British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders: An update

https://doi.org/10.1177/0269881119855343

Journal of Psychopharmacology

2019, Vol. 33(8) 923 –947

The Author(s) 2019

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DOI: 10.1177/0269881119855343

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British Association for Psychopharmacology

consensus statement on evidence-based

treatment of insomnia, parasomnias and

circadian rhythm disorders: An update

Sue Wilson

, Kirstie Anderson

, David Baldwin

, Derk-Jan Dijk

Audrey Espie

, Colin Espie

, Paul Gringras

, Andrew Krystal

David Nutt

, Hugh Selsick

and Ann Sharpley

Abstract

This British Association for Psychopharmacology guideline replaces the original version published in 2010, and contains updated information and

recommendations. A consensus meeting was held in London in October 2017 attended by recognised experts and advocates in the field. They were

asked to provide a review of the literature and identification of the standard of evidence in their area, with an emphasis on meta-analyses, systematic

reviews and randomised controlled trials where available, plus updates on current clinical practice. Each presentation was followed by discussion,

aiming to reach consensus where the evidence and/or clinical experience was considered adequate, or otherwise to flag the area as a direction for

future research. A draft of the proceedings was circulated to all speakers for comments, which were incorporated into the final statement.

Keywords

Sleep disorders, insomnia, circadian rhythm disorders, parasomnias, guidelines, evidence-based treatment

855343

JOP0010.1177/0269881119855343Journal of PsychopharmacologyWilson et al.

research-article2019

BAP Guidelines

Table of Contents

Introduction 2

Method 2

Insomnia 2

Scope of the guidelines 2

Table 1 Levels of evidence 3

Epidemiology of insomnia 3

Table 2 Insomnia: diagnostic criteria 4

Diagnosis of insomnia 4

Figure 1 Diagnosis of insomnia 5

Comorbidity 5

Costs and consequences of insomnia 5

Figure 2 The ideal sleeping pill 6

Recommendation 6

Psychological treatment of insomnia 7

Underpinning principles – cognitive

behavioural therapy 7

Recommendation 7

Drug treatments for insomnia 7

Underpinning principles - pharmacology 8

Underpinning principles – pharmacokinetics 8

Figure 3 treatment of insomnia 9

Tolerance, dependence and withdrawal 9

Pharmacological treatment of insomnia 10

Recommendations 10

Long-term use of sleeping medications 10

Recommendation 11

Using drugs for depression to treat insomnia 11

Recommendations 12

Drugs for psychosis for treatment of insomnia 12

Recommendations 13

Antihistamines (H1 antagonists) 13

Recommendations 13

Circadian rhythm disorders 13

Diagnosis of circadian rhythm disorders 14

Treating circadian rhythm disorders 14

Recommendations 14

Parasomnias 15

Diagnosis of parasomnias 15

Treatment of parasomnias 15

Special populations 16

Sleep disorders in women: effects of

menopause and pregnancy 16

Menopause 16

Recommendations 16

Pregnancy 16

Recommendations 16

Treatment of insomnia in older adults 17

Recommendation 17

Sleep problems in children 17

Recommendations 18

Sleep disturbance in adults with intellectual disability 18

Assessment 18

Treatment considerations 18

Recommendations 19

References 19

Appendix 1 25

924 Journal of Psychopharmacology 33(8)

Introduction

Sleep disorders are common in the general population, and even

more so in clinical practice, yet are relatively poorly understood

by doctors and other health care practitioners. These British

Association for Psychopharmacology (BAP) guidelines address

this problem by providing an accessible yet up-to-date and evi-

dence-based outline of the major issues, especially those relating

to reliable diagnosis and appropriate treatment. We limited our-

selves to discussion of sleep problems that are not regarded as

being secondary to sleep disordered breathing; National Institute

of Clinical Excellence (NICE) guidelines for this are summarised

on the NICE website and an updated guideline will be available

in 2020; a comprehensive toolkit is available at the British Sleep

Society website, http://www.sleepsociety.org.uk. We also did not

consider certain sleep disorders for which sets of guidelines

already exist, such as narcolepsy (Billiard et al., 2006) and rest-

less legs syndrome (Picchietti et al., 2015). Thus, the main scope

of this document is to address insomnia, circadian rhythm disor-

ders (CRDs) and the more common parasomnias which are likely

to present to primary care physicians and psychiatrists.

The BAP is an association of psychiatrists, psychopharma-

cologists and preclinical scientists who are interested in the broad

field of drugs and the brain. BAP is the largest national organisa-

tion of its kind worldwide, and publishes the Journal of

Psychopharmacology. The association started publishing con-

sensus statements more than two decades ago, and the first BAP

guidelines on depression were considered a landmark publication

when they appeared in 1993 (Montgomery et al., 1993). There

are now guidelines for the treatment and management of most of

the disorders encountered in psychiatry; all guidelines are avail-

able to download from the BAP website (http://www.bap.org.uk).

Method

This British Association for Psychopharmacology guideline

replaces the original version published in 2010, (Wilson et al

2010) and contains updated information and recommendations. A

consensus meeting was held in London in October 2017, attended

by recognised experts and advocates in the field. They were

asked to provide a review of the literature and identification of

the standard of evidence in their area, with an emphasis on meta-

analyses, systematic reviews and randomised controlled trials

(RCTs) where available, plus updates on current clinical practice.

Each presentation was followed by discussion, aiming to reach

consensus where the evidence and/or clinical experience was

considered adequate, or otherwise to flag the area as a direction

for future research. The previous consensus statement was then

updated with the new evidence and references.

Categories of evidence for causal relationships, observational

relationships and strength of recommendations are given in

Table 1 and are taken from (Shekelle et al., 1999). The strength

of recommendation reflects not only the quality of the evidence,

but also the importance of the area under study. For example, it is

possible to have methodologically sound (category I) evidence

about an area of practice that is clinically irrelevant, or has such

a small effect that it is of little practical importance and therefore

attracts a lower strength of recommendation. However, more

commonly, it has been necessary to extrapolate from the available

evidence leading to weaker levels of recommendation (B, C or

D) based upon category I evidence statements. The costs of the

meeting were defrayed by BAP. All speakers completed conflict

of interest statements that are held at the BAP office according to

BAP policy.

Insomnia

Scope of the guidelines

Our intention is to provide an updated statement to guide clini-

cians who manage patients in primary or secondary medical care.

There have been three sets of guidelines for the treatment of

insomnia since the previous BAP consensus (Qaseem et al.,

2016; Riemann et al., 2017; Sateia et al., 2017). The first set of

guidelines concerns adults with insomnia and includes insomnia

comorbid with other disorders such as depression; the second set

addresses primary insomnia without comorbidity; the third set

covers all adults with chronic insomnia disorder. These sets were

discussed by the expert group and where appropriate some ele-

ments were incorporated in the present consensus.

Since the publication of the 2010 BAP guideline, there has

been an important shift in thinking about the diagnosis and clas-

sification of insomnia. The historical perspective that insomnia

could be either ‘primary’ or ‘secondary’, is no longer regarded as

valid or evidence-based. Rather, the expanding literature has led

the American Psychiatric Association (APA) (Diagnostic and

Statistical Manual of Mental Disorders (DSM)-5) and the

American Academy of Sleep Medicine (AASM) (International

Classification of Sleep Disorders (ICSD)-3) to recommend that

chronic insomnia disorder (APA) should be considered as a dis-

order in its own right.

This means that insomnia disorder should be diagnosed

whenever insomnia diagnostic criteria are met, irrespective of

any concurrent physical disorder or mental disorder; and, impor-

tantly, also irrespective of any other concurrent sleep disorder. It

is anticipated that International Classification of Diseases 11

Revision (ICD-11) will reflect the same conclusions when it is

presented at the World Health Assembly for adoption by member

states in 2019.

Centre for Psychiatry, Imperial College London, London, UK

Regional Sleep Service, Freeman Hospital, Newcastle Upon Tyne, UK

Clinical and Experimental Sciences, University of Southampton,

Southampton, UK

Sleep Research Centre, University of Surrey, Guildford, UK

Psychology Department, NHS Fife, Dunfermline, UK

Nuffield Department of Clinical Neurosciences, University of Oxford,

Oxford, UK

Guy’s and St Thomas’ NHS Foundation Trust, London, UK

Psychiatry and Behavioral Science, University of California, San

Francisco, CA, USA

Royal London Hospital for Integrated Medicine, London, UK

Department of Psychiatry, University of Oxford, Oxford, UK

Corresponding author:

Sue Wilson, Centre for Psychiatry, Division of Brain Sciences, Imperial

College, Burlington Danes Building, Hammersmith Hospital campus,

160 Du Cane Road, London, W12 0NN, UK.

Email: [email protected]

Wilson et al. 925

The complex relationship between insomnia and psychiat-

ric disorders has been the subject of much recent research. It is

increasingly recognised that sleep plays a central role in the

regulation of emotion and emotion processing (Palmer and

Alfano, 2017; Tempesta et al., 2018). Therefore, it is not sur-

prising to see a bidirectional relationship between insomnia

and mental disorder. There is considerable evidence that pre-

existing insomnia confers risk for the development of (or

relapse into) depression). This makes it all the more important

to consider the time-course of how insomnia and other psychi-

atric symptoms develop and resolve (Sánchez-Ortuño and

Edinger, 2012).

Insomnia often starts with a specific problem, for example

a stressful life event such as the loss of a job or change to a

more demanding one; or through something that changes sleep

patterns, such as the birth of a child or starting shift work. In

some people this acute insomnia persists into a chronic state.

Factors involved in the persistence of insomnia are not fully

established, but include anxiety about sleep, maladaptive sleep

habits and the possibility of an underlying vulnerability in

sleep-regulating mechanisms. Persistence of the precipitating

stressor can also contribute. Some cases of insomnia are pre-

cipitated by, or co-morbid with, other psychiatric disorders

especially anxiety and depression, or by physical illness such

as cancer or arthritis.

The nature of sleep changes with age. Older age is associated

with poorer objectively-measured sleep with shorter sleep time,

diminished sleep efficiency, and more arousals. These changes

may be more marked in men than women according to a very

large study of elderly people living at home in the USA (Sleep

Heart Health Study; Unruh et al., 2008). In the same study, the

association of subjective report of poor sleep with older age was

stronger in women. The higher prevalence of chronic health con-

ditions, including sleep apnoea, in older adults did not explain

changes of sleep parameters with aging and age-sex differences

in these relationships.

There is now greater consensus about how long insomnia

should have been present before it merits intervention. Chronic

insomnia is regarded as established after three months of persis-

tent poor sleep. There is also general agreement that when insom-

nia causes significant personal distress or marked impairment

then some form of treatment is appropriate. The cause of insom-

nia may be known or not, and knowledge of causation is not nec-

essary for a diagnosis.

Epidemiology of insomnia

Studies of prevalence of insomnia in the general population indi-

cate that one third of adults in Western countries experience dif-

ficulty with sleep initiation or maintenance at least once a week

(LeBlanc et al., 2009; Leger and Poursain, 2005; Sateia et al.,

2000), and 6–15% are thought to meet the criteria of insomnia in

that they report sleep disturbance as well as significant daytime

dysfunction (LeBlanc et al., 2009; Sivertsen et al., 2009). One-

year incidence rates have been reported to be 30.7% for insomnia

symptoms and 7.4% for insomnia syndrome. These rates

decreased to 28.8% and 3.9% for those without a prior lifetime

episode of insomnia (LeBlanc et al., 2009). There is much evi-

dence that insomnia can be a long-term disorder. In one large UK

study, about three-quarters of patients reported symptoms lasting

at least a year (Morphy et al., 2007) and, in a population-based

three-year longitudinal study, 46% of subjects who had insomnia

at baseline still had it at the three-year time point. The course of

insomnia was more likely to be persistent in those with more

severe insomnia at baseline and in women and older adults

(Morin et al., 2009). Two studies have described an increase of

insomnia over time: in the UK, insomnia diagnosis increased

from 3.1% to 5.8% (National Psychiatric Morbidity Surveys

1993–2007; Calem et al., 2012); and in Norway, insomnia diag-

nosis increased from 11.9% to 15.5% between two surveys in

2000–2010 (Pallesen et al., 2014).

Table 1. Levels of evidence.

Category of evidence:

Ia — evidence for meta-analysis of randomised controlled trials.

Ib — evidence from at least one randomised controlled trial.

IIa — evidence from at least one controlled study without randomisation.

IIb — evidence from at least one other type of quasi-experimental study.

III — evidence from non-experimental descriptive studies, such as comparative studies, correlation studies, and case-control studies.

IV — evidence from expert committee reports or opinions or clinical experience of respected authorities, or both.

Strength of recommendation:

A — directly based on category I evidence.

B — directly based on category II evidence or extrapolated recommendation from category I evidence.

C — directly based on category III evidence or extrapolated recommendation from category I or II evidence.

D — directly based on category IV evidence or extrapolated recommendation from category I, II or III evidence.

What is known about prevalence of insomnia:

 Estimates of prevalence of insomnia vary according to the

definition used (Ia).

 Prevalence of symptoms varies with age, with increase of

nocturnal awakenings but decrease in complaints of non-

restorative sleep as people age (Ib).

 Prevalence is between 1.5–2 times higher in women than in

men (Ia).

 Insomnia is a long-term disorder; many people have had

insomnia for more than two years (Ib).

 Approximately half of all diagnosed insomnia is comorbid with

a psychiatric disorder (Ib).

What is not known:

 What is the prevalence of distress about sleep?

 What is the significance of duration of symptoms on distress?

926 Journal of Psychopharmacology 33(8)

There is a higher incidence of insomnia in women, and the

incidence increases in men and women as they get older (see

below – special populations). The symptom prevalence changes

with age, so that people aged over 65 years show more sleep

maintenance problems but a decrease in reported daytime prob-

lems compared with younger age groups, with little change in the

prevalence of sleep onset insomnia.

Diagnosis of insomnia

Diagnostic criteria from the APA, AASM and World Health

Organization (WHO) are summarised in Table 2. They agree that

insomnia is a complaint of unsatisfactory sleep, either in terms of

sleep onset, sleep maintenance or early waking. In DSM-5 and

ICSD-3 this complaint must be present three or more nights per

week, for at least three months, and be associated with impair-

ment to day-time functioning or well-being. In this sense insom-

nia can be considered a ‘24-hour’ disorder, because a complaint

of unsatisfactory sleep without reported functional sequelae

would not meet clinical diagnostic criteria.

Like other disorders and conditions classified within DSM-5,

insomnia is largely a subjectively determined disorder.

Polysomnographic (PSG) and actigraphic studies do indicate that

people with insomnia take longer to fall asleep and have sleep that

is more fragmented than healthy good sleepers. However, these

parameters do not reflect the level of sleep disturbance reported by

people with insomnia; and they do not sample daytime experience.

Moreover, PSG and actigraphy are not indicated for use in insom-

nia – except if other sleep disorders are suspected (Sateia et al.,

2017) – and, in any case, are seldom available in routine care.

Like depression, anxiety or pain, there is no objective test for

insomnia, and in practice it is evaluated clinically. Diagnosis,

therefore, is through appraisal against diagnostic criteria, clinical

observations and the use of validated rating scales.

There are a number of ways in which sleep can be assessed.

The simplest is by asking the patient about their sleep. Are they

having difficulty getting to sleep and/ or staying asleep? Is this

occurring most nights? Is this persistent and affecting how they

feel during the day?

An extension of this interview enquiry is to administer a

clinical rating scale. The Sleep Condition Indicator (SCI) is

one such scale being based on contemporary diagnostic criteria

and has been validated in over 200,000 adults. It also has a

short-form screening version comprising only two items (Espie

et al., 2014, 2018b; Luik et al., 2019; see Appendix 1).

A further step is to provide the patient with a sleep diary. This

allows the assessment of sleep difficulties over time, and gauges

the potential contribution of poor sleep and lifestyle habits to

daytime impairment. Some patients appreciate completing a

diary to capture the nature of their sleep problems, including the

unpredictability of their sleep from night to night. The SCI and

the diary may also be useful to assess treatment-related change.

Finally, it is important to determine if another sleep disorder (see

preliminary questions below), or a physical (such as pain, heart or

metabolic disease), neurological (such as Parkinson’s disease or cer-

ebrovascular disease) or psychiatric (such as depressive illness,

anxiety disorder or substance use disorder) disorder is present along-

side the insomnia. The insomnia problem should be actively treated,

but consideration of the interplay between conditions is good clinical

practice. A diagram illustrating diagnosis is given in Figure 1.

Table 2. Insomnia: diagnostic criteria.

International Classification

of Sleep Disorders (ICSD-3)

and (Sateia etal. 2017)

The patient reports (or the patient’s

parent or caregiver reports) marked

concern about, or dissatisfaction

with, sleep comprising one or more

of the following:-difficulty initiating

sleep, difficulty maintaining sleep,

waking up earlier than desired,

resistance in going to bed on the

appropriate schedule,

difficulty sleeping without the

parent or caregiver present.

Occurs despite adequate

opportunity and

circumstances for sleep.

At least one form of daytime

impairment e.g.

fatigue; mood disturbance;

interpersonal problems; reduced

cognitive function; reduced

performance; daytime sleepiness;

behavioural problems (e.g.

hyperactivity, impulsivity,

aggression); reduced motivation/

initiative; proneness to errors/

accidents.

International Classification

of Diseases (ICD)-10; World

Health Organization (WHO),

1992

Difficulty

- falling asleep,

- maintaining sleep or

- non-refreshing sleep

Three times a week and for

longer than 1 month

Marked personal distress or

interference with personal

functioning in daily living

Diagnostic and Statistical

Manual of Mental Disorders

(DSM-5; insomnia disorder)

Unhappiness with the quality or

quantity of sleep, which can include

trouble falling asleep, staying asleep

or waking up early and being unable

to get back to sleep. The problem

occurs despite ample opportunity to

sleep. The difficulty cannot be better

explained by other physical, mental

or sleep-wake disorders. The problem

cannot be attributed to substance

use or medication.

Three nights a week for at

least 3 months.

The sleep disturbance causes

significant distress or

impairment in functioning,

such as within the individual’s

working or personal life,

behaviourally or emotionally.

