Insomnia and other conditions

Question 1

DSM-5: Sleep - Wake disorders
What are the 10 disorders or groups of sleep conditions it is compromised of?

Answer 1

• Insomnia
• Hypersomnolence (a lot of sleepiness)
• Narcolepsy (caused by lack of orexin, stabilizes the flip flop switch)
• Breathing-related disorders (most prevalent is sleep apnea/ obstructive sleep apnea- struggling to breath during the night)
• Circadian rhythm sleep-wake disorders (going to sleep and waking up at odd times)
• Parasomnias (Rem Behaviour Disorder,- don’t have muscle atonia we have in rem sleep, so people are moving around, Restless Leg Syndrome- moving legs around)

Question 2

According to the DSM-5…
- what are sleep disorders accompanied by?
- both insomnia and excessive sleepiness …

Answer 2

• Sleep disorders are often accompanied by depression, anxiety and cognitive changes that must be addressed in treatment plans
• Both insomnia and excessive sleepiness “are established risk factors for the subsequent development of mental illnesses and substance use disorders”
• “They may also represent a prodromal expression of an episode of mental illness, allowing the possibility of early intervention to preempt or to attenuate a full-blown episode.”

Question 3

Diagnostic Criteria for Insomnia

Answer 3

Dissatisfaction with sleep quantity or quality associated with one or more of the following:
- Difficulty initiating sleep (staying awake/ tossing and turning)
- Difficulty maintaining sleep* (frequent awakenings, or trouble re-initiating sleep following awakening)
- Early morning awakening with inability to return to sleep
- Causes significant distress or impairment in social, occupational functioning etc.
- The sleep difficulty occurs at least 3 nights/week for at least 3 months.

Question 4

Insomnia:
- the diagnosis is based on….
- term used
- useful associated features
- what is it also associated with

Answer 4

• The diagnosis is based on the person’s subjective perception of sleep
• Non-restorative sleep – often the complaint of one not feeling rested upon awakening despite adequate sleep duration
• Useful associated features:
  – Difficulty initiating sleep: when more than 20-30min
  – Difficulty maintaining sleep: when awake for more than 20-30min
  – Morning awakening: when at least 30min before the scheduled time and before the total time reaches 6.5hrs
• Also associated with daytime impairments such as fatigue or daytime sleepiness (less common), cognitive impairments, mood disturbances (irritability, lability)

Question 5

Insomnia development and course

Answer 5

• Onset usually in young adulthood (less so in childhood or adolescence) and it is more prevalent in middle-aged and older adults.
  – In those older, it is usually associated with other health problems
• In women may occur during menopause and may persist even when other symptoms stop
• Insomnia can be situational (acute), persistent (recurrent)
• Some may be more vulnerable than others to precipitating events

Acute: have an important day the next day and excited about it. Happens because of a reason during that time and then it goes away, and everything returns to normal
Recurrent/ chronic: continually experience this very often

Question 6

Prevalence of Insomnia

Answer 6

• According to the DSM-5 about 33% of adults report insomnia symptoms, and about 6-10% meet the criteria for insomnia disorder
• It is the most common sleep disorder
• More prevalent complaint in females compared to males 1.4:1
• 40-50% of those with insomnia also have comorbid mental disorder

Question 7

Burden of Psychiatric Illness in Europe
(Wittchen et al 2011)

Answer 7

The most common mental health condition is anxiety
Insomnia ranks number 2 – showing it is quite prevalent

• 7% best estimate for insomnia prevalence (18+)
• Female to male ratio 2:1

Question 8

Genetic correlations between insomnia and other variables/conditions from GWAS, 2017

Answer 8

• Although there is evidence for heritability, data do not support Mendelian genetics for insomnia
• Evidence that those who suffer from insomnia will have other family members who also suffer from it
• Concordance rates for DZ twins are higher than MZ twins.

