A total of 181 RCTs with 14,790 participants met the inclusion criteria: 136 RCTs (n=9,150) compared amitriptyline with another TCA or related AD, while 45 RCTs (n=5,640) compared amitriptyline with an SSRI. Nine RCTs in which the setting was unclear were excluded from the meta-analyses. The meta-analyses included 81 RCTs of out-patients and 91 RCTs of in-patients.
Most of the studies were double-blind. Four studies used inadequate allocation concealment. Sixty studies used implicit diagnostic criteria for depression, 54 used explicit criteria, and 67 used explicit criteria and a specification of severity of illness at baseline. The studies averaged medium to low quality; the quality scores ranged from 8 to 32 out of 46 points (mean 18).
No differences were found between studies of in-patients and out-patients with respect to sample size, duration of follow-up, diagnostic criteria and quality score.
Dichotomous outcomes.
Amitriptyline was significantly more effective than other ADs in in-patients (OR 1.22, 95% CI: 1.04, 1.42), but not out-patients (OR 1.01, 95% CI: 0.88, 1.17). Among in-patients, amitriptyline was significantly more effective than TCAs (OR 1.20, 95% CI: 1.02, 1.42; 46 RCTs), but not more effective than SSRIs (OR 1.30, 95% CI: 0.87, 1.96; 5 RCTs). For out-patients, there was no statistically significant difference between amitriptyline and TCAs (OR 0.98, 95% CI: 0.81, 1.17; 31 RCTs), or between amitriptyline and SSRIs (OR 1.08, 95% CI: 0.86, 1.35; 10 RCTs).
Continuous outcomes.
Amitriptyline was significantly more effective than other ADs in in-patients (SMD 0.28, 95% CI: 0.08, 0.46; 18 RCTs), but not in out-patients (SMD 0.10, 95% CI: -0.02, 0.23; 31 RCTs). Among in-patients, amitriptyline was significantly more effective than TCAs (SMD 0.23, 95% CI: 0.03, 0.44; 11 RCTs), but not more effective than SSRIs (SMD 0.34, 95% CI: -0.03, 0.72; 7 RCTs). For out-patients, there was no statistically significant difference between amitriptyline and TCAs (SMD 0.13, 95% CI: -0.14, 0.40; 16 RCTs), or between amitriptyline and SSRIs (SMD 0.08, 95% CI: -0.05, 0.20; 15 RCTs).
Adverse effects.
Amitriptyline was significantly less well tolerated than other ADs in out-patients (OR 0.90, 95% CI: 0.81, 0.99; 80 studies with 8,360 patients), but there was no statistically significant difference between treatments among in-patients (OR 1.09, 95% CI: 0.95, 1.25; 66 studies with 4,627 patients). Among in-patients, there was no statistically significant difference between amitriptyline and TCAs, or between amitriptyline and SSRIs. Among out-patients, amitriptyline was significantly less well tolerated than SSRIs (OR 0.77, 95% CI: 0.67, 0.89), but there was no statistically significant difference between amitriptyline and TCAs.
The meta-regression showed that in studies in out-patients, amitriptyline was associated with significantly lower response rates than control ADs.