Wilson et al. 927

Comorbidity

There is a generally high incidence of sleep disorders in psychi-

atric conditions. The most widely reported are shown below:

Costs and consequences of insomnia

Insomnia is now recognised as reliably associated with mental

health disorders including risk of depression and suicide

(Baglioni and Riemann, 2012; Pigeon et al., 2017), cardiovascu-

lar disease (Khan and Aouad, 2017) and type 2 diabetes

(Cappuccio et al., 2010; Vgontzas et al., 2009). Increased fatigue,

impaired work productivity, reduced quality of life, and relation-

ship dissatisfaction are also common in those with insomnia

(Espie et al., 2012; Kyle et al., 2010; Roth and Ancoli-Israel,

1999). Indeed, such impaired functioning is an important driver

for help-seeking behaviour (Morin et al., 2006).

There is at least a two-fold increased risk of subsequent

depression and anxiety disorder in patients with pre-existing

insomnia (Baglioni and Riemann, 2012). Insomnia has been asso-

ciated with: (a) an increased risk of developing subsequent depres-

sion; (b) an increased duration of established depression; and (c)

relapse following treatment for depression (Riemann, 2009). Poor

sleep quality also seems to correlate with high negative and low

positive emotions, both in clinical and subclinical samples. Good

sleep seems to be associated with high positive emotions, though

not necessarily with low negative emotions (Baglioni et al., 2010).

The strong relationship between insomnia and emotional vul-

nerability has been established for 30 years. The National

Institute of Mental Health Epidemiologic Catchment Area inter-

viewed 7954 adults on two occasions a year apart, and high-

lighted the strong association between sleep disturbance and

subsequent depression. It was found that 14% of those with

insomnia at the first interview had developed a new major depres-

sive episode one year later (Ford and Kamerow, 1989). This

increased risk of developing depression has been confirmed in

numerous investigations: in a survey of 1200 young adults in

Michigan, the odds ratio of new depression was four times

greater in those subjects who had insomnia three years earlier

(Breslau et al., 1996) and of new anxiety disorder the risk was

Figure 1. Diagnosis of insomnia.

Asking about another sleep disorder: preliminary questions:

 Are you a very heavy snorer? Does your partner say that you

sometimes stop breathing at night? (obstructive sleep apnoea

syndrome (OSAS)).

 When you try to relax in the evening or sleep at night, do you

ever have unpleasant, restless feelings in your legs that can be

relieved by walking or movement? (restless legs syndrome (RLS)).

 Do you sometimes fall asleep in the daytime completely without

warning? Do you have collapses or extreme muscle weakness

triggered by emotion, for instance when you’re laughing?

(narcolepsy).

 Do you tend to sleep well but just at the ‘wrong times’; and are

these sleeping and waking times regular? (circadian rhythm

sleep disorder (CRD); evidence also from sleep diary).

 Do you have unusual or unpleasant experiences or behaviours

associated with your sleep that trouble you or that are

dangerous? (parasomnias).

Major depressive disorder Up to 70% insomnia

Up to 15% hypersomnia

Post-traumatic stress disorder

(PTSD)

Insomnia

Nightmares

Non-REM parasomnia

Schizophrenia CRD

Dementia Insomnia

CRD

Substance abuse Insomnia

Parkinson’s disease, Lewy Body

dementia

REM behaviour disorder

RLS

What is known about detrimental effects of insomnia:

 Quality of life is impaired in insomnia (Ia).

 There is an increased risk of subsequent first-episode

depression, and of relapse into depression, in those with a pre-

existing chronic insomnia (Ia).

 There is an increased risk of type 2 diabetes and hypertension in

insomnia with objectively-measured short sleep duration (II).

 ‘Presenteeism’ (lack of productivity at work), absenteeism, acci-

dents at work and road accidents are increased in insomnia (II).

What is not known:

 What are the potential confounding effects of medication and

comorbid disorders in reports of increased accidents?

 To what extent do insomnia treatments rectify risk markers for

emotional, metabolic and cardiovascular disease, or prevent

development of disorders at a clinical level?

928 Journal of Psychopharmacology 33(8)

two-fold greater. In a questionnaire survey of adults in the UK,

there was a three-fold increased risk of new depression and a

two-fold risk of new anxiety disorder if subjects had reported one

sleep problem occurring ‘on most nights’ a year earlier (Morphy

et al., 2007). In a much longer study in Norway, with two surveys

10 years apart (Neckelmann et al., 2007), the risk of having an

anxiety disorder diagnosis at the second time point increased by

about one and a half times if insomnia had been present at the

first time point, and about five times if insomnia was present at

both time points. Doctors in a prospective study who had com-

plained of insomnia whilst studying at medical school in the

1950s and 1960s were twice as likely to have developed depres-

sion at follow-up in the 1990s (Chang et al., 1997).

Insomnia is associated with activation of the hypothalamic-

pituitary-adrenal (HPA) axis, with increased adrenocorticotrophin

(ACTH) and cortisol in most studies (Varkevisser et al., 2005;

Vgontzas et al., 1998; Vgontzas et al., 2001). When the complaint

of insomnia is accompanied by short duration of sleep measured

objectively, there is a 3–5-fold increase in overall risk of hyperten-

sion which is comparable to that seen with other common sleep

disorders, such as sleep disordered breathing (Vgontzas et al.,

2009). In France, Japan and the USA, insomnia patients scored

significantly lower on all eight domains of the SF-36 quality of life

questionnaire, compared with good sleepers (Leger, 2012).

People with a diagnosis of insomnia also have subjective

complaints of poor daytime function. When compared with

matched controls, they show increased subjective sleepiness but

decreased objective sleepiness, due to the fact that they are usu-

ally over-aroused, but feel subjectively tired. Objectively, they

show poorer performance on psychomotor tasks, particularly

those requiring the switching of attention (e.g. frontal/executive

tasks) (Edinger et al., 2008): objectively measured time awake

after sleep onset (WASO) was the best predictor of impaired

daytime performance. Likewise, Altena et al. (Altena et al.,

2008) reported that people with insomnia perform more poorly

on complex cognitive tasks, an effect which normalises follow-

ing cognitive behavioural therapy (CBT) intervention. A meta-

analysis of 24 studies (Fortier-Brochu et al., 2012). comparing

the daytime cognitive performance of people with insomnia and

good sleeper controls found that those with insomnia exhibited

performance impairments of small to moderate magnitude in

working memory, episodic memory and some aspects of execu-

tive functioning. However no significant group differences were

observed for tasks assessing general cognitive function, percep-

tual and psychomotor processes, procedural learning, verbal

functions, different dimensions of attention (alertness, complex

reaction time, speed of information processing, selective atten-

tion, sustained attention/vigilance) and some aspects of execu-

tive functioning (verbal fluency, cognitive flexibility).

The economic burden of insomnia is high, with overall costs

thought to exceed US$100 billion per year in the USA (Wickwire

et al., 2016). In Europe, the economic costs of insufficient sleep,

including disruption from insomnia and other sleep difficulties

were modelled across five countries; in the UK costs were esti-

mated at 1.86% of Gross Domestic Product or US$50 billion to

the economy (Hafner et al., 2017). Costs are both direct (pre-

scription costs, appointments and inpatient care) and indirect

(lost workplace productivity/presenteeism, absenteeism, and

increased risk of traffic and workplace accidents) (Daley et al.,

2009; Leger et al., 2014). Increased insomnia severity has also

been shown to be associated with increased healthcare utilisation

(Wickwire et al., 2016) and people with insomnia have higher

healthcare costs than controls (Wickwire et al, 2019). The major-

ity of studies indicate that the cost of treating insomnia is less

than the cost of not treating insomnia, and that treatment costs

appear to be recouped within 6–12 months (Morgan et al., 2004;

Wickwire et al., 2016).

Recommendations

It is important to treat insomnia because the condition

causes decreased quality of life, is associated with impaired

functioning in many areas, and leads to increased risk of

depression, anxiety and possibly diabetes and cardiovascu-

lar disorders (A).

Goal of treatment:

 To lessen suffering.

 Improve daytime function.

Type of treatment:

 Cognitive-behavioural therapy for insomnia (CBTi)

should be offered as first line treatment.

 In case of treatment failure, unavailability of CBTi, or

inability to engage with CBTi, pharmacological treatment

with an evidence base should be offered (see Figure 2).

Figure 2. Treatment of insomnia.

Wilson et al. 929

Psychological treatment of insomnia

Underpinning principles – CBT. Psychological treatment of

insomnia should be considered appropriate for a number of

reasons.

First, insomnia has across diagnostic and classification sys-

tems been long regarded as a ‘psychophysiological’ disorder in

which mental and behavioural factors play crucial roles as predis-

posing, precipitating and perpetuating factors (Espie, 2002; Espie

et al., 2006; Kalmbach et al., 2018; Riemann et al., 2010;

Spielman et al., 1987). Core features of insomnia are heightened

arousal and learned sleep-preventing associations. Arousal can

reflect a general cognitive hypervigilance and many patients

describe ‘racing thoughts’ as a problem when they are trying to

sleep. A cycle develops in which the more one strives to sleep,

the more agitated one becomes, and the less able one is to fall

asleep. All of these sleep-related behaviours and attitudes con-

trast with those of the ‘good sleeper’ who seems to sleep without

much thought or planned behaviour.

Second, CBTi directly addresses these cognitive and behav-

ioural factors, particularly those that maintain insomnia. CBTi

employs a package of interventions designed to encourage ‘poor

sleepers’ to think and behave like ‘good sleepers’. The therapy is

manualised and health professionals can be trained to administer

it either individually or in a group setting. Therapies are multi-

modal, embodying techniques such as sleep restriction and stim-

ulus control as well as cognitive restructuring. CBT then is a

treatment modality, as is pharmacotherapy. The latter comprises

a range of licensed medications, and the former a range of proven

psychotherapeutic methods.

Third, and most importantly, there is a substantial evidence base

for the safety, efficacy and clinical effectiveness of CBTi. Systematic

reviews and meta-analyses have consistently found that CBTi

reduces sleep latency and the duration and frequency of night-time

wakenings, as well as increasing sleep efficiency with moderate to

large effect sizes. CBT also increases total sleep time, and the ben-

efits of CBTi are durable at medium to long-term follow up.

Importantly, side-effects with CBTi are relatively minimal,

with some patients reporting mild daytime sleepiness in the early

stages of sleep restriction and stimulus control. However, there is

considerable evidence of generalised benefit to mood, wellbeing,

and to social and occupational functioning in controlled trials

(Espie et al., 2018a; Van Houdenhover, 2011). Recent insomnia

CBT studies have demonstrated a causal relationship between

improvements in sleep and improvements in mental health symp-

toms, wellbeing and quality of life (Espie et al., 2018a, b;

Freeman et al., 2017)

CBTi is therefore lastingly effective, and is the recommended

treatment of first choice for chronic insomnia in guideline docu-

ments (e.g. American College of Physicians: Qaseem et al., 2016;

European Insomnia Guidelines, Riemann et al., 2017).

A longstanding problem for CBTi is not its effectiveness but

its availability. At the time of writing of the 2010 BAP guideline,

reference was made to this ongoing challenge and how it hin-

dered real world implementation. CBT is traditionally offered

face-to-face and so has been restricted by the number of available

therapists to provide treatment. The advent of digital CBT

(dCBT; Web and mobile delivery) has changed this landscape.

There are now four published meta-analyses of dCBT which

indicate comparable effectiveness to in-person CBTi and demon-

strate the emerging opportunity for patients to access this form of

CBT treatment (Cheng and Dizon, 2012; Seyffert et al., 2016; van

Straten et al., 2018; Zachariae et al., 2016). Two dCBT interven-

tions in particular have a considerable evidence base. There are

seven published RCTs of the SHUT-i product (with a total sample

size n~2100 and eight published RCTs of the Sleepio product

(total n~6900). The available evidence base is not just for CBT (in

general), but also for discrete dCBT ‘products’; a situation that

more closely aligns with the pharmaceutical literature where spe-

cific drugs can be seen as discrete pharmacotherapy products that

can be offered as part of a formulary-driven pharmacopeia.

Recommendations

CBT-based treatment packages for chronic insomnia

including sleep restriction and stimulus control are effective

and therefore should be offered to patients as a first-line

treatment (A).

Both face to face CBTi and dCBTi are efficacious (A).

dCBTi has the potential to offer patients and clinicians a

choice amongst evidence-based alternatives (CBT or drugs)

in routine clinical care (A).

Drug treatments for insomnia

What is known about psychological treatment of insomnia:

 CBTi is an effective treatment for insomnia when delivered

individually or in small group format (Ia).

 CBTi is an effective treatment for insomnia when delivered

digitally as a Web/mobile intervention (1a).

 CBTi is as effective as prescription medications for short-term

treatment of chronic insomnia. Moreover, there are indications

that the beneficial effects of CBT may last well beyond the

termination of active treatment (Ia).

 Improvements in sleep following CBTi for chronic insomnia

mediate improvements in mental health symptoms, wellbeing

and quality of life (1a).

What is not known:

 What are the predictors of failure to respond to CBTi?

 Does hypnotic medication enhance the effects of CBTi and, if it

does, under what circumstances?

What is known about drug treatments for short-term treatment

of insomnia:

 Gamma-aminobutyric acid (GABA)-positive allosteric modulators

(PAMs) are efficacious for insomnia (Ia).

 Safety concerns (adverse events and carry-over effects) are

fewer and less serious in hypnotics with shorter half-lives (Ib).

 Prolonged release melatonin improves sleep onset latency and

quality in patients over 55 years (Ib).

 Suvorexant is efficacious in insomnia (Ia).

 Doxepin in very low doses (3 mg and 6 mg) is efficacious in

insomnia (Ia).

What is not known:

 Does improvement in insomnia last after treatment is stopped?

 Does treatment reduce the risk of subsequent depression?

 Who responds and who does not?

930 Journal of Psychopharmacology 33(8)

Underpinning principles – pharmacology.

Most drugs which

affect the brain do so by affecting neurotransmitter function in

the brain, which they can do by:

 simulating the action of a brain neurotransmitter on the

receptor (agonists, partial agonists)

 blocking neurotransmitter action on postsynaptic recep-

tors (antagonists)

 changing receptor sensitivity (allosteric modulators)

 increasing the amount of neurotransmitter present in the

synapse, either by increasing the release of it into the syn-

aptic cleft, blocking its transportation out of the cleft, or

preventing the action of enzymes which break it down.

Arousal is maintained by parallel neurotransmitter systems with

cell bodies located in brainstem or midbrain centres, with projec-

tions to the thalamus and forebrain. These activating neurotrans-

mitters are noradrenaline, serotonin (5-HT), acetylcholine,

dopamine, histamine and the orexin system with cell bodies in

the hypothalamus, which together promote wakefulness through

regulating arousal pathways (and inhibiting sedating ones). For

all of these arousing neurotransmitters, waking can be promoted

by increasing their function, and sleep or sedation by decreasing

their function in the brain.

The promotion of sleep is regulated by a number of other neu-

rotransmitters; primary amongst these is GABA, the main inhibi-

tory neurotransmitter in the brain. The majority of brain cells are

inhibited by GABA so increasing its function reduces arousal and

produces sleep, and eventually anaesthesia. There are many sub-

sets of GABA neurones distributed throughout the brain but a

particular cluster in the hypothalamus (ventrolateral preoptic

nucleus) can be considered to be the sleep ‘switch’ (Saper et al.,

2005). These neurones ‘switch off’ brain arousal systems at the

level of the cell bodies and therefore promote sleep. GABA

receptors in the cortex can also promote sedation and sleep by

inhibiting the target neurones of the arousal system.

Benzodiazepines, so-called ‘Z drugs’ and barbiturates all enhance

the effects of GABA at the GABA

receptor (GABA-PAMs).

There are a number of subtypes of this receptor which are rele-

vant for sleep not only because of their different location in the

brain but also because of the fact that some drugs for insomnia

are selective for a particular subtype. The alpha-1 subtype is

highly expressed in the cortex and probably mediates the seda-

tive and hypnotic effects of many drugs that act at the benzodiaz-

epine site; zolpidem targets this subtype preferentially (Sanna

et al., 2002). The alpha-3 subtype predominates in the reticular

nucleus of the thalamus which plays an important role in regulat-

ing sleep. This subtype is particularly targeted by eszopiclone

(Jia et al., 2009). Traditional benzodiazepine drugs for insomnia

act on the alpha-1, alpha-2, alpha-3 and alpha-5 subtypes.

The other main sleep-promoting neurotransmitter is adeno-

sine. Brain levels rise during the day and are thought to lead to

sleepiness, which increases the longer the time since the last

sleep. The arousing and sleep-impairing effects of caffeine

(Landolt et al., 2004) are thought to be due to blockade of aden-

osine-A2 receptors, so attenuating this natural process (Porkka-

Heiskanen et al., 2002).

Histamine neurons form part of the neurotransmitter network

promoting arousal. Histamine levels are high in daytime and low

during sleep. Drugs which reduce histamine function (H1 recep-

tor antagonists or antihistamines) reduce arousal. Antihistamine

medications which cross the blood-brain barrier, such as promet-

hazine and diphenhydramine, are widely used ‘over-the-counter’

and prescribed to promote sleep. Unfortunately, they are not

selective for histamine, and their actions at other brain receptors

(particularly antagonism at cholinergic, noradrenergic and (pro-

methazine) dopaminergic receptors contribute to an adverse

effect profile. The most selective available medication is very

low dose doxepin, which, at doses from 1–6 mg, has little or no

effect at brain receptors other than H1 receptor antagonism. This

drug is approved in the USA for insomnia, but is not available in

Europe. Esmirtazapine, the S-enantiomer of mirtazapine is also

selective for H1 receptors, and is undergoing evaluation (Ivgy-

May et al., 2015; Ruwe et al., 2016).

Orexin is a neurotransmitter intimately involved in sleep and

waking. When the orexin receptors 1 and 2 (OR1 and OR2) in the

hypothalamus are activated they promote waking, and antago-

nists for these have been found to promote sleep. Several recep-

tor antagonists have been developed and one, suvorexant, is

licensed in the USA for insomnia (Herring et al., 2016). These

drugs are not yet available in Europe but several agents are being

evaluated in clinical trials.

Melatonin is produced in the pineal gland and has an important

role in regulating circadian rhythms (Cajochen et al., 2003; Dijk

and von Schantz, 2005). The circadian ‘pacemaker’ is the supra-

chiasmatic nucleus (SCN) of the hypothalamus and when active it

inhibits melatonin secretion in the pineal gland. Once melatonin

appears in the plasma it enters the brain and binds to melatonin

receptors in the hypothalamus. Melatonin has both phase-shifting

effects, so changing the timing of the biological clock, and direct

sleep-facilitating effects. Administering exogenous melatonin or

analogues such as ramelteon (licensed in the USA) can promote

sleep onset. A slow-release formulation of melatonin has been

licensed on the basis of improved sleep continuity and daytime

well-being in people aged over 55 years with insomnia. Melatonin

production is reported to decline with age and to be lower in mid-

dle-aged and elderly patients with insomnia than in good sleepers

(Attenburrow et al., 1996; Dowling et al., 2008; Haimov, 2001;

Leger et al., 2004). Beta-adrenergic receptor blockers and non-

steroidal anti-inflammatory drugs inhibit melatonin secretion.