Question 9

Hammerschlag et al 2017, Nat Genet
(looking at genetic correlation)

Answer 9

Using people look at SNPs (single nucleotide polymorphisms- one base in genetic code may be different) having a lot of points of aspects of genome that are different will lead to accumulating- many SNPs means can start to infer genetic diffs

There is a genetic component- concordance rates that are higher with MZ than DZ conditions
Those who suffer with insomnia are more likely to suffer from depression, anxiety, major depression (red scale) whereas on the other side those with insomnia are less likely to experience subjective wellbeing, longevity ect. (blue scale)

Question 10

Behavioural Model of Insomnia Spielman, 1987

Answer 10

• Spielman’s 3P model of insomnia
• Insomnia occurs by a combination of factors:
  - Predisposing factors: personality, demographics and biological traits of the person
  - Precipitating factors: triggering events (acute or short-term insomnia)
  - Perpetuating factors: behaviours that the person adopts to tackle insomnia such as going to bed early, staying in bed while awake, napping, etc

— These behaviours are maladaptive and perpetuate the problem, as being in bed is increasingly associated with wakefulness and not sleep (chronic insomnia)

The factors that play a role in insomnia all start with a P

Perpetuating factors: Turning acute phase into a longer-term condition (eg. maybe ill have a nap in the afternoon to get sleep so you don’t miss out- this is counter productive and creates a worsening of the situation)

Question 11

Behavioural Model of Insomnia Spielman, 1987

What can predisposing factors be?

Answer 11

- Biological: Hyperarousal

- Psychological: worry, tendency to ruminate (ruminate: think about/ worry about things in our mind without finding solutions)

- Social factors: bed partner, incompatible sleep schedule, social pressures

*insomniacs may get more sleep in novel sleep environments – perhaps fewer cues although little research has been done on this (Hauri et al 1989 reported the ‘reverse first-night effect’; Riedel et al 2001)

Question 12

Harvey’s Cognitive Model of Insomnia 2002
1- what is chronic insomnia due to?
2- what does increased physiological arousal lead to?
3- leads to…
4- may be accompanied by…
5- what does chronic worry lead to?

Answer 12

1- Chronic insomnia is due to negative cognitive biases (i.e. sleep worry) which perpetuate the condition
2- Increased physiological arousal leads to attentional bias towards internal and external stimuli that may be threatening or will be interfering with sleep i.e. fatigue, or alarm clock
3- Leads to exaggerated perception of sleep continuity disturbance
4- May be accompanied by incorrect beliefs about the impact of reduced sleep and worrying i.e. cancelling appointments etc
5- Constant worry which leads to more increased arousal- (start to be a bit of a detective), scan environment internally or external -> leads to further arousal which makes it harder for them to go to sleep

Question 13

Examples of reports from people suffering from insomnia

Answer 13

“oh no… it’s already 2 a.m… that means I’ll only get 4 hours of sleep tonight”

“If I can’t get to sleep soon there is no way I’ll cope tomorrow”

“Its 1:25 a.m… I’ve been lying here for 2 hours and 25 minutes!”

Heart pounding quickly, muscle tension

Question 14

Explain the steps of Harvey’s Cognitive Model, 2002

Answer 14

Starts in bed when someone is not having a good night and they start to think about negative things about their sleep. Having excessive negatively toned cognitive activity leads to arousal and distress. Then this causes the individual to have selective attention and monitoring** (start paying attention to more things). Then they may have a distorted perception of their sleep deficit. They may exaggerate the consequences of this. That also leads to safety behaviours – they may start to cancel appointments/ get a nap during the day and also beliefs. This feeds back to the whole system and makes things worse. (real deficit in sleep)
This whole system makes a deficit in sleep due to arousal and neg thinking but also has a spill over effect for the next day. Same steps occur when person is awake (haven’t slept last night, what if I cant sleep again tonight). This shows they have a problem with sleep and eventually leads to a real deficit in performance/ functioning.

