poor | |
| PK studies for TCAs | |||||||||
| a) John, vs. A. 1980 b) Luscombe, 1980 c) Seldrup, 1980 Funding source not stated (See Gringas, 1980 for clinical outcomes) |
PK Parallel | Women aged 18–40 with depression, n=46 a) 21 COC users/15 completed 25 non-OC users/20 completed b) 19 COC users/14 completed 23 non-OC users/20 completed c) 11 COC users 16 Non-OC users |
Clomipramine 25 mg orally at bedtime for 4 weeks | COC use (any type with either 0.015 or 0.03 mg EE) for >2 months | a) Mean plasma clomipramine across 4 weeks and dropout rate for side effects b) Mean plasma clomipramine at 4 weeks c) Correlation between clinical response and steady state plasma levels of clomipramine |
All results reported as “not significant but no p-values given a) Side effects: 13% COC users vs. 10% non-OC users Mean plasma level across 4 weeks COC users 14 ng/ml vs non-OC 17 ng/ml b) Mean plasma levels (day 28) COC users 13.2 ng/ml vs. non-OC 16.8 ng/ml c) OC users-r=0.1 Nonusers- r=−0.42 |
Steady sate of perpetrator drug achieved, repeated blood sampling over 4 weeks | Unclear how COC use was measured with a mix of doses and formulations used Results didn’t report on depression scale findings just stated “Clinical response and tolerability in the two groups were also similar” Limited relevance of PK parameters since only concentrations given |
Fair |
| Abernethy, D. R. 1984 U.S. Public Health Service and Charles A, King Trust, Inc. |
PK Parallel | Healthy women age 20–39, within 20% of ideal body weight on COC for >3 months 6 COC users 5 nomedication use |
Imipramine 50 mg once (cycle day not indicated) | COC (any type with EE≤50 mcg) | t1/2, AUC, clearance, of imipramine | Imipramine parameters for OCP users vs. non-users: ↑ AUC by 104% (415 ng/mL h.−1 vs 203) ↓ oral clearance (2322 ml/min vs 4649 ml/min) No change in oral elimination t1/2 |
Steady sate of perpetrator drug achieved | Unclear how COC use was measured with likely a range of doses and formulations used Poor sample size and one time imipramine dose |
Poor |
| Edelbroek, P. M. 1987. Funding source not stated |
PK Parallel | Women aged 18–43 with bulimia (at least 5 binges per week and at least 75% of ideal body weight) 5 OC users 13 non-OC users |
Amitriptyline 25 mg for 6 weeks | OC use (any type) | Plasma concentration of amitriptyline and metabolites (NT, Z-10-OH-NT and E-10-OH-NT) (drawn on days 15, 36 and 57) | For day 36 levels OC users had: 89.7% higher mean amitriptyline concentration 74 vs 39 mcg/L; p-0.0007 100% higher [Z- 10-OH-NT] 14 vs. 7 mcg/L; p=.02 |
Only study with amitriptyline | Women with bulimia. However when looking at PK for d-d interaction may not be relevant. Inadequate sample size (n=5 for OC user arm) Wide range of OC types and doses presumably used. OC exposure assessment not reported. Limited relevance of PK parameters since only one time concentrations given. Unclear why statistics performed only on day 36 values |
Poor |
Cmax, Maximum concentration; GPCR, general practitioner clinical research group; NT, nortriptyline; t1/2, half life; Z-10-OH-NT, Z-10-hydroxynortriptyline.