Underpinning principles – pharmacokinetics. The principles

of the ideal drug for insomnia have been discussed for decades

and are outlined in Figure 3. All licensed drugs for insomnia

improve one or more aspects of subjective sleep, and some also

improve daytime functioning (see below – but note that many

drugs have not been evaluated on this parameter).

Kinetic aspects are important both in terms of how quickly the

drug enters the brain and how long its effects last (for comparison

of drugs see Tables 3 and 4 in Wilson et al., 2010). The faster the

drug enters the brain, the sooner sleep is induced. Some agents

used for insomnia have not been active in this aspect of sleep

because of poor kinetic properties: for example, temazepam tablets

have a poorer bioavailability and slower absorption (and thus a

longer presence in the body) than the previous gel formulations.

Drugs that enter the brain very quickly, though effective, may need

to be taken in the bedroom or even in bed to prevent people falling

asleep before they are in bed (see Zentiva Pharma UK Limited,

2002; zolpidem Summary of Product Characteristics (SPC)).

Wilson et al. 931

The ease of waking and the propensity to daytime carry-over

(‘hangover’) effects are determined by the duration of action –

with GABA-PAMs this is typically defined by the elimination

half-life of the drugs (see Tables 3 and 4 in Wilson et al., 2010)

and the dose taken. Drugs with half-lives of more than six hours

tend to leave sufficient residual drug in the brain to cause hango-

ver effects in the morning. This was particularly the case with the

first benzodiazepine drugs for insomnia such as nitrazepam,

which was associated with daytime sedation and falls (Trewin

et al., 1992). The rationale for developing zopiclone, zolpidem

and zaleplon was to make shorter half-life drugs with minimal

carry-over effects (Nutt, 2005b). This was largely achieved,

although some hangover effects are seen with zopiclone and esz-

opiclone (Boyle et al., 2012; Staner et al., 2005).

A very short half-life limits a drug’s duration of action on

sleep, and zolpidem is less effective at maintaining sleep

throughout the night than drugs with a longer half-life. A con-

trolled release formulation of zolpidem (currently only availa-

ble in the USA) prolongs its nocturnal actions and enhances

sleep continuity, though only by 10s of minutes (Greenblatt

et al., 2006). Individual factors seem important and some peo-

ple are more susceptible to carry-over effect than others, prob-

ably due to individual differences either in the rate of drug

clearance, which can vary by as much a two-fold between sub-

jects, or sensitivity to drug actions. In particular, women tend to

have higher blood concentrations of zolpidem, and greater

impairment of driving ability, the following morning than do

men (Farkas et al., 2013). The US Food and Drugs Administration

responded to this finding by requiring manufacturers to recom-

mend gender-specific labelling with dosing for women being

half that of men.

Tolerance, dependence and withdrawal. Dose escalation

above recommended doses in patients with insomnia alone

appears uncommon, and tolerance to the effects of GABA-PAM

drugs for insomnia is not a frequently encountered problem in

clinical experience. Many patients use the same dose for months

or years and still feel it works. However, a temporary worsening

of sleep, usually with increased sleep onset latency, is reported

during the withdrawal period for most GABAergic agents (Hajak

et al., 2009; Soldatos et al., 1999; Voshaar et al., 2004). Although

there have been no head-to-head studies of this question, there is

some lower level evidence in humans that subtype-selective

drugs such as eszopiclone produce less tolerance and rebound

(Krystal et al., 2003; Nutt and Stahl, 2010).

Animal and human research demonstrates that brain receptor

function changes in response to chronic treatment with benzodi-

azepine receptor agonists, and this takes time to return to pre-

medication levels after cessation of medication. There is evidence

from animal studies that chronic administration of benzodiaz-

epines produces adaptive changes in the receptor which attenuate

the effects of the endogenous neurotransmitter GABA, and so

produce symptoms on withdrawal (Bateson, 2002). It may be

possible to develop drugs with a lower propensity to such effects:

through targeting specific subtypes of the benzodiazepine recep-

tor by changing the chemical structure to produce a different

interaction at the pharmacophore; or by making partial agonists

(Doble et al., 2004).

Considerations of dependence on GABA-PAMs are contingent

on what happens when treatment is stopped. A psychological

dependence is seen in many patients and some are reluctant to stop

treatment. If they do stop, there can be relapse, where the patient’s

original symptoms return; or rebound of symptoms, where for one

Figure 3. The ideal sleeping pill.

932 Journal of Psychopharmacology 33(8)

What is known about long-term treatment:

 Insomnia is often long-lasting and is in practice often treated

with hypnotics for long periods in clinical practice (Ib).

 Studies suggest that dependence (tolerance/withdrawal) is

not inevitable with hypnotic therapy up to one year with

eszopiclone, zolpidem, ramelteon (Ib).

 Intermittent dosing may reduce the risk of tolerance and

dependence (Ib).

What is not known:

 How can we predict the needed treatment duration?

 How and when should treatment be discontinued?

 Should dosing for longer periods be nightly or intermittent?

 How do we detect the abuse prone individual in the clinic?

 Does hypnotic therapy affect the course of insomnia or

associated conditions?

or two nights there is a worsening of sleep disturbance, with longer

sleep onset latency and increased waking during sleep; this is com-

monly reported by patients and has been documented in some

research studies (Hajak et al., 2009; Soldatos et al., 1999). More

rarely, there is a longer withdrawal syndrome. All of these can be

ameliorated by resuming medication. The withdrawal syndrome is

characterised by the emergence of symptoms not previously

reported, such as agitation, headache, dizziness, dysphoria, irrita-

bility, fatigue, depersonalization, hypersensitivity to noise and

visual stimuli. Physical symptoms which have been described

include nausea, vomiting, muscle cramps, sweating, weakness,

muscle pain or twitching and ataxia. This syndrome usually

resolves within a few weeks, but persists in some patients, and this

persistence may be related to personality traits and cognitive fac-

tors (Murphy and Tyrer, 1991).

Pharmacological treatment of insomnia. All licensed drugs

licensed for insomnia are efficacious (I). As explained above,

some may improve sleep earlier in the night, as they enter the

brain more quickly, and thus reduce sleep onset latency. Duration

of action depends to a great extent on half-life and for instance in

a patient with predominantly sleep-onset insomnia, a shorter act-

ing drug such as zolpidem or melatonin might be appropriate,

and for those with awakenings throughout the night a slightly

longer acting drug such as zopiclone may be preferable.

Most of the drugs approved for insomnia enhance GABA

function in the brain. As well as promoting sleep these drugs are

anxiolytic, anticonvulsant and myorelaxant, and can cause ataxia

and memory problems when taken other than just before a period

in bed. If their effect in the brain persist after waking in the morn-

ing they are sometimes described as ‘hangover effects’ therefore

differences in the pharmacokinetics of individual benzodiaz-

epines (or ‘Z drugs’) are particularly important. Melatonin does

not give rise to motor or memory effects; however the synthetic

melatonin agonist ramelteon gives rise to sleepiness which can

persist for 12–14 h (Cohen et al., 2010). Recent clinical trials

have measured daytime outcomes after drugs for insomnia, and

beneficial effects have been reported for melatonin in those over

55 years, and for zolpidem, zopiclone, eszopiclone and lormetaz-

epam. These measures have not been used in studies of other

drugs, so their effects on daytime function are not documented.

In systematic reviews of GABA-PAMs, adverse events/side

effects are less common and less severe for the Z-drugs zolpidem

and eszopiclone (Buscemi et al., 2007). Controlled studies meas-

uring cognitive and psychomotor function (such as digit-symbol

substitution test, and memory) in insomnia patients have only

shown next-day deleterious effects consistently after use of flu-

razepam (very long-acting) or very high doses of other benzodi-

azepines (Buscemi et al., 2005). Evidence for hypnotic effects on

next day driving in insomnia patients is limited, however epide-

miological studies show that road accidents are increased in peo-

ple taking benzodiazepines or zopiclone (Barbone et al., 1998;

Neutel, 1995). Studies in healthy volunteers show that residual

effects of drugs for insomnia increase with their half-life duration

(Verster et al., 2006). Effects of insomnia itself on driving have

not been studied extensively, though sleep deprivation does

impair driving performance (Connor et al., 2002). In a controlled

study of patients with insomnia in a driving simulator, there was

next-day impairment after zopiclone and lormetazepam but not

zolpidem, when compared with placebo (Staner et al., 2005).

Very low doses of doxepin, (1, 2 or 6 mg when doxepin acts

only as a histamine antagonist) improve sleep in adult (18–65

years) and elderly (65 years and older) insomnia patients (Yeong

et al., 2015). Doxepin has a preferential effect on reducing awak-

enings in the latter half of the night (Krystal et al., 2010) and does

not appear to give rise to residual daytime effects (Krystal et al.,

2011). Suvorexant, an antagonist at OR1 and OR2 receptors,

improves sleep in adult and elderly insomnia patients. It increases

subjective total sleep time and decreases subjective wake time in

the middle and end of the night and subjective time to sleep

onset; a few healthy volunteers had impairment of driving ability

nine hours after higher doses of suvorexant (Vermeeren et al.,

2015). Neither of these drugs is currently available in Europe.

Recommendations

Factors which clinicians need to take into account when

prescribing are efficacy, safety, and duration of action (A).

Other factors are previous efficacy of the drug or adverse

effects, history of substance abuse or dependence (D).

Long-term use of sleeping medications

The question of long-term hypnotic treatment is one of the more

controversial areas in psychopharmacology. It has long been

stated that sleeping medication should not be used long-term for

the treatment of insomnia. This was the consensus view of the

panel of a 1983 National Institute of Health (NIH; 1983)

Consensus Conference on the medication treatment of insomnia,

which became a guideline for clinical practice in the USA, and

later the UK Committee on Safety of Medicines and the Royal

College of Psychiatrists both recommended only short-term use.

While it was appreciated that benzodiazepine hypnotic agents

had a favourable risk-benefit ratio and were first-line agents for

insomnia management, all of these reports expressed concerns

about the risks of physical dependence and recommended their

use should be limited to periods of 2–3 weeks. Despite the rec-

ommendation for treatment with hypnotic drugs being only 2–4

weeks, many millions of patients worldwide remain on long-term

treatment (Ohayon et al., 1999; Maust et al., 2019).

The reasons for longer term use are complicated and difficult

to research but are probably similar to those which affect

Wilson et al. 933

understanding of longer term benzodiazepine treatment in

patients with anxiety disorders. We do not know the proportions

of longer term users that have continuing insomnia requiring

daily drug treatment, or who do not need the drug at all, or who

are afraid to try discontinuing because of fear or experience of

rebound insomnia. In one study where people were successful in

discontinuing benzodiazepine hypnotics, a follow-up after two

years revealed approximately 40% had resumed regular use

(Belanger et al., 2005; Morin et al., 2005a), which suggests some

people have enduring problems with sleep which benefit from

treatment. Insomnia may have some similarities with depression,

in that both represent long-term disorders in which maintenance

treatment may be needed in many patients (Jindal et al., 2004). A

related issue is whether early intervention at the onset of insom-

nia might reduce the likelihood of it persisting.

Placebo-controlled trials of treatment for durations longer than

three weeks that can more definitely assess safety and efficacy,

and determine whether dependence phenomena occur, have been

undertaken. Trials of nightly dosing for up to 12 months duration

suggest that tolerance and withdrawal do not generally occur with

some hypnotics: zolpidem (one study of 12 months and one of

eight months duration) eszopiclone (two studies of six months

duration); ramelteon (a six-month study with outcome assessed

with polysomnography but not self report); and temazepam (a

two-month study) (Ancoli-Israel et al., 2010; Bastien et al., 2003;

Krystal et al., 2003; Mayer et al., 2009; Morin et al., 1999; Roehrs

2012; Walsh et al., 2007). Others agents have not been studied for

longer durations. The available evidence does not suggest there is

an unfavourable risk/benefit transition at 3–4 weeks for any agent.

Open-label studies of nightly dosing for periods up to one year

with the agents studied (zolpidem, eszopiclone, and ramelteon)

suggest that discontinuation symptoms are generally mild and

infrequent (Ancoli-Israel et al., 2005; Randall, 2012; Richardson

et al., 2009). Intermittent, non-nightly, dosing is also an important

consideration with respect to long-term hypnotic treatment. Many

individuals do not have nightly insomnia and treatment only when

needed can decrease the risks and costs of therapy and reduce psy-

chological dependence/treatment withdrawal anxiety. There is

evidence from a placebo-controlled trial for sustained efficacy

and safety for six months of ‘as needed’ treatment (subjects being

required to take at least three doses per week) with controlled

release zolpidem 12.5 mg (Krystal et al., 2008).

In conclusion, insomnia is often long-lasting and often treated

with hypnotics for long periods in clinical practice. Controlled

trials of longer-term use are being undertaken and these suggest

dependence (tolerance/withdrawal) is not inevitable with hyp-

notic therapy up to one year, and is not characteristic of the sev-

eral agents studied. The longer-term safety and efficacy of many

other commonly used hypnotics remains uncertain.

A number of critical issues remain unresolved. We currently

lack the means to determine who should receive longer-term

treatment and to predict the required treatment duration. Lacking

the means to determine the optimal duration of therapy, a rational

approach is to carry out periodic trials of tapering and discon-

tinuing medication to determine if continued therapy is indi-

cated (Krystal, 2009). As such, the duration of treatment is

decided by a series of risk/benefit decisions based on trial dis-

continuations. This approach provides an ‘exit strategy’ and

addresses concerns that once started hypnotic therapy could be

unending. Concomitant CBT during tapered discontinuation is

helpful (Morin et al., 2004; Parr et al., 2009; Belleville et al.,

2007). Another unresolved issue is whether to implement nightly

or intermittent dosing of hypnotics for a given patient. It is clear

that the medication works on the nights it is taken but poor sleep

occurs when it is not. In many instances this is a practical deci-

sion based on whether the patient can predict when they go to

bed whether they will have sleep difficulty. In addition, some

have argued that intermittent dosing may reinforce psychologi-

cal dependence on the drug.

Recommendations

Use as clinically indicated (A).

In general, hypnotic discontinuation should be based on

slowly tapering off medication (A).

CBTi during taper improves outcome (A).

Using drugs for depression to treat insomnia

Tricyclic antidepressants have long been used for insomnia, with

little evidence of efficacy (see Everitt et al., 2018), whereas the

serotonin reuptake inhibitors (SRIs) as a class generally disrupt

sleep early in the course of treatment (Mayers and Baldwin, 2005).

The alerting effect of SRIs can sometimes be offset by co-adminis-

tration of sedating drugs for depression such as trazodone, probably

because they block 5-HT2 receptors that are being overstimulated

by an increase in 5-HT (Kaynak et al., 2004); alpha-1 adrenergic

antagonism may also contribute. Other 5-HT2 antagonist drugs for

depression such as nefazodone (now discontinued) (Hicks et al.,

2002) and mirtazapine (Winokur et al., 2003) have been shown to

reduce insomnia in depression, especially early in treatment.

Low doses (sub-therapeutic for depression) of sedating tricy-

clics, particularly amitriptyline, have been used for decades to

treat insomnia. This is particularly common practice in primary

care in the UK, where amitriptyline 10 or 25 mg is also used for

long periods in many patients with chronic illness, particularly

those with pain syndromes. At this dose, amitriptyline is proba-

bly acting mostly as a histamine H1 receptor antagonist although

a degree of 5-HT2 and cholinergic muscarinic antagonism may

also contribute. There are no controlled studies of hypnotic effi-

cacy of low-dose amitriptyline in insomnia, and tricyclics are

more likely to be lethal than licensed hypnotics in overdose

(Nutt, 2005a). Controlled trials demonstrate an effect of doxepin

What is known about the use of drugs for depression to treat

insomnia:

 There is limited evidence for efficacy of trimipramine,

trazodone and paroxetine in insomnia (Ib).

 Older drugs for depression may affect a wide range of brain

receptors and have longer lasting carry-over effects than

traditional drugs for insomnia. They are associated with

increased risks of road accidents especially early in treatment

in depression (Ib).

What is not known:

 Duration of effect (particularly as they are often prescribed for

long periods).

 How their effects compare with approved medications for

insomnia.

934 Journal of Psychopharmacology 33(8)

in insomnia at sub-antidepressant dose (25 mg) (Hajak et al.,

2001) for four weeks, with rebound insomnia.

Trazodone is an agonist at 5-HT1A receptors, an antagonist at

5-HT2 and α1 adrenergic receptors and a weak 5-HT reuptake

inhibitor: it is the second most prescribed medication for insomnia

in the USA. It has a perceived absence of risk and is cheap, but

25–30% patients experience difficulty tolerating trazodone and

dropout rates tend to be higher than for benzodiazepine hypnotics

or Z-drugs. Although there have been 18 trazodone studies meas-

uring sleep outcomes, only two were in primary insomnia, and

only one was a controlled study (Walsh et al., 1998). This study

used 50 mg trazodone vs placebo, and found a significant effect

on sleep maintenance parameters at week 1 but not week 2, and a

high incidence of daytime somnolence. Trimipramine is a drug for

depression which blocks α-1 adrenergic, histamine H1, dopamine

D2, 5-HT2 and cholinergic receptors (Gross et al., 1991;

Richelson, 1994). There is one controlled trial (Riemann et al.,

2002) in insomnia at doses of 50–200 mg for four weeks which

found a significant improvement in sleep efficiency as measured

by polysomnography, paralleled by subjective improvements.

Side effects were described as marginal. Paroxetine, an SRI, was

studied in patients with insomnia aged over 55 years, at a median

dose of 20 mg for six weeks (Reynolds, III et al., 2006), there

being a 50% response rate (placebo 38%) with subjective sleep

quality and daytime well-being improved. This seeming paradoxi-

cal action of paroxetine to improve sleep is probably related to its

good efficacy in many anxiety disorders where it seems to reduce

recurrent thinking and ruminations.

