Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders. In the US, roughly every tenth child and adolescent is affected and more often than not, ADHD persists into adulthood (Kessler et al., 2006).

Controversy still surrounds the treatment of ADHD: Generally, medication with adjuvant psychological interventions such as cognitive-behavioural therapy is favoured. While the stimulant methylphenidate has been the pharmacological mainstay for years, in some cases, atomoxetine may be efficacious too (Garnock-Jones & Keating, 2009). As ADHD continues to be the cause of significant health and societal problems, however, improved treatment options are direly needed.

Recently, interest has been growing in tricyclic antidepressants (TCAs) as drugs to tackle ADHD, but a concise overview is still lacking. To this end, a recent Cochrane Review (Otasowie, Castells, Ehimare, & Smith, 2014) has taken a look at the evidence.

Methods

The authors screened several medical databases and trial registers for randomised controlled trials (RCTs) comparing any TCA with either placebo or active comparator (e.g. methylphenidate) in children or adolescents with ADHD. Patients with comorbidities, as is often the case in ADHD, were included as well. Standardised mean differences (SMD), Odds ratios (OR) and 95% confidence intervals (CI) were calculated to provide summary statistics.

Six RCTs with 216 patients were identified as satisfying inclusion criteria. Of those, five compared desipramine against placebo and one used nortriptyline. Among desipramine trials, one evaluated desipramine against clonidine (another ADHD drug) and placebo, while one trial compared desipramine and clomipramine (another TCA) with methylphenidate and placebo. Comorbidities included tic or Tourette disorder in one study, while another tested children with comorbid tic disorder only.

Overall methodological quality varied from low to very low.

Results

As a group, TCAs were significantly more effective than placebo regarding improvement of core ADHD symptoms (OR 18.50, 95% CI 6.29 to 54.39, 3 trials with 125 participants, low quality).

Looking at individual drugs, it was found that desipramine significantly improved core symptoms of ADHD (impulsivity, hyperactivity, inattention) in children and adolescents as rated by:

• Parents (SMD -1.42, 95% CI -1.99 to 0.85, 2 trials with 99 participants, low quality)
• Teachers (SMD -0.97, 95% CI -1.66 to -0.28, 2 trials with 89 participants, low quality)
• Clinicians (OR 26.41, 95% CI 7.41 to 94.18, 2 trials with 108 participants, low quality)

Compared to clonidine, desipramine was more efficacious in reducing parent-reported ADHD symptoms in a sample with comorbid tics or Tourette disorder (SMD -0.90, 95% CI -1.40 to -0.40, 1 trial with 68 participants, very low quality).

Nortriptyline was also efficacious, improving core symptoms according to clinicians (OR 7.88, 95% CI 1.10 to 56.12), although this was only supported by a single study.

Even though no serious adverse effects occurred, participants reported nausea, confusion, sedation, dry mouth and several other unpleasant experiences well known to be caused by TCAs. Also, mild increases in diastolic blood pressure and pulse were noted. Desipramine was associated with reduced appetite, while nortriptyline led to weight gain compared to placebo. However, treatment discontinuation was comparable among desipramine and placebo arms.

Summary

The authors concluded that:

Findings suggest that, in the short term, desipramine improves the core symptoms of ADHD, but its effect on the cardiovascular system remains an important clinical concern. Thus, evidence supporting the clinical use of desipramine for the treatment of children with ADHD is low.

Limitations

Overall, the quality of the RCTs included in this review was low to very low, indicating a concerning risk of bias. In addition, with only six RCTs making up this heterogeneous group of participants and designs, it remains doubtful whether sound conclusions can be drawn at this stage. In three trials, the treatment duration of just three weeks was too short to evaluate TCA therapy.

Discussion

Clearly, there’s no silver bullet for treating ADHD in children and young people. This review by Otasowie and colleagues shows that TCAs are generally a pretty bad idea to give to anyone with ADHD. We also know that there are more efficient and better tolerated pharmacological interventions (Wolraich et al., 2011).

Besides drugs, the evidence shows that adjuvant psychotherapy may help to stabilise and improve the benefits of already approved and available medications (Sonuga-Barke et al., 2013).

From a patient perspective, it’s better knowledge about successful psychological treatments that is lacking, not recycling of yet another drug.

Links

Otasowie J, Castells X, Ehimare UP, Smith CH. Tricyclic antidepressants for attention deficit hyperactivity disorder (ADHD) in children and adolescents. Cochrane Database of Systematic Reviews 2014, Issue 9. Art. No.: CD006997. DOI: 10.1002/14651858.CD006997.pub2.

Garnock-Jones KP, Keating GM. (2009). Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents. Paediatric Drugs, 11(3), 203–26. doi:10.2165/00148581-200911030-00005 [PubMed abstract]

Gellad WF, Stein BD, Ruder T, Henderson R, Frazee SG, Mehrotra A, Donohue JM. (2014). Geographic Variation in Receipt of Psychotherapy in Children Receiving Attention-Deficit/Hyperactivity Disorder Medications. JAMA Pediatrics. doi:10.1001/jamapediatrics.2014.1647 [Abstract]

Kessler RC, Adler L, Barkley R, Biederman J, Conners CK, Demler O, Zaslavsky AM. (2006). The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication (PDF). The American Journal of Psychiatry, 163(4), 716–23. doi:10.1176/appi.ajp.163.4.716

Sonuga-Barke, E. J. S., Brandeis, D., Cortese, S., Daley, D., Ferrin, M., Holtmann, M., … Sergeant, J. (2013). Nonpharmacological interventions for ADHD: systematic review and meta-analyses of randomized controlled trials of dietary and psychological treatments. The American Journal of Psychiatry, 170(3), 275–89. doi:10.1176/appi.ajp.2012.12070991 [PubMed abstract]

Wolraich, M., Brown, L., Brown, R. T., DuPaul, G., Earls, M., Feldman, H. M., … Visser, S. (2011). ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents (PDF). Pediatrics, 128(5), 1007–22. doi:10.1542/peds.2011-2654