TIMELAPSE study—efficacy of low-dose amitriptyline versus cognitive behavioral therapy for chronic insomnia in patients with medical comorbidity: study protocol of a randomized controlled multicenter non-inferiority trial

Abstract

Background Insomnia is common in people with long-term medical conditions and is related to increased mortality and morbidity. Cognitive behavioral therapy for insomnia (CBT-I) is first choice treatment and effective for people with insomnia and comorbid long-term medical conditions. However, CBT-I has some limitations as it might not always be available or appeal to patients with medical conditions. Furthermore, a small proportion of patients do not respond to CBT-I. Preliminary evidence and clinical experience suggest that low-dose amitriptyline (AM) might be an effective alternative to treat insomnia in patients with medical comorbidity. In this randomized controlled trial, we will determine whether AM is non-inferior to the first choice treatment for insomnia, CBT-I. Methods/design This study will test if treatment with low-dose amitriptyline for insomnia in patients with medical comorbidity is non-inferior to CBT-I in a multicenter randomized controlled non-inferiority trial. Participants will be 190 adults with a long-term medical condition and insomnia. Participants will be randomly allocated to one of two intervention arms: 12 weeks AM (starting with 10 mg per day, and if ineffective at 3 weeks, doubling this dose) or 12 weeks of CBT-I consisting of 6 weekly sessions and a follow-up session 6 weeks later. The primary outcome is subjective insomnia severity, measured with the Insomnia Severity Index (ISI). The primary endpoint is at 12 weeks. Secondary outcomes include sleep quality (e.g., sleep efficiency), questionnaires on daytime functioning (physical functioning and impairment of functioning), and symptoms (e.g., fatigue, pain, anxiety) at 12 weeks and 12 months post treatment and relapse of insomnia until 12 months after treatment. Discussion Irrespective of the outcome, this study will be a much-needed contribution to evidence based clinical guidelines on the treatment of insomnia in patients with medical comorbidity. Trial registration Dutch Trial Register NTR NL7971. Registered on 18 August 2019

Comparative responses to 17 different antidepressants in major depressive disorder: Results from a 2‐year long‐term nation‐wide population‐based study emulating a randomized trial

“…26 In relation to TCA's, our data show that amitriptyline was significantly more efficacious than nortriptyline, which may be due to its "real world" effects on anxiety, sleep, and pain symptoms in MDD. 27,28 Our study supports the use of the following antidepressants for long-term treatment within: (1) SSRIs: sertraline and citalopram (2) NARI: sertraline over reboxetine (3) SNRIs: venlafaxine over duloxetine (4) NaSSAs: mirtazapine (5) other antidepressants: sertraline over vortioxetine and agomelatine (6) TCAs: amitriptyline or imipramine. These recommendations are in line with the findings and interpretations in an earlier metaanalysis from 2009 of randomized controlled trials of acute antidepressant effects for MDD by Cipriani et al 19 showing that sertraline and venlafaxine were significantly more efficacious than other antidepressants and reboxetine less efficacious than all other antidepressants.…”

“…This prescription pattern at least partly aligns with the Danish national guidelines within SSRI's recommending sertraline as first choice due to lower side effects and interaction risks and within TCA's recommending nortriptyline as first choice due to lower risk of orthostatic hypertension 26 . In relation to TCA's, our data show that amitriptyline was significantly more efficacious than nortriptyline, which may be due to its “real world” effects on anxiety, sleep, and pain symptoms in MDD 27,28 …”