Taking SRIs, venlafaxine, mianserin or mirtazapine increases

the risk of restless legs syndrome and periodic limb movements

of sleep (Hoque and Chesson, Jr., 2010) and SRIs can induce or

exacerbate sleep bruxism (Wilson and Argyropoulos, 2005).

Recommendations

Use drugs according to a knowledge of pharmacology (A).

Consider drugs for depression when there is co-existent

mood disorder (A).

Beware toxicity of TCAs in overdose even when low unit

doses prescribed (A).

Drugs for psychosis for treatment of insomnia

Dopamine-5-HT antagonists, particularly quetiapine and olan-

zapine, have become widely used in the treatment of sleep prob-

lems with very little controlled trial evidence. For example,

prescriptions of quetiapine for sleep disturbances increased by

300% in Canada between 2005–2012 (Pringsheim and Gardner,

2014) and a cross-sectional study conducted using the US

National Health and Nutrition Examination Survey data from

1999–2010 found that quetiapine was the fourth most common

drug prescribed for insomnia (11%) (Bertisch et al., 2014).

PSG sleep studies in healthy participants have shown changes

in sleep architecture. These include increases in slow wave sleep

and decreases in rapid eye movement (REM) sleep with ziprasi-

done and olanzapine (Cohrs et al., 2004; Cohrs et al., 2005;

Sharpley et al., 2000). Some positive changes in measures of sleep

maintenance have been shown with clozapine, quetiapine, olan-

zapine and risperidone (Gimenez et al., 2007; Lindberg et al.,

2002; Sharpley et al., 2000). Subjective sleep was improved by

risperidone, olanzapine and quetiapine.

In models of transient insomnia, such as acoustic stress and

phase advance in healthy volunteers, quetiapine, ziprasidone and

lurasidone have shown improvements in sleep initiation and

maintenance (Cohrs et al., 2004, 2005; Karsten et al., 2017;

Krystal and Zammit, 2016).

In patients with schizophrenia (see Monti et al., 2017) clozap-

ine increased total sleep time (Kluge et al., 2014); olanzapine

increased slow-wave sleep and improved sleep-continuity meas-

ures (Gao et al., 2013; Kluge et al., 2014; Monti et al., 2017;

Muller et al., 2004; Salin-Pascual et al., 1999, 2004). Quetiapine

administration has generated mixed results in patients with schiz-

ophrenia, with Loebel et al. (2014) finding increases in daytime

sleepiness after six weeks quetiapine extended release (XR) 600

mg compared with placebo, whereas Keshavan et al. (2007) found

reduced sleep continuity compared with drug naïve patients.

In bipolar patients (see Monti 2016) six months add-on clozap-

ine treatment increased total sleep time compared with baseline

(Armitage et al., 2004). Risperidone and olanzapine both improved

sleep continuity when added to an SRI in depression (Sharpley

et al., 2003; 2005; Lazowski et al., 2014). Furthermore, Moreno

et al. (2007) found that olanzapine improved sleep continuity in

patients with bipolar disorder during a manic episode. Using actig-

raphy, Todder et al. (2006) and Kim et al. (2014) showed that

adjunctive or monotherapy quetiapine improved sleep continuity

in patients with unipolar or bipolar disorder. A PSG study with

ziprasidone augmentation in bipolar patients with an acute depres-

sive episode improved sleep induction, sleep continuity and sleep

architecture (Baskaran et al. 2013). Overall, these results indicate a

potential beneficial effect on sleep of dopamine -serotonin antago-

nists in patients prescribed them for a labelled indication.

In patients with insomnia, a small open study of quetiapine (25

mg in most patients) for six weeks (Wiegand et al., 2008) showed

improvements in sleep, with transient adverse effects of morning

hangover and dry mouth. A double-blind, placebo- controlled

study which investigated the efficacy of quetiapine (25 mg) in pri-

mary insomnia (Tassniyom et al., 2010) had a small sample size

(n=13) and subjective improvements in sleep were not significant.

Side effects are well documented, and include weight gain, met-

abolic syndrome, extrapyramidal symptoms and risk of tardive

dyskinesia. There are some case reports of abuse of quetiapine in

inpatients and prisoners (Sansone and Sansone, 2010). A review of

quetiapine for use in insomnia (Anderson and Vande Griend, 2014),

concluded that its benefit in the treatment of insomnia has not been

What is known about use of drugs for psychosis in treatment of

insomnia:

 Dopamine serotonin antagonists particularly olanzapine and

quetiapine improve sleep in healthy participants (Ib).

 Quetiapine, ziprasidone and lurasidone improve sleep in models

of transient insomnia (Ib).

 When used on label, clozapine, olanzapine, quetiapine,

risperidone and ziprasidone improve sleep continuity in

schizophrenia, unipolar and bipolar disorder (I).

 Minor improvements in sleep in primary insomnia are seen after

quetiapine (IIb).

 Side effects are common because of the broad pharmacological

actions of these drugs (I).

What is not known:

How drugs for psychosis compare with approved drugs for

insomnia?

Wilson et al. 935

proven to outweigh potential risks, even in patients with a comorbid

labelled indication for quetiapine. An American Academy of Sleep

Medicine clinical practice guideline for the pharmacologic treat-

ment of chronic insomnia in adults also concluded that quetiapine

was not indicated for use in insomnia (Sateia et al., 2017).

Recommendations

Side effects are common because of the pharmacological

actions of drugs for psychosis and there are a few reports of

abuse.

Together these indicate no indication for use as first-line

treatment (D).

Antihistamines (H1 antagonists). Antihistamines are sedating

and are sold as ‘over the counter’ (OTC) sleeping medi cations.

There is only limited evidence that these older non-selective anti-

histamines work, although some modest benefits have been

reported after two weeks dosing with diphenhydramine in mild

insomnia (Morin et al., 2005b). More profound acute effects on

sleep have been reported for both promethazine and hydroxyzine

in healthy volunteers (Adam and Oswald, 1986; Alford et al.,

1992) but the latter is not available OTC, and both have quite long

durations of action so are likely to cause hangover effects.

Antihistamines are sometimes used in alleviation of insomnia

in drug and alcohol withdrawal where traditional hypnotics are

less suitable due to the risk of cross-dependence, although there

are no controlled trials in this setting. These drugs have anticho-

linergic side effects, making them dangerous in overdose.

The selective antihistamine (low-dose) doxepin 1–6 mg has

been shown to be effective in insomnia in adults and the elderly,

with few residual effects, and is approved in the USA but not in

Europe. It has been shown to particularly reduce awakenings in

the latter part of the night. Another selective agent, low-dose

esmirtazapine, is currently undergoing evaluation.

Recommendations

The selective antihistamine doxepin (very low dose) is

effective in insomnia (A).

Non-selective histamine antagonists have a limited role in

psychiatric and primary care practice for the management of

insomnia (D).

Circadian rhythm disorders

Daily rhythms of sleeping and waking are controlled by a variety

of brain mechanisms, the most prominent of these being the cir-

cadian process (the ‘body clock’ signalling time for sleep) and

the homeostatic process (a build-up of sleep pressure during the

hours of wakefulness). These two processes work together to

consolidate sleep and wakefulness (Diik and von Schantz, 2005).

Circadian rhythm is a roughly 24-hour cycle in the physiolog-

ical processes of living beings. It is internally generated, although

it can be modulated by external cues (zeitgebers) such as sun-

light, and feeding and drinking, and in humans by daily routines

of work, exercise etc. Circadian rhythms are controlled by a brain

pacemaker in the SCN of the anterior hypothalamus, which has a

direct input from the retina signalling light levels. Most body sys-

tems, not only sleeping and waking, are to some degree modu-

lated by input from this circadian pacemaker.

The innate frequency of the circadian clock in humans is

slightly longer than 24 h, and synchronisation with the external

24-hour physical environment and day- to-day activities requires

daily adjustments to the internal clock. The light-dark cycle is the

strongest synchronising agent for the circadian system. In humans,

light exposure in the evening produces delays, and in the early

morning produces advances. The SCN also receives internal sig-

nals from the pineal gland, via the nocturnal release of melatonin.

Endogenous melatonin release begins to increase 2–3 hours

before sleep onset, and peaks in the middle of the night. Exogenous

melatonin given during the early morning delays the timing of

circadian rhythms and, given during the early evening, induces

advances in this timing, which contrasts with the effects of light.

There are differences within humans in their preference for

sleep times (chronotype). Some people preferring to rise early and

are at their best in the morning (‘morningness’, or ‘larks’) and

those who rise later and are at their peak later in the day (‘evening-

ness’, or ‘owls) These preferences be determined in part by genet-

ics. Children are early chronotypes and become progressively

later (delaying) as they grow older, reaching a maximum in their

‘lateness’ at around the age of 20 years. After 20 years, they

become earlier again (advancing) with increasing age. Young

women reach their maximum in lateness earlier than men; men

continue to delay their sleep until around the age of 21 years and

remain later chronotypes for most of their adulthood (Roenneburg

et al., 2004). This gender difference disappears at around the age

of 50 years, which coincides with the average age of menopause.

Circadian rhythm sleep-wake disorders (CRSWDs) occur

when there is an alteration of the endogenous circadian system or

a misalignment between the endogenous circadian rhythm and

the sleep-wake schedule required by the physical environment or

social or work timetable. This results in insomnia when they are

needing to sleep, and sleepiness when alertness is required, caus-

ing significant distress and impairment of function.

There are six CRSWDs defined in ICSD:

Jet Lag Disorder occurs when the circadian clock has a tem-

porary misalignment after rapid transition across time zones.

Symptoms of insomnia, daytime sleepiness and physical

discomfort normally disappear once there is exposure to

zeitgebers in the new environment, within a length of time

proportional to the number of time zones crossed. Thus after

an eastbound trip from the USA west coast the circadian clock

might take several days to settle into the UK routine. This

condition tends not to present to health professionals for treat-

ment, although it is likely to have some destabilising impact

on conditions such as bipolar disorder.

Delayed Sleep Wake Phase Disorder (DSWPD) affects 2–8%

of the population and is most prevalent in young adults. There

is usually difficulty falling asleep before 02:00–03:00 (some-

times later), and on days without work/school/college the

preferred wake time is after 10:00, resulting in sleep-onset

insomnia and difficulty waking up in the morning on days

when an early bedtime for an early start time is necessary.

There is a high incidence of comorbidity with psychiatric dis-

order in those with DSWPD with up to 60% of people having

a diagnosis of depression, substance abuse, or anxiety (Abe

et al., 2011; Murray et al., 2017; Reid et al., 2012).

Advanced Sleep Wake Phase Disorder (ASWPD) is much rarer,

with reports of an average sleep onset from 18:00–21:00 and

936 Journal of Psychopharmacology 33(8)

Current understanding of circadian rhythms and sleep physiology

provides a strong theoretical basis for the use of melatonin in

some, but not all CRDs. Empirical evidence for efficacy is strong

in some CRDs, but weak or absent in others. Melatonin agonists

may be promising in the treatment of CRDs, e.g. non-24-hour

SWRD (Lockley et al., 2015), but there remains a need for RCTs

in well-characterised CRD populations.

There is solid evidence to support the use of melatonin in

jet lag (Spiegelhalder et al., 2017) but (immediate release)

melatonin has to be taken near desired bedtime otherwise there

may undesired daytime sleepiness. An evidence-based strategy

for minimising jetlag which includes strategic scheduling of

sleep combined with melatonin is given by Sack (Sack, 2010).

In DSWPD, there is both a theoretical and an empirical basis for

use of melatonin, which is effective in practice, shown in two sys-

tematic reviews (MacMahon et al., 2005; Sack et al., 2007a); how-

ever studies in these reviews vary in the physiological and subjective

outcomes measured. Direct comparison with other therapies such

as timed-light exposure, for which there is a little evidence of effi-

cacy (see below), or chronotherapy, for which there are no con-

trolled trials, has not been reported. In one trial, efficacy of

melatonin combined with sleep scheduling was compared to sleep

scheduling alone and found to be effective (Sletten et al., 2018).

In non-24-hour sleep rhythm disorder, in sighted individuals, case

reports (n=5) suggest a positive benefit of melatonin. The evidence in

blind people is more compelling where case reports and two small,

single-blind placebo-controlled studies are positive (Sack et al.,

2007a; Skene and Arendt, 2007; Skene et al., 1999). Two RCTs of the

selective melatonin agonist tasimelteon in totally blind individuals

showed a positive effect on entrainment (Lockley et al., 2015).

There is no evidence of the efficacy of melatonin in irregular

sleep wake rhythm, or in shift work disorder, although there have

been some reports of use in shift workers with varying results

(Sack et al., 2007b).

Bright-light therapy has been used effectively in delayed

sleep phase syndrome (Shirani and St Louis, 2009). Exposure to

bright light of 2500 lux for two hours in the early morning,

combined with light restriction after 16:00 (dark goggles) is an

effective treatment for delayed sleep phase syndrome and a

light mask offering exposure to gradually increasing light inten-

sity through closed eyelids over the last four hours of habitual

sleep time has been shown to be effective in these patients.

In the elderly patient with dementia with an irregular sleep

wake disorder there is a little evidence to support the use of bright-

light therapy in combination with behavioural interventions, but

the use of melatonin is discouraged (Auger et al., 2015).

Recommendations

Clinical assessment is essential in delayed sleep wake

phase disorder, non-24-hour sleep rhythm disorder [A].

Melatonin may be useful in delayed sleep wake phase dis-

order, non-24-hour sleep rhythm disorder in non-sighted

individuals and jet lag disorder [B].

Other approaches such as behavioural regimes and sched-

uled light exposure (in sighted individuals) can also be used

[B/C].

Because of the necessity for careful timing of interven-

tions, patients with these disorders need to be treated in spe-

cialised sleep disorders centres (D).

wake time of 02:00–05:00. However, if allowed to sleep during

their preferred times, the sleep quality and duration are normal

for age. Prevalence is around 1%, but this may be a low estimate

as the lifestyle disruption may be less of a problem with earlier

timings. There sometimes a hereditary component to advanced

sleep wake phase disorder, and mutations of clock genes have

been identified in familial cohorts (Hirano et al., 2016).

In Irregular Sleep Wake Rhythm Disorder (ISWRD), there is

no clear main sleep period, but sleep and wake periods distrib-

uted irregularly through the 24-hour period with at least three

sleep bouts. There is thought to be a disruption of either the

central pacemaker, or of perception of environmental cues,

and this disorder is most common among young people with

neurodevelopmental disorders and adults with neurodegen-

erative disorders and occasionally with traumatic brain injury.

Non-24-hour Sleep Wake Rhythm Disorder (SWRD) occurs

when individuals are unable to entrain to the 24-hour day but

follow their endogenous circadian period, which is usually

slightly longer than 24 h. Their sleep-wake routine moves pro-

gressively later each day, and sleep complaints may consist of

insomnia, excessive daytime sleepiness, or both. A large pro-

portion of people with this disorder are visually impaired, and

without light perception, so the resetting of endogenous rhythms

through the retino-hypothalamic pathway is not possible.

Shift work sleep disorder (SWSD) is characterised by exces-

sive sleepiness during work and insomnia when trying to sleep

between shifts. There are many shift work schedules; they

may be permanent, rotating or irregular, so the presentation

of SWSD is variable. It is not known why some people adapt

adequately to changing work period timing, and others do not.

Disruption of circadian rhythms may also be present in other

sleep disorders, such as insomnia (Flynn-Evans et al., 2017)

Diagnosis of circadian rhythm disorders

Assessment of these disorders involves interview, sleep diaries

(from parents/carers if necessary) and actigraphy for 14 days. In

the case of DSWPD and ASWPD it is recommended to give the

morningness-eveningness questionnaire (Horne and Ostberg,

1976.

Treating circadian rhythm disorders

What is known:

 Melatonin is effective in jet lag disorder (1a), delayed sleep phase

syndrome (Ib) and non-24-hour sleep rhythm disorder (IIa).

 Light therapy is effective in delayed sleep phase syndrome (III).

What is not known:

 What are the best efficacy measures – subjective or objective?

 Is there a need to distinguish between adults and adolescents

in DSWPD since sleep times are somewhat delayed in normal

adolescence?

 Is there a need to distinguish between sighted and blind

individuals?

 Is melatonin or light therapy more effective for DSWPD?

Wilson et al. 937

Parasomnias

Parasomnias are unusual episodes or behaviours occurring dur-

ing sleep which disturb the patient or others and this document

addresses those that cause significant distress and therefore pre-

sent for treatment. Violent or unusual night-time attacks may

arise from deep non-REM sleep (night terrors and sleepwalking)

or from REM sleep [sleep paralysis, severe recurrent nightmares,

REM behaviour disorder(RBD)] and treatments depend on which

disorder is present.

Night terrors (also called sleep terrors) are recurrent episodes

of abrupt awakening from deep non-REM sleep, usually in first

third of night, usually with a scream and signs of intense fear and

autonomic arousal, and the patient is unresponsive to comforting.

They may sit up in bed and sometimes engage in automatic

behaviour associated with fear and escape. There is usually no

detailed recall, and if the patient wakes from a terror (not com-

mon), there is confusion and disorientation and only a vague

memory of fear. Night terrors are common in children with 30–

40% having at least one episode and repeated episodes in about

5%. The peak age for these is at about 2–7 years with a gradual

diminution up to early adolescence (Stallman et al., 2018). In

some cases they persist into adult life; the prevalence in adults is

unknown. Almost all adult patients have had night terrors or

sleepwalking as a child (Crisp, 1996) there is a strong genetic

component (Nguyen et al., 2008), and night terrors and sleep-

walking in the same patient is fairly common. Sleepwalking

alone probably has 15–20% lifetime prevalence. The main symp-

tom is of automatic behaviour at night with the sufferer unre-

sponsive to surroundings and other people. The behaviour is

most commonly walking around, but can include other behav-

iours which are highly familiar to the subject such as dressing,

washing, making tea, arranging objects in the house. Some cases

of sleepwalking seem related to use of certain drugs e.g. alcohol

and hypnotics, especially zolpidem and triazolam, opiates (pos-

sibly related to sleep-disordered breathing) (Pressman et al.,

2007), or other sleep disorders such as sleep apnoea. It is rare for

affected individuals to present for treatment, except if they have

injured themselves or a partner, have put themselves into poten-

tial danger, or have excessive daytime fatigue because of night

time disturbance. Another reason for presentation is anxiety and

disruption of sleep of partner, family or housemates.

Sleep paralysis, nightmares and REM sleep behaviour disor-

der (RBD) are disorders arising from REM sleep. Sleep paralysis

and nightmares are recalled by the patient. REM behaviour epi-

sodes are sometimes recalled but more often only apparent to the

bed partner.