Question 15

Neurocognitive Perspective to Chronic Insomnia Perlis et al 1997

Answer 15

• Evidence that patients with insomnia are physiologically hyperaroused prior to sleep onset and or during PSG sleep (Monroe 1967; Freedman and Sattler 1982; confirmed by Bonnet and Arand 1995)
• Also, patients with insomnia are prone to intrusive cognitions around sleep onset (Michel 1977; Lichstein and Rosenthal 1980).
• Model focuses on cortical arousal – elevated EEG activity in the beta and gamma range which allows for increased sensory processing, information processing etc. (they may be hyper aroused)
• Initially (acute insomnia) this increased activity may be associated with stress-induced worry and rumination however in chronic insomnia it is a result of classical conditioning (visual, temporal cues) associated with sleepiness and sleep in the absence of situational stressors

Becomes chronic condition- people lying down in bed start to associate lying down in bed and not sleep / lying down in bed and thinking and worrying. Everything in our environment (bedroom) becomes a cue/ stimulus to our situation. Conditioned to these which makes it more chronic.
The reverse first night effect can be explained using this as taking them out of typical environment = remove stimulus cues

Question 16

Hyperarousal Hypothesis Riemann et al 2010
- what does the polysomnography show?
- what do sleep reports suggest
- how was insomnia viewed
- hyperarousal hypothesis
- what is this also
- normal sleep is largely…

Answer 16

• Polysomnography shows impairments in sleep continuity and sleep efficiency and increased time spent in NREM1 and less in NREM3.
• Sleep reports seem to suggest greater severity compared to polysomnography (subjective vs objective measures discrepancy)
• Insomnia was viewed as a psychological condition, and the pursuit of biological explanations for the condition was neglected
• Hyperarousal hypothesis: Those who tend to focus cognitively on insomnia and start to ruminate about their sleep are prone to develop “learned sleep-preventing associations” which may explain the chronicity of the problem
• There is also increased autonomic activity
• Normal sleep is largely an automatic and involuntary process that may be inhibited by directing attention to it. An increased effort to fall asleep is maladaptive

NREM1 (lighter sleep)
NREM3 (slow wave, deep restorative sleep)

Question 17

Neurocognitive Perspective Evidence in support
Perception and what do they tend to do

Answer 17

• Biased Perception:
  When awakened from PSG-verified sleep, insomniacs report being awake more frequently than good sleepers (73% of the time vs 45-50% by good sleepers) mainly at around sleep onset
• They tend to overestimate their latency to fall asleep and the time they are awake during the night when compared to objective assessments i.e. PSG
  – Those with insomnia estimate that it takes them 10-45min longer to fall asleep and that they sleep 30-45min less than what is evident from PSG
  – Good sleepers tend to estimate correctly the latency of falling asleep
  – Both insomniacs and good sleepers tend to underestimate the number of awakenings

Question 18

Animal model of Insomnia (Cano et al 2008)
- what were they able to show about rats
- what did they hypothesise
- fos activation…

Answer 18

• Able to show that rats which were subjected to the insomnia model (cage exchange) revealed a pattern of Fos expression that demonstrated simultaneous activation of sleep-promoting and arousal-related brain regions.
• Hypothesized that during insomnia the VLPO is fully activated as a result of homeostatic and circadian pressure but cannot turn off the arousal system which at the same time is intensely excited by the limbic system.
• Fos activation was as expected of a sleeping rat, but the activation of the cortex and arousal systems resembled the fully awake state – inability to “de-arouse”

Change cage of experimental group of control animals and put cage of other rats for a week- cage had scent of foreign animal which can be stressful to rats

Question 19

Fos activation in the brain during stress-induced insomnia differs from both wake and sleep states (Cano et al 2008)

Answer 19

Insomnia group- stressful event messed with flip-flop switch (sleep center- VLPO which is inhibiting all the arousal centres – can’t have both situations) and they managed to see activation of both arousal centres and sleep center at the same time.
Fos (black dots- cells previously activated- labelled by fos protein)- VLPO protein was active but also in the LC and TM which we wouldn’t expect to see. Managed to get attention of rats, these affected their subsequent sleep.

