Brief summary

Rigorous Cochrane methods have been used for this systematic review. These are described in the published protocol (Antidepressants for insomnia (Protocol). Everitt H, Baldwin DS, Mayers A, Malizia AL, Wilson S. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD010753. DOI: 10.1002/14651858.CD010753) and briefly outlined below.

Project objectives

To assess the effects, safety and tolerability of antidepressants for insomnia in adults.

This SPCR funding was aimed at progressing work on a Cochrane systematic review on Antidepressants for Insomnia. The review protocol had already been published and the SCPR funds were to support a part-time research assistant to assist with data management and sourcing of relevant papers to enable the authors to make progress with the review.

Methods

Cochrane Systematic Reviewing methods.

Criteria for considering studies for this review

Types of studies: Randomised controlled trials (RCTs) including cluster and crossover RCTs.

Types of participants: We have included adult participants (aged 18 or over with no upper age limit) with a primary diagnosis of insomnia (to include Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), International Classification of Sleep Disorders (ICSD), International Statistical Classification of Diseases and Health Related Problems, 10th revision (ICD-10) (WHO 1992) and other well-recognised classifications). We have included all participant types (including those with comorbid depression or anxiety disorder and other co-morbidities).

Types of interventions

Experimental intervention

We have included any antidepressant as monotherapy including all doses.

Antidepressants will be organised into classes for the purposes of this review, as follows.

• Selective serotonin reuptake inhibitors (SSRIs): zimelidine, fluvoxamine, fluoxetine, paroxetine, sertraline, citalopram, escitalopram.
• Tricyclic antidepressants: amitriptyline, imipramine, trimipramine, doxepin, desipramine, protriptyline, nortriptyline, clomipramine, dothiepin, lofepramine.
• Heterocyclic antidepressants: mianserin, amoxapine, maprotiline.
• MAOIs: Irreversible: phenelzine, tranylcipromine, izocarboxazid; reversible: brofaramine, moclobemide, tyrima.
• Other antidepressants: NARIs: reboxetine, atomoxetine; NDRIs: amineptine, buproprion; SNRIs: venlafaxine, milnacipram, duloxetine; NASSAs: mirtazapine; SARIs: trazodone; unclassified: agomelatine, vilazodone.

Comparator interventions

• Placebo.
• Other medications for insomnia (e.g. benzodiazepines, ’Z’ drugs).
• A different antidepressant.
• Waiting list control or treatment as usual.

Key NARI: noradrenaline reuptake inhibitor. NDRI: norepinephrine-dopamine reuptake inhibitor. SNRI: serotonin-norepinephrine reuptake inhibitor. NASSA: noradrenergic and specific serotonergic antidepressant. SARI: serotonin antagonist and reuptake inhibitor

Types of outcome measures

Primary outcomes:

1.Efficacy: any subjective improvement in sleep quality or satisfaction with sleep, total sleep duration (measured in hours or minutes), sleep onset latency (measured as time taken to fall asleep), number of nocturnal awakenings or total nocturnal awakening time (measured in hours or minutes) or sleep efficiency (measured as a ratio of time asleep over time in bed). A variety of rating scales are likely to be reported, e.g. the Pittsburgh Sleep Quality Index (PSQI) (Buysse 1989); the Sleep Impairment Index (Morin 1993). Percentage improvement may be a way of assessing outcomes across different trials.

2. Safety: number and type of spontaneously reported and measuredadverse events, including reports of toxicity.

Secondary outcomes:

3.Objective measures of change in sleep (such as electroencephalogram (EEG) data).

4. Tolerability: reported information on tolerability (e.g. problems with daytime drowsiness, dropout rates). 5. Effect on daytime symptoms/functioning: reported information on changes in daytime symptoms/functioning.

Timing of outcome assessments. 

Some trials may have multiple sleep diary endpoints. We plan to report endpoints consistently reported across studies rather than the protocol-stated primary endpoint, if this is the case.

Search methods for identification of studies:

Electronic searches:

We searched OVIDMEDLINE, EMBASE, PsycINFO and the Cochrane Central Register of Controlled Trials (CENTRAL). No language or date restrictions were applied. We translated the MEDLINE search strategy into appropriate terms (subject headings) for each database. Searching other resources We reviewed the reference lists of included studies to identify further relevant studies. Ongoing studies were identified through searching the WHO trials portal, Clinical Trials.gov and the IFPMA Clinical Trials Portal. We contacted key trialists in the area to ask about ongoing work or unpublished studies they might know of, and will list in our review those we have contacted.