Sleep paralysis is a brief state of involuntary immobility usu-

ally occurring on waking from a night’s sleep or a nap (more

rarely at sleep onset). It is often accompanied by dream imagery,

sometimes of a frightening kind, and sometimes a feeling of

chest tightness. It is attributed to waking abruptly from a REM

sleep episode with the REM atonia persisting briefly. It appears

to be more common in those with narcolepsy, and in those with

irregular sleep-wake routine and after drinking alcohol.

RBD is a disorder first described in the late 1980s with violent

complex behaviour at night. There are two sleep abnormalities:

lack of atonia during REM sleep (which can be quantified using

video-polysomnography), and increased vividness and/or nasty

content of dreams. The violent behaviour is described as ‘acting

out of dreams’, made possible by the lack of the normal muscle

paralysis in REM sleep causes injury to self or bed partner in up

to 70% of patients. Its incidence is estimated at 0.5–1% of those

over 55 years), occurs in older people with a steady rise after 55

years and has a male preponderance in older patients. It is now

well recognised as the most robust prodromal, non-motor symp-

tom of a subsequent neurodegeneration, typically an alpha synu-

cleinopathy. Several cohorts under long term follow-up have

shown that 50% at five years and 91% at 15 years will have

developed another neurodegenerative problem. It is often associ-

ated with Parkinson’s disease (PD) (it is seen in up to 50% of PD

patients), Lewy body dementia (~70%), multiple system atrophy

(>90%). RBD often precedes other symptoms of neurodegenera-

tion by several years (Iranzo et al., 2014).

Diagnosis of parasomnias

Assessment of parasomnia may be possible with a detailed his-

tory from patient or witness, but in general for adequate diag-

nosis, referral to a specialist sleep centre for polysomnography

and video recording may be necessary especially for RBD

where loss of REM atonia is seen.

Treatment of parasomnias

There is little high-level evidence for treatments in these disor-

ders. There are no controlled trials of treatment of non-REM

parasomnias in adults (Harris and Grunstein, 2009). Priorities

are to minimise possible trigger factors such as noise, frighten-

ing films, caffeine, alcohol or meals late at night; and to make

sure there is a stable and adequate sleep-wake schedule. It is

important to safeguard against harm to the patient, such as by

locking windows, bolting doors, or sleeping on the ground

floor, and safety of the bed partner or nearby children also

requires attention.

Drug treatment decisions should be based on the frequency

and severity of events. Clonazepam in doses up to 3 mg per night

has been reported to be effective (case series, n=69) (Schenck

and Mahowald, 1996). Smaller case series have reported good

effects of paroxetine (Wilson et al., 1997) and imipramine

(Cooper, 1987) (both effective immediately) and there are several

case series of hypnotherapy in sleepwalkers (Becker PM, 2015).

A randomised controlled study of three weeks’ treatment with

5-hydroxytryptophan in children found evidence of efficacy at

six-month follow-up (Bruni et al., 2004).

For nightmares, psychological treatments are effective and

these focus on exposure – writing down dreams – or guided

imagery, pleasant images, and ‘changing the ‘ending’ (Burgess

et al., 1998; Hansen et al., 2013; Krakow et al., 2001). There is

good evidence of beneficial effects of the alpha-1 adrenergic

blocker prazosin in reducing nightmares related to PTSD in both

military and civilian settings and in the paediatric population

(Keeshin et al., 2017; Nadorff et al., 2014). Nightmares have

been reported to be triggered or worsened by many drug treat-

ments including cholinesterase inhibitors, beta-blockers, SRIs

(especially paroxetine) levodopa, and following withdrawal from

drugs for depression.

938 Journal of Psychopharmacology 33(8)

For RBD, all data on treatment comes from retrospective

case notes review and for melatonin, a single, small crossover

randomised trial. There are no prospective or controlled studies

of clonazepam for RBD, but large case series suggest a good

effect when used at doses between 1–4 mg (Aurora et al., 2010;

Boeve et al., 2004) in reducing number of episodes and injury

during them. Dose-limiting side effects are common in those

with dementia, disorders of gait or balance, or concomitant

OSAS (Anderson and Schneerson, 2009). Beneficial effects

have been reported for melatonin 3–12 mg but with fewer

adverse events. A single, small RCT has shown benefit for mel-

atonin including in quantitative measure of REM atonia (Kunz

and Mahlberg, 2010). Single case studies and small series have

reported beneficial effects of clonidine (Nash et al., 2003),

donepezil (Massironi et al., 2003), and sodium oxybate (Kosky

et al., 2008).

Drugs which can worsen RBD or provoke its symptoms

include SRIs, venlafaxine, mirtazapine, bisoprolol and tramadol

(Gagnon et al., 2006).

Special populations

Sleep disorders in women: effects of

menopause and pregnancy

Menopause. Insomnia increases as women approach and pass

through the menopause ( Bixler et al., 2009; Kuh et al., 1997;

Owens and Matthews, 1998). Post-menopausal women have a

longer sleep latency and decreased slow-wave sleep. This is due

to a variety of reasons – climacteric symptoms e.g. hot flushes

due to hormonal changes and psychiatric disorders are most often

cited. Hormone therapy appears to protect women from these

changes (Bixler et al., 2009).

CBTi has been shown to be effective in insomnia in this

group, with long lasting benefits up to six months post-treatment

(McCurry et al., 2016). There are modest benefits from some but

not all studies of pharmacotherapy with SRIs including escitalo-

pram, citalopram and venlafaxine although short duration of

follow-up limits the conclusions that can be drawn from the

studies (Ensrud et al., 2012; Davari-Tahna et al., 2016).

Post-menopause, there is also a rise in the incidence of

sleep-disordered breathing (Young et al., 2003) (Bixler et al.,

2001). Post-menopausal women with sleep-disordered breath-

ing are more likely to complain of depression and insomnia

than men with a similar degree of OSAS (Shepertycky et al.,

2005).

Recommendations

Clinicians should appreciate that there is a rise in inci-

dence of sleep-disordered breathing after the menopause and

that clinical presentation, often including insomnia, in women

is different to men (D).

The use of hormone therapy should involve informed indi-

vidualised treatment of symptoms, looking at risks and ben-

efits in light of recent studies (A).

Follow recommendations for insomnia in other sections (A).

Pregnancy. Many women report poor sleep during preg-

nancy with the reasons varying depending on the trimester. In

the first trimester, nausea, backache and urinary frequency

can cause sleep disturbance. The second trimester tends to be

easier but foetal movements and heartburn may be trouble-

some. By the third trimester, sleep is more disturbed with

complaints again of urinary frequency, backache in addition

to cramps, itching and unpleasant dreams. Most women fall

asleep fairly easily but wake more frequently (Sedov et al.,

2018).

If a patient suffers from intractable insomnia and a phar-

macological agent is required, it is helpful to note that zolpi-

dem and diphenhydramine are in FDA class B (foetal harm

possible, but unlikely; no evidence of foetal harm in animal

studies) (for review see (Pien and Schwab, 2004). However,

non-selective histamine antagonists such as diphenhydramine

can exacerbate restless legs syndrome (RLS) and have anticho-

linergic actions. Zolpidem may be preferable as it is short-

acting and does not have anticholinergic side effects. The

hypnotics temazepam and zopiclone have not been associated

with any increase in congenital malformations (Ban et al.,

2014).

RLS is common in pregnancy, with a prevalence between

15–25%, peaking in the third trimester with improvement in

the last two weeks and often resolving post-partum. It is some-

times associated with anaemia (Hubner et al., 2013; Neau

et al., 2010). Iron replacement is safe and may be effective

based on small case series, with carbidopa/levodopa or clonaz-

epam only recommended in severe and refractory cases

(Picchietti et al., 2015).

Snoring and sleep disordered breathing, especially in obese

subjects, is increasingly recognised, is associated with worse foe-

tal outcomes and affects up to 8% of women by the third trimes-

ter. (O’Brien et al., 2014).

Recommendations

Good sleep hygiene and lifestyle (D).

Manage general pregnancy associated complaints e.g.

decrease fluid intake, pillow support (D).

The effects of CBTi in pregnancy have only been assessed

in one small open-label study, but this approach seems sensi-

ble (B).

Recognise RLS by careful history and investigations if

necessary.

○ Dopamine agonists are contraindicated (FDA category C

or greater).

○ Iron supplementation has been shown to be effective in

RLS. Supplementation is suggested even if levels are not

low (D).

○ Keep caffeine low as it can exacerbate RLS (D).

○ Mild-moderate exercise in the early evening, stretching,

massage (D).

If patient suffers from intractable insomnia and a phar-

macological agent is required, zolpidem or zopiclone should

be used short-term after discussion on potential risks and

benefits (D).

Wilson et al. 939

What is known about treatment of insomnia in older adults:

 CBTi is effective in older adults and is associated with minimal

side effects (Ia).

 Eszopiclone, suvorexant and doxepin improve global and sleep

outcomes (Ib).

 Prolonged release melatonin given for three weeks improves sleep

onset latency and sleep quality in patients over 55 years (Ib).

 Drugs with sedative effects increase the risk of falls in older

adults (III).

 Benzodiazepine hypnotics have an unfavourable risk/benefit

ratio (B).

 Insomnia increases the risk of falls and fractures in nursing

homes independently of medication (III).

What is not known:

Is there an effective treatment for sleeplessness in older adults

with dementia?

Treatment of insomnia in older adults

Insomnia in elderly patients often responds well to CBTi (see

psychological treatment section above). Meta-analyses compar-

ing CBT outcomes in older adults (55 years plus), have reported

moderate to large effect sizes, whether or not insomnia is comor-

bid with other disorders (Alessi and Vitiello, 2015).

A meta-analysis (Glass et al., 2005) concluded that benzo-

diazepine hypnotics had an unfavourable risk/benefit ratio in

elderly patients, but the different methods of collection and cate-

gorisation of drug-related side effects in the studies included

makes them difficult to interpret. Individual randomised con-

trolled studies with short-acting Z drugs show little evidence of

adverse effects, particularly cognitive side effects in the morning.

However if a patient needs to rise within a few hours after taking

a benzodiazepine agonist drug there may be undesired effects on

motor control. Falls are increased after sedatives and hypnotics,

drugs for depression or psychosis, benzodiazepines, nonsteroidal

anti-inflammatory drugs and calcium channel antagonists

(Woolcott et al., 2009) but this study did not specify daytime/

night-time use. There is a 2.5-fold risk of falls in hospital after

zolpidem (Rhalimi et al., 2009), but in nursing homes the situation

may be different; in a large study (Avidan et al., 2005) insomnia

itself, but not hypnotic use, was associated with an increase in

falls and hip fractures. Therefore the development of sleep-pro-

moting drugs without motor side effects has been welcomed.

Prolonged release melatonin has been shown to reduce sleep

onset latency and increase subjective sleep quality in patients

over 55 years (Lemoine et al., 2007; Wade et al., 2007, 2011); its

effects are modest but it has no known motor side effects.

The antihistamine drug doxepin (in very low dose 3 mg, see

above) has been found effective in insomnia in the older patient, in

particular decreasing awakenings in the latter half of the night with-

out daytime effects (Lankford et al., 2012; Krystal et al., 2013).

A Cochrane review, looking at pharmacotherapies for sleep

disturbances in dementia (McCleery et al., 2016) found a lack of

evidence to help guide drug treatment of sleep problems in

dementia. Few RCTs have been conducted. There is some evi-

dence to support the use of low dose trazodone (Camargos,

2014). This is an area with a high need for pragmatic trials, par-

ticularly of those drugs that are in common clinical use for sleep

problems in dementia.

Recommendations

CBTi is effective and should be offered as a first line treat-

ment where available (A).

When a hypnotic is indicated in patients over 55 years

prolonged release melatonin should be tried first (B).

If a GABA-A hypnotic is used then a shorter half-life will

minimise unwanted hangover effects (A).

Sleep problems in children

Sleep problems are commonly associated with certain genetic

and neuro-developmental problems seen in childhood including

ADHD, autism, learning difficulties and epilepsy. Training and

awareness of paediatric sleep disorders is poor and accurate

diagnoses and hence appropriate treatments are often delayed.

Settling and sleep maintenance problems may be exacerbated

by a sleep disorder such as obstructive sleep apnoea or RLS.

Evidence from systematic review suggests that most sleep dis-

orders in childhood respond well to behavioural treatments

(Mindell et al., 2006). Appropriate sleep hygiene measures and

more specific techniques of extinction, or graduated extinction, are

all more effective than placebo at improving sleep and reducing the

number of weekly night wakes in otherwise healthy children who

regularly wake up in the night (Ramchandani et al., 2000). These

interventions hold for both typically developing children and chil-

dren with learning difficulties and sleep problems. These interven-

tions may not change sleep parameters in the child, but instead

improve outcomes related to impact on parents and other carers.

The sedative side effects of antihistamines may speed up

behavioural programmes over short periods (France et al., 1991)

but seem not to work without behavioural interventions; in a

placebo-controlled double-blind trial in infants aged 6–27 months

the same authors found no significant effect of 15 mg or 30 mg

trimeprazine tartrate, and concluded that it is not recommended

as a pharmacological treatment for infant sleep disturbance

unless as an adjunct to a behavioural therapy program (France

et al., 1999). Clinically the short term use of an H1 blocker for

transient or extreme insomnia is frequently employed: however,

tolerance can develop quickly and some children can experience

dramatic and paradoxical over-arousal. The TIRED RCT specifi-

cally investigated the use of diphenhydramine in infants aged

from 6–15 months and found it was no more effective than pla-

cebo in reducing night-time awakening (Merenstein et al., 2006).

It is important to consider the effects of these medications at neu-

rotransmitter systems other than H1 receptors, particularly in

relation to side effects due to anticholinergic or dopamine antag-

onist action.

What is known:

 Most sleep settling and maintenance problems in childhood

respond well to behavioural treatments (I).

 Melatonin reduces long sleep latency (following appropriate

behavioural interventions) in children with sleep onset

insomnia or delayed sleep phase syndrome and learning

difficulties, autism and attention deficit hyperactivity disorder

(ADHD) (II).

What is not known:

 What are the long-term effects of melatonin?

940 Journal of Psychopharmacology 33(8)

The evidence supporting use of melatonin to reduce long

sleep latency (following appropriate behavioural interventions)

in populations of children with idiopathic sleep onset insomnia

(Smits et al., 2003) or delayed sleep phase syndrome and learning

difficulties, autism and ADHD (Gringras et al., 2017; Maras

et al., 2018; Rossignol and Frye, 2011; van der Heijden et al.,

2007) is increasingly robust.

There is evidence to support a behavioural intervention both

before a trial of melatonin (Gringras et al., 2012) (as many will

respond without requiring melatonin), and for continuing a

behavioural intervention whilst administering melatonin. The

combination of both has been shown to be more effective than

either one alone (Cortesi et al., 2012).

The most recent randomised controlled study showed a paedi-

atric mini-pill sustained release melatonin at a dose of 2–10 mg

was well-tolerated, efficacious and safe compared to placebo for

treatment of insomnia in children with autistic spectrum disorder

(ASD). These studies have resulted in the first licensed sleep med-

ication for insomnia in children with ASD. They showed clini-

cally meaningful improvements in total sleep time (TST), duration

of uninterrupted sleep (longest sleep episode) and sleep latency

(SL) with corresponding behavioural improvements for the chil-

dren, and improved quality of life measures in their parents over a

two-year period. (Gringras et al., 2017; Maras et al., 2018)

Melatonin at doses between 0.5–12 mg is commonly used as a

sleep-promoting agent in children undergoing procedures such as

EEG, as an alternative to sleep deprivation to induce drowsiness

and sleep that does not affect the EEG morphology. A melatonin-

induced sleep EEG was as useful as a sleep-deprived EEG but chil-

dren’s behaviour on the day of the melatonin-induced sleep EEG

recording was more acceptable to parents (Wassmer et al., 2001).

Clonidine is an antihypertensive agent with sedative side

effects that is licensed for children with ADHD and improves

sleep maintenance in some children. The therapeutic window is

narrow, both for adverse effects on sleep architecture and tolera-

bility. Tolerance to the sleep-inducing effects develops over time

leading to the need for increased doses with concomitant risk of

adverse effects.

Chloral hydrate and triclofos are still popular hypnotics for

children but have a very long half-life and considerable potential

for ‘hang-over’ effects in children. The half-life of chloral hydrate

itself is short (a few minutes), but the half-lives of its active

metabolites are longer, being 8–12 h for trichloroethanol and 67

h for trichloroacetic acid. Toxicity is an important concern due to

central nervous system depressant action, arrhythmogenic poten-

tial and stomach irritation.

Recommendations

Behavioural strategies should be tried first in children

with disturbed sleep (A).

Melatonin improves sleep in children with ASDs (A).

Melatonin administration can be used to advance sleep

onset to normal values in children with ADHD who are not on

stimulant medication (B).

Sleep disturbance in adults with intellectual

disability

There is little clarity in the definition of sleep problems in adults

with intellectual disability. This is primarily because it is

difficult to obtain subjective measures from the patient who may

be unable to communicate verbally or even perceive that they

are having a problem. Reports of sleep difficulties tend to be

from carers as they struggle to cope with issues which only seem

to be exacerbated when they, and the person they care for, expe-

rience sleep disturbance. There is a compelling need to develop

a more accurate, standardised measure of sleep for this popula-

tion (Meltzer and Mindell, 2014), to obtain essential information

about prevalence.

Difficulties in assessing sleep disorders include diagnostic

overshadowing, where behaviours such as daytime sleepiness,

inattention and challenging behaviour are regarded as sympto-

matic of the intellectual disability as opposed to being indicative

of a sleep disorder. In these circumstances therefore, clinicians

may fail to consider the possibility of sleep disturbance and thus

neglect to undertake more detailed investigations.

The situation is further compounded by the fact that health

and behavioural problems can increase as sleep problems

develop. For example, the inability to problem solve combined

with daytime somnolence exacerbates cognitive processing prob-

lems in those already compromised intellectually (Carr et al.,

2003; Symons et al., 2000).

Within this population there are additional high-risk groups

including those with co-morbidities such as Down syndrome

where people may present with sleep related breathing disorders,

or Smith-Magenis syndrome where melatonin rhythm is inverted.