Question 20

Insomnia and Other Mental Health Conditions

Answer 20

• Mental health conditions are prevalent and often treatment is initiated years after onset
• Many of those who receive treatment relapse or do not respond to medication with implications for the quality of life and productivity for each person and society
• Preventative strategies are preferred
• Strong link between insomnia and depression (perhaps ‘learned helplessness’

Question 21

Insomnia and Depression

Answer 21

• The first major study to address insomnia and depression was in 1989 in JAMA by Ford and Kamerow: “Epidemiologic study of sleep disturbances and psychiatric disorders: an opportunity for prevention?”
• 7,954 respondents were questioned at baseline and 1 year later about sleep complaints and psychiatric symptoms. It was found that 10% had insomnia at the first interview.
• Those with insomnia had a greater risk of developing a psychiatric disorder (40%) compared to those without insomnia (16%)
• The risk of developing new major depression was much higher in those who had insomnia at both interviews compared with those without insomnia

Question 22

A prelude to depression?
- Riemann and Voderholzer 2003
- Baglioni et al 2011

Answer 22

• Riemann and Voderholzer 2003: reviewed 8 longitudinal epidemiological studies and found that insomnia at baseline predicted increased depression risk 1-3 years later
• Baglioni et al 2011: Non-depressed people with insomnia have a twofold risk to develop depression (increased risk of depression), compared to people with no sleep difficulties.
  – Early treatment programs for insomnia may reduce the risk of depression in the general population
  – It may be a preventative strategy in the area of mental health care.

first comes insomnia, then depression

Question 23

Insomnia beyond depression

Answer 23

Hertenstein et al (2019): Meta-analysis of longitudinal studies investigating whether insomnia at baseline constitutes a risk factor for the later onset (12-24m or +24m) of mental disorder.

The first study to find evidence that insomnia is a significant predictor for several mental health conditions

→

Insomnia can predict: Depression, anxiety, alcohol abuse, psychosis

Question 24

A systematic review and meta-analysis
(Hertenstein et al 2019)

Answer 24

Insomnia as a predictor of mental disorders

• Allows for at least temporal association and not causation. Perhaps it is an early symptom of a condition
• If it is causal relationship-treating insomnia would prevent the emergence of mental disorders

Summary of the meta-analysis for the predictive value of insomnia for future psychopathology.

Important: insomnia always comes first then people develop another condition (mental health)

Pure category:
These studies included pp’s that only had insomnia and no other conditions. They also developed depression ad anxiety later on.

Question 25

Insomnia summary: 1- insomnia commonality as a sleep condition 2- what is its aetiology due to? 3- those susceptible to insomnia may... 4- what reinforce insomnia? 5- what is insomnia often associated with?

Answer 25

1- Insomnia is the most common sleep condition 2- Its aetiology is due to a complex interplay between genetic and environmental components 3- Those susceptible to insomnia may tend to worry and be hyperaroused, which may result in difficulties with sleep onset and maintenance. 4- Cognitive factors and conditioning reinforce insomnia so that it becomes more permanent 5- Insomnia is often associated with other common mental health conditions and usually, it precedes their emergence

Question 26

Can we tackle depression by treating insomnia?

Answer 26

- Several studies have reported evidence in support that behavioural interventions (mostly CBT-i) for insomnia can benefit depressive symptoms - Hertenstien et al 2022: Meta-analysis of CBT-I for patients with insomnia and other mental health conditions -- CBT-I reduces insomnia severity (large effect size) and the severity of the comorbid disorder (medium effect size). -- Depression, PTSD and alcohol dependency are the comorbid disorders with the best evidence for CBT-I. If we treat insomnia, depressive symptoms can be solved CBT-I can be used to treat insomnia

Question 27

The treatment of primary insomnia relies on three elements: OUTLINE THESE

Answer 27

- Sleep hygiene- the foundation of our daily lives - CBT-I*- uses techniques to target sleep and our behaviour around sleep - Pharmacotherapy (only for short-term use)- used for only f needed, if necessary and short-term use *Highly effective even if delivered completely remotely (automated internet-delivered CBT-I) Ritterband et al, 2017 JAMA * CBT-I Coach – a mobile app (Hoffman et al 2013)