Data collection and analysis

Selection of studies:

All studies identified were assessed independently by two review authors using a previously prepared inclusion criteria form. Disagreements concerning the selection of studies were resolved by a third author. The review authors were not be blinded to the names of the trial authors, institutions or journal of publication. The process of study identification and its results will be outlined as flow diagrams according to the PRISMA statement (Moher 2009).

Data extraction and management

Data was extracted separately by two review authors using a data extraction form. In the case of discrepancy, a third author was consulted. We collected information on participants (age, gender, diagnosis criteria, sample size, country, setting, number of participants randomised and followed up), intervention (drug, dosage, length of treatment, any co-interventions, controls, placebo) and outcome measures (subjective improvement in sleep, rating scale, numbers of adverse events, objective measures of change in sleep, reported information on tolerability).

Main planned comparisons

The main planned comparisons are each identified antidepressant versus:

1. placebo;

2. other medications for insomnia (e.g. benzodiazepines, ’Z’ drugs);

3. other antidepressants; and

4. waiting list control or treatment as usual.

These comparisons will be made initially on a drug level, but it is likely they will need combining at a class of drug level due to the amount of data available.We will only combine drugs in analyses if they are from the same class. The ’other antidepressants’ category (see Types of interventions) will be presented together, but again only drugs of the same class will be combined to produce a pooled effect, e.g. duloxetine and venlafaxine.

Results and Conclusions

Good progress has been made with the review. 3737 titles were identified on the systematic search and these were first screened by two authors and 209 progressed to second screening. These papers were found in full text and second screened by two authors with currently 19 papers deemed eligible for inclusion in the review. Data extraction by two authors on the included papers is near completion. A further 500 titles have been identified on an updated search of the literature and a currently being screened by 2 authors.

Analysis of the data extracted is underway. We anticipate completion of the review towards the end of 2015. The results will help clinicians to make informed decisions on the use of antidepressants for insomnia and highlight areas for further research to improve the management of insomnia.

Plain English summary

Insomnia is common, 10-38% of the general population report sleep problems in the last year. Insomnia can cause daytime fatigue, distress, impairment of daytime functioning and reduced quality of life. It is associated with increased mental health problems, drug and alcohol abuse and increased healthcare utilisation.  Management of insomnia depends on the duration and nature of the sleep problem. It may involve: treating existing co-existing medical problems; advice on sleep habits and lifestyle (known as sleep hygiene); medications and psychological therapies such as cognitive behavioural therapy.

The most common medications used to treat insomnia are called ‘hypnotics’ and consist of benzodiazepines, such as temazepam, and ‘Z’ drugs, such as zopiclone. These drugs are effective in helping with sleep but have problems such as the potential of addiction and dependence. Guidelines recommend only short term use of hypnotic medications for two to four weeks duration because of these concerns. However, millions of people worldwide are on long-term hypnotic medication.

Antidepressants are widely prescribed for insomnia despite not being licensed for this use, and there being poor evidence for their effectiveness in insomnia. A significant factor in this wide prescription is likely to be concern regarding the use of hypnotic medications and clinicians seek alternative treatments for insomnia that can be used longer term. There is poor availability of psychological treatments, thus alternative medications such as antidepressants and antihistamine are tried. This review is looking in a rigorous systematic way at the evidence (or lack of it) behind the use of antidepressants for insomnia, including their efficacy, safety and tolerability using the best practice in systematic reviewing as defined by the Cochrane Collaboration. The SPCR funding has significantly enhanced the progress of this review. We are currently analysing the data extracted from relevant papers and we anticipate that the review will be complete near the end of 2015.

The results will help clinicians to make informed decisions on the use of antidepressants for insomnia and highlight areas for further research to improve the management of insomnia.

Dissemination

Everitt H, Baldwin DS, Stuart B, Lipinska G, Mayers A, Adrea L Malizia AL ,  Manson CCF, Wilson S. Antidepressants for insomnia in adults http://cochranelibrary-wiley.com/doi/10.1002/14651858.CD010753.pub2/abstract;jsessionid=B6EB3C0A797CA798A4C19B965E8D85D7.f02t04 

Public involvement

Not involved

Impact

The results of this rigorously conducted systematic review will help clinicians to make informed decisions on the use of antidepressants for insomnia and highlight areas for further research to improve the management of insomnia.

This project was funded by the National Institute for Health Research School for Primary Care Research (project number 237)

Department of Health Disclaimer

The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR School for Primary Care Research, NIHR, NHS or the Department of Health.