In general, there are a wide range of precipitating and per-

petuating factors to consider including maladaptive coping strat-

egies, the impact of medication e.g. drugs used in psychosis,

depression, epilepsy including side-effects and the impact of

polypharmacy on sleep and daytime functioning. For those in

institutional or residential living environments the environment

itself may contribute to disturbed or inconsistent sleep patterns,

as other patients/residents wake others up or staff shift patterns

determine wake/sleep times rather the individuals themselves.

Assessment. Sound clinical assessment should elicit any aetio-

logical or exacerbating factors which can be reversed. This may

be best undertaken by direct observation initially. Carers should

be supported to keep a structured 24-hour record of sleep pattern

and behaviour. Actigraphy or EEG may be useful when a sleep

disorder other than insomnia or settling difficulties is suspected,

but clinicians should be aware that the recording equipment may

not be tolerated by people with more moderate to severe levels of

intellectual disability. The possibility of a CRD should also be

excluded in individuals with additional visual impairment.

Treatment considerations. There is a varying degree of evi-

dence for treatments of sleep difficulties in this heterogeneous

population. Systematic review (van de Wouw et al., 2012) used

SIGN 50 methodology but no statistical analysis in 50 studies

using behavioural interventions in adults with intellectual dis-

abilities. They concluded there was some indication of the effec-

tiveness of behavioural interventions. In addition, they reported

that in some cases sleep problems were associated with challeng-

ing behaviour and medication.

The relatively small number of controlled studies in this area

give support to parental/carer education and modifying environ-

mental factors (Montgomery et al., 2004). Behavioural regimes

such as chronotherapy, bedtime fading, extinction, distancing/

desensitisation and sleep-wake scheduling (Wiggs and France,

Wilson et al. 941

2000; Gunning and Espie, 2003) may also prove bene ficial. The use

of light therapy has been described (Short and Carpenter, 1998).

There is little evidence for effectiveness of sleep-promoting

drugs, apart from melatonin. A meta-analysis (Braam et al., 2009)

indicated that melatonin (1–9 mg) decreases sleep latency and

number of wakes per night, and increases total sleep time in indi-

viduals with intellectual disabilities. There were few adverse

events in the relatively short-term studies included, however long

term safety requires further research.

Recommendations

Clinical assessment should describe sleep disturbance

and elicit aetiological and exacerbating factors (A).

Environmental, behavioural and educational approaches

should be used first line (A).

Melatonin is effective in improving sleep (A).

Treatment should be planned within a capacity/best inter-

ests framework (D).

Acknowledgements

Although the first author prepared the document for publication, all

authors contributed equally to the consensus.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to

the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship,

and/or publication of this article.

References

Abe T, Inoue Y, Komada Y, et al. (2011) Relation between morningness-

eveningness score and depressive symptoms among patients with

delayed sleep phase syndrome. Sleep Med 12: 680–684.

Adam K and Oswald I (1986) The hypnotic effects of an antihistamine:

Promethazine. Br J Clin Pharmacol 22: 715–717.

Alessi C and Vitiello MV (2015) Insomnia (primary) in older people:

Non-drug treatments. BMJ Clin Evid 2015: 2302.

Alford C, Rombaut N, Jones J, et al. (1992) Acute effects of hydroxyzine

on nocturnal sleep and sleep tendency the following day: A C-EEG

study. Hum Psychopharmacol Clin Exp 7: 25–35.

Altena E, Van Der Werf YD, Strijers RL, et al. (2008) Sleep loss affects

vigilance: Effects of chronic insomnia and sleep therapy. J Sleep Res

17: 335–343.

Ancoli-Israel S, Krystal AD, McCall WV, et al. (2010) A 12-week, ran-

domized, double-blind, placebo-controlled study evaluating the effect

of eszopiclone 2 mg on sleep/wake function in older adults with pri-

mary and comorbid insomnia. Sleep 33: 225–234.

Ancoli-Israel S, Richardson GS, Mangano RM, et al. (2005) Long-term

use of sedative hypnotics in older patients with insomnia. Sleep Med

6: 107–113.

Anderson KN and Shneerson JM (2009) Drug treatment of REM sleep

behavior disorder: The use of drug therapies other than clonazepam.

J Clin Sleep Med 5: 235–239.

Anderson SL and Vande Griend JP (2014) Quetiapine for insomnia: A

review of the literature. Am J Health Syst Pharm 71: 394–402.

Armitage R, Cole D, Suppes T, et al. (2004) Effects of clozapine on sleep

in bipolar and schizoaffective disorders. Prog Neuropsychopharma-

col Biol Psychiatry 28: 1065–1070.

Attenburrow M, Dowling B and Sharpley A (1996) Case-control study

of evening melatonin concentration in primary insomnia. Br Med J

312: 1263–1264.

Auger RR, Burgess HJ, Emens JS, et al. (2015) Clinical practice guideline

for the treatment of intrinsic circadian rhythm sleep-wake disorders:

Advanced sleep-wake phase disorder (ASWPD), delayed sleep-wake

phase disorder (DSWPD), non-24-hour sleep-wake rhythm disorder

(N24SWD), and irregular sleep-wake rhythm disorder (ISWRD). An

update for 2015: an American academy of sleep medicine clinical

practice guideline. J Clin Sleep Med 11: 1199–1236.

Aurora RN, Zak RS, Maganti RK, et al. (2010) Best practice guide for

the treatment of REM sleep behavior disorder (RBD). J Clin Sleep

Med 6: 85–95.

Avidan AY, Fries BE, James ML, et al. (2005) Insomnia and hypnotic

use, recorded in the minimum data set, as predictors of falls and hip

fractures in Michigan nursing homes. J Am Geriatr Soc 53: 955–962.

Baglioni C and Riemann D (2012) Is chronic insomnia a precursor to

major depression? Epidemiological and biological findings. Curr

Psychiatry Rep 14: 511–518.

Baglioni C, Spiegelhalder K, Lombardo C, et al. (2010) Sleep and emo-

tions: A focus on insomnia. Sleep Med Rev 14: 227–238.

Ban L, West J, Gibson JE, et al. (2014) First trimester exposure to anxio-

lytic and hypnotic drugs and the risks of major congenital anomalies: A

United Kingdom population-based cohort study. PLoS One 9: e100996.

Barbone F, McMahon AD, Davey PG, et al. (1998) Association of road-

traffic accidents with benzodiazepine use. Lancet 352: 1331–1336.

Baskaran A, Summers D, Willing SL, et al. (2013) Sleep architecture

in ziprasidone-treated bipolar depression: A pilot study. Ther Adv

Psychopharmacol 3: 139–149.

Bastien CH, LeBlanc M, Carrier J, et al. (2003) Sleep EEG power spectra,

insomnia, and chronic use of benzodiazepines. Sleep 26: 313–317.

Bateson AN (2002) Basic pharmacologic mechanisms involved in benzo-

diazepine tolerance and withdrawal. Curr Pharm Des 8: 5–21.

Becker PM (2015) Hypnosis in the management of sleep disorders. Sleep

Med Clin 10: 85–92.

Belanger L, Morin CM, Bastien C, et al. (2005) Self-efficacy and compli-

ance with benzodiazepine taper in older adults with chronic insom-

nia. Health Psychol 24: 281–287.

Belleville G, Guay C, Guay B, et al. (2007) Hypnotic taper with or with-

out self-help treatment of insomnia: A randomized clinical trial. J

Consult Clin Psychol 75: 325–335.

Bertisch SM, Herzig SJ, Winkelman JW, et al. (2014) National use of

prescription medications for insomnia: NHANES 1999–2010. Sleep

37: 343–349.

Billiard M, Bassetti C, Dauvilliers Y, et al. (2006) EFNS guidelines on

management of narcolepsy. Eur J Neurol 13: 1035–1048.

Bixler EO, Papaliaga MN, Vgontzas AN, et al. (2009) Women sleep

objectively better than men and the sleep of young women is more

resilient to external stressors: Effects of age and menopause. J Sleep

Res 18: 221–228.

Bixler EO, Vgontzas AN, Lin HM, et al. (2001) Prevalence of sleep-

disordered breathing in women: Effects of gender. Am J Respir Crit

Care Med 163: 608–613.

Boeve BF, Silber MH and Ferman TJ (2004) REM sleep behavior disor-

der in Parkinson's disease and dementia with Lewy bodies. J Geriatr

Psychiatry Neurol 17: 146–157.

Boyle J, Groeger JA, Paska W, et al. (2012) A method to assess the

dissipation of the [corrected] residual effects of [corrected] hyp-

notics: Eszopiclone versus zopiclone. J Clin Psychopharmacol 32:

704–709.

Braam W, Smits MG, Didden R, et al. (2009) Exogenous melatonin for

sleep problems in individuals with intellectual disability: A meta-

analysis. Dev Med Child Neurol 51: 340–349.

Breslau N, Roth T, Rosenthal L, et al. (1996) Sleep disturbance and psy-

chiatric disorders: A longitudinal epidemiological study of young

adults. Biol Psychiatry 39: 411–418.

942 Journal of Psychopharmacology 33(8)

Bruni O, Ferri R, Miano S, et al. (2004) L -5-Hydroxytryptophan treat-

ment of sleep terrors in children. Eur J Pediatr 163: 402–407.

Burgess M, Gill M and Marks I (1998) Postal self-exposure treatment of

recurrent nightmares. Randomised controlled trial. Br J Psychiatry

172: 257–262.

Buscemi N, Vandermeer B, Friesen C, et al. (2005) Manifestations and

management of chronic insomnia in adults. Evid Rep Technol Assess

(Summ.): 125: 1–10.

Buscemi N, Vandermeer B, Friesen C, et al. (2007) The efficacy and

safety of drug treatments for chronic insomnia in adults: A meta-

analysis of RCTs. J Gen Intern Med 22: 1335–1350.

Cajochen C, Krauchi K and Wirz-Justice A (2003) Role of melatonin in

the regulation of human circadian rhythms and sleep. J Neuroendo-

crinol 15: 432–437.

Calem M, Bisla J, Begum A, et al. (2012) Increased prevalence of insom-

nia and changes in hypnotics use in England over 15 years: Analysis

of the 1993, 2000, and 2007 National Psychiatric Morbidity Surveys.

Sleep 35: 377–384.

Camargos EF, Louzada LL, Quintas JL, et al. (2014) Trazodone improves

sleep parameters in Alzheimer disease patients: A randomized, dou-

ble-blind, and placebo-controlled study. Am J Geriatr Psychiatry 22:

1565–1574.

Cappuccio FP, D'Elia L, Strazzullo P, et al. (2010) Quantity and quality

of sleep and incidence of type 2 diabetes: A systematic review and

meta-analysis. Diabetes Care 33: 414–420.

Carr EG, Magito McLaughlin D, Giacobbe-Grieco T, et al. (2003) Using

mood ratings and mood induction in assessment and intervention for

severe problem behavior. Am J Ment Retard 108: 32–55.

Chang PP, Ford DE, Mead LA, et al. (1997) Insomnia in young men and

subsequent depression. The Johns Hopkins Precursors Study. Am J

Epidemiol 146: 105–114.

Cheng SK and Dizon J (2012) Computerised cognitive behavioural ther-

apy for insomnia: A systematic review and meta-analysis. Psycho-

ther Psychosom 81: 206–216.

Cohen DA, Wang W, Klerman EB, et al. (2010) Ramelteon prior to a

short evening nap impairs neurobehavioral performance for up to 12

hours after awakening. J Clin Sleep Med 6: 565–571.

Cohrs S, Meier A, Neumann AC, et al. (2005) Improved sleep continuity

and increased slow wave sleep and REM latency during ziprasidone

treatment: A randomized, controlled, crossover trial of 12 healthy

male subjects. J Clin Psychiatry 66: 989–996.

Cohrs S, Rodenbeck A, Guan Z, et al. (2004) Sleep-promoting properties

of quetiapine in healthy subjects. Psychopharmacology (Berl) 174:

421–429.

Connor J, Norton R, Ameratunga S, et al. (2002) Driver sleepiness and

risk of serious injury to car occupants: Population based case control

study. BMJ 324: 1125.

Cooper AJ (1987) Treatment of coexistent night-terrors and somnam-

bulism in adults with imipramine and diazepam. J Clin Psychiatry

48: 209–210.

Cortesi F, Giannotti F, Sebastiani T, et al. (2012) Controlled-release

melatonin, singly and combined with cognitive behavioural ther-

apy, for persistent insomnia in children with autism spectrum

disorders: A randomized placebo-controlled trial. J Sleep Res 21:

700–709.

Crisp AH (1996) The sleepwalking/night terrors syndrome in adults.

Postgrad Med J 72: 599–604.

Daley M, Morin CM, LeBlanc M, et al. (2009) Insomnia and its relation-

ship to health-care utilization, work absenteeism, productivity and

accidents. Sleep Med 10: 427–438.

Davari-Tanha F, Soleymani-Farsani M, Asadi M, et al. (2016) Com-

parison of citalopram and venlafaxine’s role in treating sleep

disturbances in menopausal women, a randomized, double-blind,

placebo-controlled trial. Arch Gynecol Obstet 293: 1007–1013.

Dijk DJ and von Schantz M (2005) Timing and consolidation of human

sleep, wakefulness, and performance by a symphony of oscillators. J

Biol Rhythms 20: 279–290.

Doble A, Martin IL and Nutt DJ (2004) Calming the Brain: Benzodiaze-

pines and Related Drugs from Laboratory to Clinic. London: Martin

Dunitz Limited.

Dowling GA, Burr RL, Van Someren EJ, et al. (2008) Melatonin and

bright-light treatment for rest-activity disruption in institutionalized

patients with Alzheimer’s disease. J Am Geriatr Soc 56: 239–246.

Edinger JD, Means MK, Carney CE, et al. (2008) Psychomotor perfor-

mance deficits and their relation to prior nights’ sleep among indi-

viduals with primary insomnia. Sleep 31: 599–607.

Ensrud KE, Joffe H, Guthrie KA, et al. (2012) Effect of escitalopram

on insomnia symptoms and subjective sleep quality in healthy peri-

menopausal and postmenopausal women with hot flashes: A ran-

domized controlled trial. Menopause 19: 848–855.

Espie CA (2002) Insomnia: Conceptual issues in the development, per-

sistence, and treatment of sleep disorder in adults. Annu Rev Psychol

53: 215–243.

Espie CA, Broomfield NM, MacMahon KM, et al. (2006) The attention-

intention-effort pathway in the development of psychophysiologic

insomnia: A theoretical review. Sleep Med Rev 10: 215–245.

Espie CA, Emsley R, Kyle SD, et al. (2018a) Effect of digital cognitive

behavioral therapy for insomnia on health, psychological well-being,

and sleep-related quality of life: A randomized clinical trial. JAMA

Psychiatry. DOI: 10.1001/jamapsychiatry.2018.2745

Espie CA, Farias Machado P, Carl JR, et al. (2018b) The sleep condition

indicator: Reference values derived from a sample of 200 000 adults.

J Sleep Res 27: e12643.

Espie CA, Kyle SD, Hames P, et al. (2012) The daytime impact of DSM-5

insomnia disorder: Comparative analysis of insomnia subtypes from

the Great British Sleep Survey. J Clin Psychiatry 73: e1478–1484.

Espie CA, Kyle SD, Hames P, et al. (2014) The sleep condition indicator:

A clinical screening tool to evaluate insomnia disorder. BMJ Open 4:

e004183.

Everitt H, Baldwin DS, Stuart B, et al. (2018) Antidepressants for insom-

nia in adults. Cochrane Database Syst Rev 5: CD010753.

Farkas RH, Unger EF and Temple R (2013) Zolpidem and driving impair-

ment—identifying persons at risk. N Engl J Med 369: 689–691.

Flynn-Evans EE, Shekleton JA, Miller B, et al. (2017) Circadian phase

and phase angle disorders in primary insomnia. Sleep 40(12): 1–11.

Ford DE and Kamerow DB (1989) Epidemiological study of sleep dis-

turbances and psychaitric disorders: An opportunity for prevention?

JAMA 262: 1479–1484.

Fortier-Brochu E, Beaulieu-Bonneau S, Ivers H, et al. (2012) Insomnia

and daytime cognitive performance: A meta-analysis. Sleep Med Rev

16: 83–94.

France KG, Blampied NM and Wilkinson P (1991) Treatment of infant

sleep disturbance by trimeprazine in combination with extinction. J

Dev Behav Pediatr 12: 308–314.

France KG, Blampied NM and Wilkinson P (1999) A multiple-baseline,

double-blind evaluation of the effects of trimeprazine tartrate on

infant sleep disturbance. Exp Clin Psychopharmacol 7: 502–513.

Freeman D, Sheaves B, Goodwin GM, et al. (2017) The effects of

improving sleep on mental health (OASIS): A randomised controlled

trial with mediation analysis. Lancet Psychiatry 4: 749–758.

Gagnon JF, Postuma RB and Montplaisir J (2006) Update on the phar-

macology of REM sleep behavior disorder. Neurology 67: 742–747.

Gao K, Mackle M, Cazorla P, et al. (2013) Comparison of somnolence

associated with asenapine, olanzapine, risperidone, and haloperidol

relative to placebo in patients with schizophrenia or bipolar disorder.

Neuropsychiatr Dis Treat 9: 1145–1157.

Gimenez S, Clos S, Romero S, et al. (2007) Effects of olanzapine, ris-

peridone and haloperidol on sleep after a single oral morning dose in

healthy volunteers. Psychopharmacology (Berl) 190: 507–516.

Glass J, Lanctot KL, Herrmann N, et al. (2005) Sedative hypnotics in

older people with insomnia: Meta-analysis of risks and benefits. BMJ

331: 1169.

Greenblatt DJ, Legangneux E, Harmatz JS, et al. (2006) Dynamics and

kinetics of a modified-release formulation of zolpidem: Comparison

Wilson et al. 943

with immediate-release standard zolpidem and placebo. J Clin Phar-

macol 46: 1469–1480.

Gringras P, Gamble C, Jones AP, et al. (2012) Melatonin for sleep prob-

lems in children with neurodevelopmental disorders: Randomised

double masked placebo controlled trial. BMJ 345: e6664.

Gringras P, Nir T, Breddy J, et al. (2017) Efficacy and safety of pediatric

prolonged-release melatonin for insomnia in children with autism

spectrum disorder. J Am Acad Child Adolesc Psychiatry 56: 948–957

e944.

Gross G, Xin X and Gastpar M (1991) Trimipramine: Pharmacological

reevaluation and comparison with clozapine. Neuropharmacology

30: 1159–1166.

Gunning MJ and Espie CA (2003) Psychological treatment of reported

sleep disorder in adults with intellectual disability using a multiple

baseline design. J Intellect Disabil Res 47: 191–202.

