The DREAMING study: Efficacy of low dose amitriptyline and mirtazapine for insomnia disorder: a double-blind, randomized, placebo-controlled trial in general practice.

insomnia is a major public health issue in general practice because of its high
prevalence and substantial impact on patients* well-being and the increased
risk of comorbidity and huge (societal) costs associated with it. Insomnia
disorder patients often require sleep medication, despite first choice
nonpharmacological treatments. These patients are at risk of benzodiazepine
misuse and abuse, given the rapid development of tolerance and dependence.
Effective and safe alternatives suitable for general practice are therefore
urgently needed. Clinical experience suggests that off-label low dose use of
well-known sedating antidepressants such as amitriptyline and mirtazapine,
might be effective, non-addictive, and well-tolerated alternatives to treat
insomnia disorder in general practice. Yet, evidence from placebo-controlled
RCTs is lacking. Hence, this pragmatic trial concerns a phase three study to
assess a new indication for well-known medication.

to assess the efficacy of a 16-week treatment period of low dose amitriptyline
(10-20 mg nightly) or mirtazapine (7.5 - 15 mg nightly) on subjective sleep
quality compared to placebo added to usual care in patients with insomnia
disorder with sleep maintenance problems in general practice. Secondary
objectives include the long-term sleep efficacy (up to 12 months), the effect
on daytime symptoms and functioning and whether it is indeed well tolerated
(safe) and sufficient in terms of pharmacological insomnia treatment.

double blind, randomized, placebo-controlled pragmatic trial in general
practice with 3 parallel treatment groups (n=3*52) in which patients are
randomized using random sequence blocks (blocks of 3) stratified by the
self-reported main type of sleep problem (frequent wakening during the night
versus waking up too early in the morning or at night and trouble falling
asleep again). It is a pragmatic trial, in which the treatment protocol mimics
current off label practice, and participants remain with their own general
practitioner during treatment and receive this treatment alongside usual
general practice care.

16-week treatment with either amitriptyline or mirtazapine or placebo, starting
at 10 mg amitriptyline and 7.5 mg mirtazapine per day, respectively, with the
possibility of doubling of these dosages if necessary following GP consultation
at 3 weeks for the period up to 14 weeks, and single dosage for all
participants during the final 2 weeks. During treatment and follow-up, usual
care by the participant*s GP continues, without restrictions.

although mild reversible side effects may be experienced, no major health risks
are expected for participants, given the extent of clinical experience with
amitriptyline and mirtazapine as antidepressants (i.e. these are generally
well-tolerated when used at the authorized, higher dose levels), and given
widespread and years of clinical experience with amitriptyline and mirtazapine,
and the exclusion of known risk groups (e.g. contra-indications, drug-drug
interactions). The intervention group may benefit from the intervention by
improved sleep quality. The placebo group may experience placebo-effects as
reported in previous studies. Participants undergo 5 questionnaire assessments:
at baseline, during treatment at 6 and 12 weeks, and during follow-up at 20
weeks and 12 months. A one-week sleep diary is requested at baseline, 12 and 20
weeks. During treatment, participants consult their GP at least twice. Both
approval and rejection of the hypothesis would contribute to an evidence-based
clinical guideline on the use of sleep medication.