Question 28

Sleep Hygiene (first proposed in 1977 by Hauri)

Answer 28

- Set an appropriate atmosphere to promote sleep (lighting, colours, temperature, etc) - Use your bed only for sleep and sex - Avoid using electronics before bedtime - Sleep in total darkness - Reduce other *intense* activities before bedtime Avoid the following around bedtime: - Caffeine or energy drinks - Heavy meals - Alcohol and drugs - Excessive consumption of liquids - Exercising - If you cannot go to sleep, do something else instead - Do not use sleeping pills

Question 29

Can we use sleep hygiene to tackle insomnia?

Answer 29

- Mixed findings however, those with insomnia are more likely to smoke and drink alcohol before bed - American Academy of Sleep Medicine (AASM) summarised data from several studies and concluded that **there is insufficient data to suggest that sleep hygiene is a *stand-alone* therapy for insomnia** - Supported also by a meta-analysis by Chang et al 2017

Question 30

Sleep Hygiene has three main functions in insomnia: OUTLINE

Answer 30

- Serves as an active control in intervention trials - Serves as the psycho-educational component in CBT-I - Serves as an alternative to pharmacotherapy in primary care when necessary

Question 31

CBT-Insomnia (CBT-I)

Answer 31

- It is the first-line treatment for Insomnia, improves outcome for up to 2 years following treatment - Initially investigates what is going on in the person’s life and then the person has to keep track of their behaviour relating to sleep: with a sleep log note down bedtime, how long it took to go to sleep, awakenings during the night, daytime sleepiness, any naps etc - Meta-analysis of 20 studies using CBT-I on patients with chronic insomnia has found sleep onset latency, wake after sleep onset, TST, and sleep efficiency all significantly improved (Trauer et al 2015) - Superior to placebo and equivalent or superior to pharmacotherapy for insomnia and it is effective even in the presence of comorbid conditions such as depression and chronic pain!

Question 32

CBT-I - Behaviour 2 core components

Answer 32

Two core components: **stimulus control** and **sleep restriction therapy**, in addition to the optional components of cognitive therapy, sleep hygiene and relaxation **Stimulus control:** focuses on strengthening the association between the *bed & bedroom with sleep* and to establish a consistent sleep schedule (to do with conditioning) - Use the bedroom only for sleep and avoid staying in bed for more than 15-20 min if unable to sleep return to bed only when sleepy **Sleep restriction therapy:** specific to address the mismatch between *sleep ability and sleep opportunity* by reducing sleep opportunity (time in bed), to match ability (time asleep) and then slowly increasing the opportunity. Delaying going to sleep, gradually extend the period they are in bed. Reduce sleep opportunity to increase the time they do sleep when they are there.

Question 33

Sleep restriction objectives

Answer 33

— To increase the homeostatic sleep drive and reduce the arousal caused by the person’s effort to fall asleep — To reduce the time spent awake at night by consolidating sleep into longer more restorative periods

Question 34

CBT-I - Cognitive

Answer 34

- Most common report: **“I CANNOT TURN OFF MY MIND AT NIGHT”** - **Cognitive therapy component** (cognitive restructuring) seeks to identify and replace dysfunctional beliefs and attitudes about sleep and insomnia - Goal to identify problematic thoughts that may contribute to the development of pre-sleep worry - Establish more adaptive cognitive patterns Cognitive: Address though processes Restructuring: address the way different pieces of our thoughts and put them together in ways which are more adaptive

Question 35

CBT-I –Relaxation

Answer 35

- Relaxation training addresses the high levels of physiological, cognitive and/or emotional arousal both at night and day. - Deep breathing and progressive relaxation, meditation, etc have been shown to lower pre-sleep arousal (i.e. racing thoughts) and improve sleep