Hafner M, Stepanek M, Taylor J, et al. (2017) Why sleep matters-the

economic costs of insufficient sleep: A cross-country comparative

analysis. Rand Health Q 6: 11.

Haimov I (2001) Melatonin rhythm abnormalities and sleep disorders in

the elderly. CNS Spectr 6: 502–506.

Hajak G, Hedner J, Eglin M, et al. (2009) A 2-week efficacy and safety

study of gaboxadol and zolpidem using electronic diaries in primary

insomnia outpatients. Sleep Med 10: 705–712.

Hajak G, Rodenbeck A, Voderholzer U, et al. (2001) Doxepin in the

treatment of primary insomnia: A placebo-controlled, double-blind,

polysomnographic study. J Clin Psychiatry 62: 453–463.

Hansen K, Hofling V, Kroner-Borowik T, et al. (2013) Efficacy of psy-

chological interventions aiming to reduce chronic nightmares: A

meta-analysis. Clin Psychol Rev 33: 146–155.

Harris M and Grunstein RR (2009) Treatments for somnambulism in

adults: Assessing the evidence. Sleep Med Rev 13: 295–297.

Herring WJ, Connor KM, Ivgy-May N, et al. (2016) Suvorexant in

patients with insomnia: Results from two 3-month randomized con-

trolled clinical trials. Biol Psychiatry 79: 136–148.

Hicks JA, Argyropoulos SV, Rich AS, et al. (2002) Randomised con-

trolled study of sleep after nefazodone or paroxetine treatment in out-

patients with depression. Br J Psychiatry 180: 528–535.

Hirano A, Shi G, Jones CR, et al. (2016) A Cryptochrome 2 mutation

yields advanced sleep phase in humans. eLife 5 pii: e16695.

Hoque R and Chesson AL, Jr (2010) Pharmacologically induced/exacer-

bated restless legs syndrome, periodic limb movements of sleep, and

REM behavior disorder/REM sleep without atonia: Literature review,

qualitative scoring, and comparative analysis. J Clin Sleep Med 6:

79–83.

Horne JA and Ostberg O (1976) A self-assessment questionnaire to deter-

mine morningness-eveningness in human circadian rhythms. Int J

Chronobiol 4: 97–110.

Hubner A, Krafft A, Gadient S, et al. (2013) Characteristics and determi-

nants of restless legs syndrome in pregnancy: A prospective study.

Neurology 80: 738–742.

Iranzo A, Fernandez-Arcos A, Tolosa E, et al. (2014) Neurodegenerative

disorder risk in idiopathic REM sleep behavior disorder: Study in

174 patients. PLoS One 9: e89741.

Ivgy-May N, Roth T, Ruwe F, et al. (2015) Esmirtazapine in non-elderly

adult patients with primary insomnia: Efficacy and safety from a

2-week randomized outpatient trial. Sleep Med 16: 831–837.

Jia F, Goldstein PA and Harrison NL (2009) The modulation of synaptic

GABA(A) receptors in the thalamus by eszopiclone and zolpidem. J

Pharmacol Exp Ther 328: 1000–1006.

Jindal RD, Buysse DJ and Thase ME (2004) Maintenance treatment of

insomnia: What can we learn from the depression literature? Am J

Psychiatry 161: 19–24.

Kalmbach DA, Cuamatzi-Castelan AS, Tonnu CV, et al. (2018) Hyper-

arousal and sleep reactivity in insomnia: Current insights. Nat Sci

Sleep 10: 193–201.

Karsten J, Hagenauw LA, Kamphuis J, et al. (2017) Low doses of

mirtazapine or quetiapine for transient insomnia: A randomised,

double-blind, cross-over, placebo-controlled trial. J Psychopharma-

col 31: 327–337.

Kaynak H, Kaynak D, Gozukirmizi E, et al. (2004) The effects of tra-

zodone on sleep in patients treated with stimulant antidepressants.

Sleep Med 5: 15–20.

Keeshin BR, Ding Q, Presson AP, et al. (2017) Use of prazosin for pedi-

atric PTSD-associated nightmares and sleep disturbances: A retro-

spective chart review. Neurol Ther 6: 247–257.

Keshavan MS, Prasad KM, Montrose DM, et al. (2007) Sleep quality and

architecture in quetiapine, risperidone, or never-treated schizophre-

nia patients. J Clin Psychopharmacol 27: 703–705.

Khan MS and Aouad R (2017) The effects of insomnia and sleep loss on

cardiovascular disease. Sleep Med Clin 12: 167–177.

Kim SJ, Lee YJ, Lee YJ, et al. (2014) Effect of quetiapine XR on depres-

sive symptoms and sleep quality compared with lithium in patients

with bipolar depression. J Affect Disord 157: 33–40.

Kluge M, Schacht A, Himmerich H, et al. (2014) Olanzapine and clozap-

ine differently affect sleep in patients with schizophrenia: Results

from a double-blind, polysomnographic study and review of the lit-

erature. Schizophr Res 152: 255–260.

Kosky C, Bonakis A, Merritt S, et al. (2008) Sodium oxybate improves

coexisting REM behavior disorder in narcolepsy with cataplexy. J

Sleep Res 17: 97.

Krakow B, Hollifield M, Johnston L, et al. (2001) Imagery rehearsal

therapy for chronic nightmares in sexual assault survivors with post-

traumatic stress disorder: A randomized controlled trial. JAMA 286:

537–545.

Krystal AD (2009) A compendium of placebo-controlled trials of the

risks/benefits of pharmacological treatments for insomnia: The

empirical basis for U.S. clinical practice. Sleep Med Rev 13: 265–274.

Krystal AD, Durrence HH, Scharf M, et al. (2010) Efficacy and safety of

doxepin 1 mg and 3 mg in a 12-week sleep laboratory and outpatient

trial of elderly subjects with chronic primary insomnia. Sleep 33:

1553–1561.

Krystal AD, Erman M, Zammit GK, et al. (2008) Long-term efficacy

and safety of zolpidem extended-release 12.5 mg, administered 3 to

7 nights per week for 24 weeks, in patients with chronic primary

insomnia: A 6-month, randomized, double-blind, placebo-controlled,

parallel-group, multicenter study. Sleep 31: 79–90.

Krystal AD, Lankford A, Durrence HH, et al. (2011) Efficacy and safety

of doxepin 3 and 6 mg in a 35-day sleep laboratory trial in adults with

chronic primary insomnia. Sleep 34: 1433–1442.

Krystal AD, Richelson E and Roth T (2013) Review of the histamine

system and the clinical effects of H1 antagonists: Basis for a new

model for understanding the effects of insomnia medications. Sleep

Med Rev 17: 263–272.

Krystal AD, Walsh JK, Laska E, et al. (2003) Sustained efficacy of

eszopiclone over 6 months of nightly treatment: Results of a random-

ized, double-blind, placebo-controlled study in adults with chronic

insomnia. Sleep 26: 793–799.

Krystal AD and Zammit G (2016) The sleep effects of lurasidone: A pla-

cebo-controlled cross-over study using a 4-h phase-advance model

of transient insomnia. Hum Psychopharmacol 31: 206–216.

Kuh DL, Hardy R and Wadsworth M (1997) Women’s health in midlife:

The influence of the menopause, social factors and health in earlier

life. Br J Obstet Gynaecol 104: 1419.

Kunz D and Mahlberg R (2010) A two-part, double-blind, placebo-con-

trolled trial of exogenous melatonin in REM sleep behaviour disor-

der. J Sleep Res 19: 591–596.

Kyle SD, Morgan K and Espie CA (2010) Insomnia and health-related

quality of life. Sleep Med Rev 14: 69–82.

Landolt HP, Retey JV, Tonz K, et al. (2004) Caffeine attenuates waking

and sleep electroencephalographic markers of sleep homeostasis in

humans. Neuropsychopharmacology 29: 1933–1939.

Lankford A, Rogowski R, Essink B, et al. (2012) Efficacy and safety of

doxepin 6 mg in a four-week outpatient trial of elderly adults with

chronic primary insomnia. Sleep Med 13: 133–138.

944 Journal of Psychopharmacology 33(8)

Lazowski LK, Townsend B, Hawken ER, et al. (2014) Sleep architecture and

cognitive changes in olanzapine-treated patients with depression: A dou-

ble blind randomized placebo controlled trial. BMC Psychiatry 14: 202.

LeBlanc M, Merette C, Savard J, et al. (2009) Incidence and risk factors

of insomnia in a population-based sample. Sleep 32: 1027–1037.

Leger D and Poursain B (2005) An international survey of insomnia:

Under-recognition and under-treatment of a ploysymptomatic condi-

tion. Curr Med Res Opin 21: 1785–1792.

Leger D, Bayon V, Ohayon MM, et al. (2014) Insomnia and accidents:

Cross-sectional study (EQUINOX) on sleep-related home, work and

car accidents in 5293 subjects with insomnia from 10 countries. J

Sleep Res 23: 143–152.

Leger D, Laudon M and Zisapel N (2004) Nocturnal 6-sulfatoxymelato-

nin excretion in insomnia and its relation to the response to melato-

nin replacement therapy. Am J Med 116: 91–95.

Leger D, Morin CM, Uchiyama M, et al. (2012) Chronic insomnia, qual-

ity-of-life, and utility scores: Comparison with good sleepers in a

cross-sectional international survey. Sleep Med 13: 43–51.

Lemoine P, Nir T, Laudon M, et al. (2007) Prolonged-release melatonin

improves sleep quality and morning alertness in insomnia patients

aged 55 years and older and has no withdrawal effects. J Sleep Res

16: 372–380.

Lindberg N, Virkkunen M, Tani P, et al. (2002) Effect of a single-dose of

olanzapine on sleep in healthy females and males. Int Clin Psycho-

pharmacol 17: 177–184.

Lockley SW, Dressman MA, Licamele L, et al. (2015) Tasimelteon for

non-24-hour sleep-wake disorder in totally blind people (SET and

RESET): Two multicentre, randomised, double-masked, placebo-

controlled phase 3 trials. Lancet 386: 1754–1764.

Loebel AD, Siu CO, Cucchiaro JB, et al. (2014) Daytime sleepiness asso-

ciated with lurasidone and quetiapine XR: Results from a randomized

double-blind, placebo-controlled trial in patients with schizophrenia.

CNS Spectr 19: 197–205.

Luik AI, Machado PF, Siriwardena N, et al. (2019) Screening for insom-

nia in primary care: Using a two-item version of the Sleep Condition

Indicator. Br J Gen Pract 69: 79–80.

MacMahon KM, Broomfield NM and Espie CA (2005) A systematic

review of the effectiveness of oral melatonin for adults (18 to 65

years) with delayed sleep phase syndrome and adults (18 to 65 years)

with primary insomnia. Curr Psychiatry Rev 1: 103–113.

Maras A, Schroder CM, Malow BA, et al. (2018) Long-term efficacy and

safety of pediatric prolonged-release melatonin for insomnia in chil-

dren with autism spectrum disorder. J Child Adolesc Psychopharmacol.

Epub ahead of print 11 October 2018. DOI:10.1089/cap.2018.0020.

Massironi G, Galluzzi S and Frisoni GB (2003) Drug treatment of REM

sleep behavior disorders in dementia with Lewy bodies. Int Psycho-

geriatr 15: 377–383.

Maust DT, Lin LA and Blow FC (2019) Benzodiazepine use and misuse

among adults in the United States. Psychiatr Serv 70: 97–106.

Mayer G, Wang-Weigand S, Roth-Schechter B, et al. (2009) Efficacy and

safety of 6-month nightly ramelteon administration in adults with

chronic primary insomnia. Sleep 32: 351–360.

Mayers AG and Baldwin DS (2005) Antidepressants and their effect on

sleep. Hum Psychopharmacol 20: 533–559.

McCleery J, Cohen DA and Sharpley AL (2016) Pharmacotherapies for

sleep disturbances in dementia. Cochrane Database Syst Rev 11:

CD009178.

McCurry SM, Guthrie KA, Morin CM, et al. (2016) Telephone-based

cognitive behavioral therapy for insomnia in perimenopausal and

postmenopausal women with vasomotor symptoms: A MsFLASH

randomized clinical trial. JAMA Intern Med 176: 913–920.

Meltzer LJ and Mindell JA (2014) Systematic review and meta-analysis

of behavioral interventions for pediatric insomnia. J Pediatr Psychol

39: 932–948.

Merenstein D, ener-West M, Halbower AC, et al. (2006) The trial of

infant response to diphenhydramine: The TIRED study—a randomized,

controlled, patient-oriented trial. Arch Pediatr Adolesc Med 160:

707–712.

Mindell JA, Kuhn B, Lewin DS, et al. (2006) Behavioral treatment of

bedtime problems and night wakings in infants and young children.

Sleep 29: 1263–1276.

Montgomery P, Stores G and Wiggs L (2004) The relative efficacy of

two brief treatments for sleep problems in young learning disabled

(mentally retarded) children: A randomised controlled trial. Arch Dis

Child 89: 125–130.

Montgomery SA, Bebbington P, Cowen P, et al. (1993) Guidelines for treat-

ing depressive illness with antidepressants: A statement from the British

Association for Psychopharmacology. J Psychopharmacol 7: 19–23.

Monti JM, Torterolo P and Pandi Perumal SR (2017) The effects of

second generation antipsychotic drugs on sleep variables in healthy

subjects and patients with schizophrenia. Sleep Med Rev 33: 51–57.

Monti JM (2016) The effect of second-generation antipsychotic drugs on

sleep parameters in patients with unipolar or bipolar disorder. Sleep

Med 23: 89–96.

Moreno RA, Hanna MM, Tavares SM, et al. (2007) A double-blind com-

parison of the effect of the antipsychotics haloperidol and olanzapine

on sleep in mania. Braz J Med Biol Res 40: 357–366.

Morgan K, Dixon S, Mathers N, et al. (2004) Psychological treatment for

insomnia in the regulation of long-term hypnotic drug use. Health

Technol Assess 8: iii-iv, 1–68.

Morin CM, Bastien C, Guay B, et al. (2004) Randomized clinical trial of

supervised tapering and cognitive behavior therapy to facilitate ben-

zodiazepine discontinuation in older adults with chronic insomnia.

Am J Psychiatry 161: 332–342.

Morin CM, Belanger L, Bastien C, et al. (2005a) Long-term outcome

after discontinuation of benzodiazepines for insomnia: A survival

analysis of relapse. Behav Res Ther 43: 1–14.

Morin CM, Belanger L, LeBlanc M, et al. (2009) The natural history of

insomnia: A population-based 3-year longitudinal study. Arch Intern

Med 169: 447–453.

Morin CM, Colecchi C, Stone J, et al. (1999) Behavioral and pharma-

cological therapies for late-life insomnia: A randomized controlled

trial. JAMA 281: 991–999.

Morin CM, Koetter U, Bastien C, et al. (2005b) Valerian-hops combi-

nation and diphenhydramine for treating insomnia: A randomized

placebo-controlled clinical trial. Sleep 28: 1465–1471.

Morin CM, LeBlanc M, Daley M, et al. (2006) Epidemiology of insom-

nia: Prevalence, self-help treatments, consultations, and determi-

nants of help-seeking behaviors. Sleep Med 7: 123–130.

Morphy H, Dunn KM, Lewis M, et al. (2007) Epidemiology of insomnia:

A longitudinal study in a UK population. Sleep 30: 274–280.

Muller MJ, Rossbach W, Mann K, et al. (2004) Subchronic effects of

olanzapine on sleep EEG in schizophrenic patients with predomi-

nantly negative symptoms. Pharmacopsychiatry 37: 157–162.

Murphy SM and Tyrer P (1991) A double-blind comparison of the effects

of gradual withdrawal of lorazepam, diazepam and bromazepam in

benzodiazepine dependence. Br J Psychiat 158: 511–516.

Murray JM, Sletten TL, Magee M, et al. (2017) Prevalence of circa-

dian misalignment and its association with depressive symptoms in

delayed sleep phase disorder. Sleep 40.

Nadorff MR, Lambdin KK and Germain A (2014) Pharmacological and

non-pharmacological treatments for nightmare disorder. Int Rev Psy-

chiatry 26: 225–236.

Nash JR, Wilson SJ, Potokar JP, et al. (2003) Mirtazapine induces REM

sleep behavior disorder (RBD) in parkinsonism. Neurology 61: 1161.

Neau JP, Marion P, Mathis S, et al. (2010) Restless legs syndrome and

pregnancy: Follow-up of pregnant women before and after delivery.

Eur Neurol 64: 361–366.

Neckelmann D, Mykletun A and Dahl AA (2007) Chronic insomnia as a

risk factor for developing anxiety and depression. Sleep 30: 873–880.

Neutel CI (1995) Risk of traffic accident injury after a prescription for a

benzodiazepine. Ann Epidemiol 5: 239–244.

Wilson et al. 945

Nguyen BH, Perusse D, Paquet J, et al. (2008) Sleep terrors in children: A

prospective study of twins. Pediatrics 122: e1164-e1167.

Nutt DJ and Stahl SM (2010) Searching for perfect sleep: The continuing

evolution of GABAA receptor modulators as hypnotics. J Psycho-

pharmacol 24: 1601–1612.

Nutt DJ (2005a) Death by tricyclic: The real antidepressant scandal? J

Psychopharmacol 19: 123–124.

Nutt DJ (2005b) NICE: The National Institute of Clinical Excellence —

or Eccentricity? Reflections on the Z-drugs as hypnotics. J Psycho-

pharmacol 19: 125–127.

O’Brien LM, Bullough AS, Chames MC, et al. (2014) Hypertension,

snoring, and obstructive sleep apnoea during pregnancy: A cohort

study. BJOG 121: 1685–1693.

Ohayon MM, Caulet M, Arbus L, et al. (1999) Are prescribed medica-

tions effective in the treatment of insomnia complaints? J Psychosom

Res 47: 359–368.

Owens JF and Matthews KA (1998) Sleep disturbance in healthy middle-

aged women. Maturitas 30: 41–50.

Pallesen S, Sivertsen B, Nordhus IH, et al. (2014) A 10-year trend of

insomnia prevalence in the adult Norwegian population. Sleep Med

15: 173–179.

Palmer CA and Alfano CA (2017) Sleep and emotion regulation: An

organizing, integrative review. Sleep Med Rev 31: 6–16.

Parr JM, Kavanagh DJ, Cahill L, et al. (2009) Effectiveness of current

treatment approaches for benzodiazepine discontinuation: A meta-

analysis. Addiction 104: 13–24.

