Depression affects about one in 20 young people, and can contribute to a variety of negative outcomes, such as poor academic functioning and difficulties in peer and family relationships. Depression also increases the risk for substance use, self harm and suicide. Beginning with imipramine, tricyclic drugs were developed from the late 1950s to alleviate the symptoms of depression. They were designed to enhance the availability of serotonin and noradrenaline to brain cells. Tricyclic drugs were first prescribed to children and adolescents for depression in the early 1960s, but were more commonly prescribed to children for the treatment of bedwetting. Since this Cochrane review was first published in 2000, tricyclic drugs have been replaced in most countries by newer-generation antidepressants.
This review contained 14 trials (with 590 participants) and tested the effectiveness of tricyclic drugs against placebo. Trial data were available for amitriptyline, desipramine, imipramine and nortriptyline. Based on nine trials (454 participants), there was no evidence that tricyclic drugs lead to higher rates of remission or response than placebo. Based on 13 of the trials (533 participants), there was evidence that people treated with a tricyclic drug had lower depression severity scores than those on placebo, however, the size of this difference was small. Consistent with their known mechanism of action, tricyclic drugs were more likely than placebo to cause vertigo, symptoms of lowered blood pressure, tremor and dry mouth. Subgroup analyses of six trials involving only adolescents (239 participants) and two trials involving only children (77 participants) found no evidence of differential rates of remission or response between the age groups. In contrast, there was lowering of depression scores in eight trials involving only adolescents (414 participants) and no lowering of depression scores in three trials involving only children (64 participants).
Most of the included studies were conducted in the era before standard methods for conducting treatment trials for depression in children and adolescents came about. There were considerable differences between the studies with regards to the clinical tools and methods used in assessment of improvement. Most trials were small. Only two trials produced a definitive result for depressive symptoms, and no trial produced a definitive result for response or remission. There was typically insufficient information to judge the quality of the trials accurately. With these limitations, it is difficult to answer questions about the effectiveness and safety of tricyclic drugs for treating depression in children and adolescents. Current evidence suggests that the situation is much the same for newer-generation antidepressants. Clinicians need to provide accurate information to children and adolescents, and their families, about the uncertainties regarding the benefits and risks of antidepressants as a treatment option for depression. Tricyclic drugs do not seem useful for treating children before puberty, and are, at most, of moderate benefit for adolescents.
Data suggest tricyclic drugs are not useful in treating depression in children. There is marginal evidence to support the use of tricyclic drugs in the treatment of depression in adolescents.
There is a need to identify effective and safe treatments for depression in children and adolescents. While tricyclic drugs are effective in treating depression in adults, individual studies involving children and adolescents have been equivocal. Prescribing of tricyclic drugs for depression in children and adolescents is now uncommon, but an accurate estimate of their efficacy is helpful as a comparator for other drug treatments for depression in this age group. This is an update of a Cochrane review first published in 2000 and updated in 2002, 2006 and 2010.
To assess the effects of tricyclic drugs compared with placebo for depression in children and adolescents and to determine whether there are differential responses to tricyclic drugs between child and adolescent patient populations.
We conducted a search of the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR) (to 12 April 2013), which includes relevant randomised controlled trials from the following bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (all years), EMBASE (1974-), MEDLINE (1950-) and PsycINFO (1967-). The bibliographies of previously published reviews and papers describing original research were cross-checked. We contacted authors of relevant abstracts in conference proceedings of the American Academy of Child and Adolescent Psychiatry, and we handsearched the Journal of the American Academy of Child and Adolescent Psychiatry (1978 to 1999).
Randomised controlled trials comparing the efficacy of orally administered tricyclic drugs with placebo in depressed people aged 6 to 18 years.
One of two review authors selected the trials, assessed their quality, and extracted trial and outcome data. A second review author assessed quality and checked accuracy of extracted data. Most studies reported multiple outcome measures including depression scales and clinical global impression scales. For each study, we took the best available depression measure as the index measure of depression outcome. We established predetermined criteria to assist in the ranking of measures. Where study authors reported categorical outcomes, we calculated individual and pooled risk ratios for non-improvement in treated compared with control subjects. For continuous outcomes, we calculated pooled effect sizes as the number of standard deviations by which the change in depression scores for the treatment group exceeded those for the control group.
Fourteen trials (590 participants) were included. No overall difference was found for the primary outcome of response to treatment compared with placebo (risk ratio (RR) 1.07, 95% confidence interval (CI) 0.91 to 1.26; 9 trials, N = 454). There was a small reduction in depression symptoms (standardised mean difference (SMD) -0.32, 95% CI -0.59 to -0.04; 13 trials, N = 533), but the evidence was of low quality. Subgroup analyses suggested a small reduction in depression symptoms among adolescents (SMD -0.45, 95% CI -0.83 to -0.007), and negligible change among children (SMD 0.15, 95% CI -0.34 to 0.64). Treatment with a tricyclic antidepressant caused more vertigo (RR 2.76, 95% CI 1.73 to 4.43; 5 trials, N = 324), orthostatic hypotension (RR 4.86, 95% CI 1.69 to 13.97; 5 trials, N = 324), tremor (RR 5.43, 95% CI 1.64 to 17.98; 4 trials, N = 308) and dry mouth (RR 3.35, 95% CI 1.98 to 5.64; 5 trials, N = 324) than did placebo, but no differences were found for other possible adverse effects. Wide CIs and the probability of selective reporting mean that there was very low-quality evidence for adverse events.
There was heterogeneity across the studies in the age of participants, treatment setting, tricyclic drug administered and outcome measures. Statistical heterogeneity was identified for reduction in depressive symptoms, but not for rates of remission or response. As such, the findings from analyses of pooled data should be interpreted with caution.
We judged none of these trials to be at low risk of bias, with limited information about many aspects of risk of bias, high dropout rates, and issues regarding measurement instruments and the clinical usefulness of outcomes, which were often variously defined across trials.