Question 36

Tackling Acute Insomnia May Be Easier

Answer 36

- Intervention termed **“one-shot”** - Involves a single 60-70min treatment session - Seems to work a month later – RCT found 1-month remission rate was 60% compared to 15% in the control group and at three months later remission rate was found to be 73% (Ellis et al 2015) - Intervention delivered in groups found remission rate at one month at 72% (Boullin et al 2016) - In male prison setting, remission at one month was found to be at 73% (Randall al 2018) - Anxiety and depression were also reduced

Question 37

Pharmacotherapy “Hypnotics”

Answer 37

- Old guidelines recommended short-term use of hypnotics (benzodiazepines) for insomnia due to concerns with safety (half-lives that are too long which may cause drug accumulation and hip fractures from falls) especially in the elderly - Issues of next-day carryover effects, sedation, memory problems - Hypnotics with too short half-lives can wear off before it is time to wake up - Loss of efficacy of hypnotics over time (tolerance) and withdrawal effects – rebound insomnia in some patients which was worse than their initial insomnia - Sleep drugs - Benzodiazepines- drugs that are not very safe, have a lot of issues associated with them. Half life. - Become tolerant- then may need larger dose. Equally when stopping them they may have withdrawal

Question 38

Benzodiazepines and z-drugs

Answer 38

- Enhance the action of GABA by binding to a site on the GABAA receptor – positive allosteric modulator - Benzodiazepines act by changing the conformation of the receptor so that tolerance generally develops, as well as some degree of dependence and withdrawal, especially for some patients - **Z-drugs** are specific to the **α1 subunit** of the GABAA receptor whereas benzodiazepines bind to four of the alpha subunits (α1, α2 α3 α5) - The α1 subunit is critical for the production of sedation and also linked to daytime sedation, anticonvulsant actions and possibly to amnesia - Unlike benzodiazepines, z-drugs do not lead to altered sensitivity of the GABA receptor after chronic treatment – thus, lower addictive potential although insufficient evidence from long-term use - GABA A- 5 subunits that link together but in centre there is a hole (channel) so when GABA and BZ are binding, they sit on receptor and activate receptor. Channel opens to allow Cl- (negative) but cell is already neg charged so it becomes more neg charged it is hard to get a AP. SO we have this sedation. - Z-drugs (newer version of BZ) that are created to induce sleep. Manufactured to target **A1** subunits. They’re more specific and have less side effects.

Question 39

Zolpidem

Answer 39

- Zolpidem - controlled-release (CR) formulation extends the duration of action of zolpidem immediate-release from 2-4 hours to a duration of 6-8 hours thus it improves sleep maintenance - Option for middle of the night sublingual zolpidem - Z-drugs have modified the way that chronic insomnia is treated - However most studies were done on primary insomnia and not on insomnia associated with other psychiatric conditions

Question 40

Effects of Pharmacotherapy

Answer 40

- Those with insomnia report exaggerated benefits from hypnotic medication, a disproportionate perceived benefit - Medication decreases sleep latency (~15min) and increases sleep time (~30min), moderately - Benzodiazepines **do not normalize sleep** – EEG is faster than during normal sleep - A distinct high-frequency component of ~12-14Hz (sigma range) referred to as *‘benzodiazepine signature’* - Subjective measures suggest the drugs are more beneficial than what objective measures show - BZ sedate brains but don’t create natural sleep - Benzodiazepine signature- if doing a recording of sleep it is more shallow when taking sleep drugs then when sleeping naturally (decrease of NREM3 and stay longer in NREM2)- can miss out on benefits of sleep

Question 41

Other options

Answer 41

- Orexin Antagonists (daridorexant) - Prolonged-release melatonin - Light therapy and exercise Orexin- wakefulness promoting drugs- orexin antagonists therefore reduce arousal/ wakefulness

Question 42

Order of using measures to help sleep

Answer 42

Sleep hygiene should be default preventative measure. Then go to measure is CBT (which draws on aspects such as behavioural, cog and relaxation component to address sleep problems). CBT for insomnia is very effective and can have positive effects longer term. Pharmacology should be used as a last resort as it does not allow natural sleep and can cause side effects. It should also only be used for short term.