Picchietti DL, Hensley JG, Bainbridge JL, et al. (2015) Consensus clini-

cal practice guidelines for the diagnosis and treatment of restless legs

syndrome/Willis-Ekbom disease during pregnancy and lactation.

Sleep Med Rev 22: 64–77.

Pien GW and Schwab RJ (2004) Sleep disorders during pregnancy. Sleep

27: 1405–1417.

Pigeon WR, Bishop TM and Krueger KM (2017) Insomnia as a precip-

itating factor in new onset mental illness: A systematic review of

recent findings. Curr Psychiatry Rep 19: 44.

Porkka-Heiskanen T, Alanko L, Kalinchuk A, et al. (2002) Adenosine

and sleep. Sleep Med Rev 6: 321–332.

Pressman MR (2007) Factors that predispose, prime and precipitate

NREM parasomnias in adults: Clinical and forensic implications.

Sleep Med Rev 11: 5–30.

Pringsheim T and Gardner DM (2014) Dispensed prescriptions for que-

tiapine and other second-generation antipsychotics in Canada from

2005 to 2012: A descriptive study. CMAJ Open 2: E225–232.

Qaseem A, Kansagara D, Forciea MA, et al. (2016) Management of

chronic insomnia disorder in adults: A clinical practice guideline from

the American College of Physicians. Ann Intern Med 165: 125–133.

Ramchandani P, Wiggs L, Webb V, et al. (2000) A systematic review of

treatments for settling problems and night waking in young children.

BMJ 320: 209–213.

Randall S, Roehrs TA and Roth T (2012) Efficacy of eight months of nightly

zolpidem: A prospective placebo-controlled study. Sleep 35: 1551–1557.

Reid KJ, Jaksa AA, Eisengart JB, et al. (2012) Systematic evaluation of

Axis-I DSM diagnoses in delayed sleep phase disorder and evening-

type circadian preference. Sleep Med 13: 1171–1177.

Reynolds CF, III, Buysse DJ, Miller MD, et al. (2006) Paroxetine treat-

ment of primary insomnia in older adults. Am J Geriatr Psychiatry

14: 803–807.

Rhalimi M, Helou R and Jaecker P (2009) Medication use and increased

risk of falls in hospitalized elderly patients: A retrospective, case-

control study. Drugs Aging 26: 847–852.

Richardson GS, Zammit G, Wang-Weigand S, et al. (2009) Safety and

subjective sleep effects of ramelteon administration in adults and

older adults with chronic primary insomnia: A 1-year, open-label

study. J Clin Psychiatry 70: 467–476.

Richelson E (1994) The pharmacology of antidepressants at the synapse:

Focus on newer compounds. J Clin Psychiatry 55(Suppl A): 34–39.

Riemann D, Baglioni C, Bassetti C, et al. (2017) European guideline for

the diagnosis and treatment of insomnia. J Sleep Res 26: 675–700.

Riemann D, Spiegelhalder K, Feige B, et al. (2010) The hyperarousal

model of insomnia: A review of the concept and its evidence. Sleep

Med Rev 14: 19–31.

Riemann D, Voderholzer U, Cohrs S, et al. (2002) Trimipramine in pri-

mary insomnia: Results of a polysomnographic double-blind con-

trolled study. Pharmacopsychiatry 35: 165–174.

Riemann D (2009) Does effective management of sleep disorders reduce

depressive symptoms and the risk of depression? Drugs 69(Suppl

2): 43–64.

Roehrs TA, Randall S, Harris E, et al. (2012) Twelve months of nightly zolpi-

dem does not lead to rebound insomnia or withdrawal symptoms: A pro-

spective placebo-controlled study. J Psychopharmacol 26: 1088–1095.

Roenneburg T, Kuehnle T, Pramstaller PP, et al. (2004) A marker for the

end of adolescence. Curr Biol 14: R1038–R1039.

Rossignol DA and Frye RE (2011) Melatonin in autism spectrum disor-

ders: A systematic review and meta-analysis. Dev Med Child Neurol

53: 783–792.

Roth T and Ancoli-Israel S (1999) Daytime consequences and correlates

of insomnia in the United States: Results of the 1991 National Sleep

Foundation Survey. II. Sleep 22(Suppl 2): S354–S358.

Ruwe F, P IJ-B, Roth T, et al. (2016) A phase 2 randomized dose-finding

study with esmirtazapine in patients with primary insomnia. J Clin

Psychopharmacol 36: 457–464.

Sack RL (2010) Clinical practice. Jet lag. N Engl J Med 362: 440–447.

Sack RL, Auckley D, Auger RR, et al. (2007a) Circadian rhythm sleep

disorders: Part I, basic principles, shift work and jet lag disorders.

An American Academy of Sleep Medicine review. Sleep 30: 1460–

1483.

Sack RL, Auckley D, Auger RR, et al. (2007b) Circadian rhythm sleep

disorders: Part II, advanced sleep phase disorder, delayed sleep

phase disorder, free-running disorder, and irregular sleep-wake

rhythm. An American Academy of Sleep Medicine review. Sleep

30: 1484–1501.

Salin-Pascual RJ, Herrera-Estrella M, Galicia-Polo L, et al. (2004) Low

delta sleep predicted a good clinical response to olanzapine adminis-

tration in schizophrenic patients. Rev Invest Clin 56: 345–350.

Salin-Pascual RJ, Herrera-Estrella M, Galicia-Polo L, et al. (1999) Olan-

zapine acute administration in schizophrenic patients increases delta

sleep and sleep efficiency. Biol Psychiatry 46: 141–143.

Sanchez-Ortuno MM and Edinger JD (2012) Cognitive-behavioral ther-

apy for the management of insomnia comorbid with mental disor-

ders. Curr Psychiatry Rep 14: 519–528.

Sanna E, Busonero F, Talani G, et al. (2002) Comparison of the effects

of zaleplon, zolpidem, and triazolam at various GABA(A) receptor

subtypes. Eur J Pharmacol 451: 103–110.

Sansone RA and Sansone LA (2010) Is seroquel developing an illicit

reputation for misuse/abuse? Psychiatry 7: 13–16.

Saper CB, Scammell TE and Lu J (2005) Hypothalamic regulation of

sleep and circadian rhythms. Nature 437: 1257–1263.

Sateia MJ, Buysse DJ, Krystal AD, et al. (2017) Clinical practice guide-

line for the pharmacologic treatment of chronic insomnia in adults:

An American Academy of sleep medicine clinical practice guideline.

J Clin Sleep Med 13: 307–349.

Sateia MJ, Doghramji K, Hauri PJ, et al. (2000) Evaluation of chronic

insomnia. An American Academy of Sleep Medicine review. Sleep

23: 243–308.

Schenck C and Mahowald M (1996) Long-term, nightly benzodiazepine

treatment of injurious parasomnias and other disorders of disrupted

nocturnal sleep in 170 adults. Am J Med 100: 333–337.

Sedov ID, Cameron EE, Madigan S, et al. (2018) Sleep quality during

pregnancy: A meta-analysis. Sleep Med Rev 38: 168–176.

Seyffert M, Lagisetty P, Landgraf J, et al. (2016) Internet-delivered cog-

nitive behavioral therapy to treat insomnia: A systematic review and

meta-analysis. PLoS One 11: e0149139.

946 Journal of Psychopharmacology 33(8)

Sharpley AL, Attenburrow ME, Hafizi S, et al. (2005) Olanzapine

increases slow wave sleep and sleep continuity in SSRI-resistant

depressed patients. J Clin Psychiatry 66: 450–454.

Sharpley AL, Bhagwagar Z, Hafizi S, et al. (2003) Risperidone augmen-

tation decreases rapid eye movement sleep and decreases wake in

treatment-resistant depressed patients. J Clin Psychiatry 64: 192–196.

Sharpley AL, Vassallo CM and Cowen PJ (2000) Olanzapine increases

slow-wave sleep: Evidence for blockade of central 5-HT(2C) recep-

tors in vivo. Biol Psychiatry 47: 468–470.

Shekelle PG, Woolf SH, Eccles M, et al. (1999) Developing clinical

guidelines. West J Med 170: 348–351.

Shepertycky MR, Banno K and Kryger MH (2005) Differences between

men and women in the clinical presentation of patients diagnosed

with obstructive sleep apnea syndrome. Sleep 28: 309–314.

Shirani A and St Louis EK (2009) Illuminating rationale and uses for

light therapy. J Clin Sleep Med 5: 155–163.

Short CA and Carpenter PK (1998) The treatment of sleep disorders in

people with learning disabilities using light therapy. Int J Psychiatry

Clin Prac 1: 143–145.

Sivertsen B, Krokstad S, Mykletun A, et al. (2009) Insomnia symptoms

and use of health care services and medications: The HUNT-2 study.

Behav Sleep Med 7: 210–222.

Skene DJ and Arendt J (2007) Circadian rhythm sleep disorders in the

blind and their treatment with melatonin. Sleep Med 8: 651–655.

Skene DJ, Lockley SW and Arendt J (1999) Melatonin in circadian sleep

disorders in the blind. Biol Signals Recept 8: 90–95.

Sletten TL, Magee M, Murray JM, et al. (2018) Efficacy of melatonin

with behavioural sleep-wake scheduling for delayed sleep-wake phase

disorder: A double-blind, randomised clinical trial. PLoS Med 15:

e1002587.

Smits MG, van Stel HF, van der HK, et al. (2003) Melatonin improves

health status and sleep in children with idiopathic chronic sleep-

onset insomnia: A randomized placebo-controlled trial. J Am Acad

Child Adolesc Psychiatry 42: 1286–1293.

Soldatos CR, Dikeos DG and Whitehead A (1999) Tolerance and rebound

insomnia with rapidly eliminated hypnotics: A meta-analysis of

sleep laboratory studies. Int Clin Psychopharmacol 14: 287–303.

Spiegelhalder K, Nissen C and Riemann D (2017) Clinical sleep-wake

disorders II: Focus on insomnia and circadian rhythm sleep disor-

ders. Handb Exp Pharmacol. Epub ahead of print 14 July 2017. DOI:

10.1007/164_2017_40.

Spielman AJ, Caruso LS and Glovinsky PB (1987) A behavioral perspec-

tive on insomnia treatment. Psychiatr Clin North Am 10: 541–553.

Stallman HM, Kohler M and White J (2018) Medication induced sleep-

walking: A systematic review. Sleep Med Rev 37: 105–113.

Staner L, Ertle S, Boeijinga P, et al. (2005) Next-day residual effects of

hypnotics in DSM-IV primary insomnia: A driving simulator study

with simultaneous electroencephalogram monitoring. Psychophar-

macology 181: 790–798.

Symons FJ, Davis ML and Thompson T (2000) Self-injurious behavior

and sleep disturbance in adults with developmental disabilities. Res

Dev Disabil 21: 115–123.

Tassniyom K, Paholpak S, Tassniyom S, et al. (2010) Quetiapine for pri-

mary insomnia: A double blind, randomized controlled trial. J Med

Assoc Thai 93: 729–734.

Tempesta D, Socci V, De Gennaro L, et al. (2018) Sleep and emotional

processing. Sleep Med Rev 40: 183–195.

Todder D, Caliskan S and Baune BT (2006) Night locomotor activity and

quality of sleep in quetiapine-treated patients with depression. J Clin

Psychopharmacol 26: 638–642.

Trewin VF, Lawrence CJ and Veitch GB (1992) An investigation of the

association of benzodiazepines and other hypnotics with the inci-

dence of falls in the elderly. J Clin Pharm Ther 17: 129–133.

Unruh ML, Redline S, An MW, et al. (2008) Subjective and objective

sleep quality and aging in the sleep heart health study. J Am Geriatr

Soc 56: 1218–1227.

van de Wouw E, Evenhuis HM and Echteld MA (2012) Prevalence,

associated factors and treatment of sleep problems in adults with

intellectual disability: A systematic review. Res Dev Disabil 33:

1310–1332.

van der Heijden KB, Smits MG, Van Someren EJ, et al. (2007) Effect of

melatonin on sleep, behavior, and cognition in ADHD and chronic

sleep-onset insomnia. J Am Acad Child Adolesc Psychiatry 46: 233–

241.

Van Houdenhove L, Buyse B, Gabriels L, et al. (2011) Treating pri-

mary insomnia: Clinical effectiveness and predictors of outcomes

on sleep, daytime function and health-related quality of life. J Clin

Psychol Med Settings 18: 312–321.

van Straten A, van der Zweerde T, Kleiboer A, et al. (2018) Cognitive

and behavioral therapies in the treatment of insomnia: A meta-analy-

sis. Sleep Med Rev 38: 3–16.

Varkevisser M, Van Dongen HP and Kerkhof GA (2005) Physiologic

indexes in chronic insomnia during a constant routine: Evidence for

general hyperarousal? Sleep 28: 1588–1596.

Vermeeren A, Sun H, Vuurman EF, et al. (2015) On-the-road driving

performance the morning after bedtime use of suvorexant 20 and 40

mg: A study in non-elderly healthy volunteers. Sleep 38: 1803–1813.

Verster J, Veldhuijzen DS, Patat A, et al. (2006) Hypnotics and driving

safety: Meta analyses of randomised controlled trials applying the

on-the-road driving test. Curr Drug Saf 1: 63–71.

Vgontzas AN, Bixler EO, Lin HM, et al. (2001) Chronic insomnia is

associated with nyctohemeral activation of the hypothalamic-pitu-

itary-adrenal axis: Clinical implications. J Clin Endocrinol Metab

86: 3787–3794.

Vgontzas AN, Liao D, Bixler EO, et al. (2009) Insomnia with objective

short sleep duration is associated with a high risk for hypertension.

Sleep 32: 491–497.

Vgontzas AN, Tsigos C, Bixler EO, et al. (1998) Chronic insomnia and

activity of the stress system: A preliminary study. J Psychosom Res

45: 21–31.

Voshaar RC, van Balkom AJ and Zitman FG (2004) Zolpidem is not

superior to temazepam with respect to rebound insomnia: A con-

trolled study. Eur Neuropsychopharmacol 14: 301–306.

Wade AG, Crawford G, Ford I, et al. (2011) Prolonged release melatonin

in the treatment of primary insomnia: Evaluation of the age cut-off

for short- and long-term response. Curr Med Res Opin 27: 87–98.

Wade AG, Ford I, Crawford G, et al. (2007) Efficacy of prolonged

release melatonin in insomnia patients aged 55–80 years: Quality

of sleep and next-day alertness outcomes. Curr Med Res Opin 23:

2597–2605.

Walsh JK, Erman M, Erwin CW, et al. (1998) Subjective hypnotic effi-

cacy of trazodone and zolpidem in DSM-III-R primary insomnia.

Hum Psychopharm Clin Exp 13: 191–198.

Walsh JK, Krystal AD, Amato DA, et al. (2007) Nightly treatment of

primary insomnia with eszopiclone for six months: Effect on sleep,

quality of life, and work limitations. Sleep 30: 959–968.

Wassmer E, Carter PF, Quinn E, et al. (2001) Melatonin is useful for

recording sleep EEGs: A prospective audit of outcome. Dev Med

Child Neurol 43: 735–738.

Wickwire EM, Shaya FT and Scharf SM (2016) Health economics of

insomnia treatments: The return on investment for a good night's

sleep. Sleep Med Rev 30: 72–82.

Wickwire EM, Tom SE, Scharf SM, et al. (2019) Untreated insomnia

increases all-cause health care utilization and costs among Medicare

beneficiaries. Sleep 42: zsz007.

Wiegand MH, Landry F, Bruckner T, et al. (2008) Quetiapine in primary

insomnia: A pilot study. Psychopharmacology 196: 337–338.

Wiggs L and France K (2000) Behavioural treatments for sleep prob-

lems in children and adolescents with physical illness, psychological

problems or intellectual disabilities. Sleep Med Rev 4: 299–314.

Wilson S and Argyropoulos S (2005) Antidepressants and sleep: A quali-

tative review of the literature. Drugs 65: 927–947.

Wilson et al. 947

Item Score

4 3 2 1 0

Thinking about the past month, to what extent has poor sleep …

1. … troubled you in general Not at all A little Somewhat Much Very much

Thinking about a typical night in the last month …

2. … how many nights a week do you have a problem with your sleep? 0–1 2 3 4 5–7

Scoring instructions: add the item scores to obtain the SCI total (minimum 0, maximum 8). A lower score means better sleep.

Wilson SJ, Lillywhite AR, Potokar JP, et al. (1997) Adult night terrors

and paroxetine. Lancet 350: 185.

Wilson SJ, Nutt DJ, Alford C, et al. (2010) British Association for Psy-

chopharmacology consensus statement on evidence-based treatment

of insomnia, parasomnias and circadian rhythm disorders. J Psycho-

pharmacol 24: 1577–1601.

Winokur A, DeMartinis NA, III, McNally DP, et al. (2003) Comparative

effects of mirtazapine and fluoxetine on sleep physiology measures

in patients with major depression and insomnia. J Clin Psychiatry

64: 1224–1229.

Woolcott JC, Richardson KJ, Wiens MO, et al. (2009) Meta-analysis of

the impact of 9 medication classes on falls in elderly persons. Arch

Intern Med 169: 1952–1960.

World Health Organization (1992) The ICD-10 Classification of

mentaland behavioural disorders: clinical descriptions and diagnostic

guidelines. Geneva: WHO. https://www.who.int/classifications/icd/en

/bluebook.pdf

Yeung WF, Chung KF, Yung KP, et al. (2015) Doxepin for insomnia:

A systematic review of randomized placebo-controlled trials. Sleep

Med Rev 19: 75–83.

Young T, Finn L, Austin D, et al. (2003) Menopausal status and sleep-

disordered breathing in the Wisconsin Sleep Cohort Study. Am J

Respir Crit Care Med 167: 1181–1185.

Zachariae R, Lyby MS, Ritterband LM, et al. (2016) Efficacy of internet-

delivered cognitive-behavioral therapy for insomnia: A systematic

review and meta-analysis of randomized controlled trials. Sleep Med

Rev 30: 1–10.

Zentiva Pharma UK Limited (2002) Zolpidem - Summary of Product

Characteristics. Available at: https://www.medicines.org.uk/emc

/product/3975/smpc (accessed 18 June 2019).

Appendix 1

Two-item version of the Sleep Condition Indicator (SCI) 02 (Luik et al. (2019) Screening for insomnia in primary care: Using a two-

item version of the Sleep Condition Indicator. Br J Gen Pract 69: 79–80.)