prescribing for insomnia

Prescribing for

Insomnia

Dr Jeremy Beider

MBBS MSc BSc MRCPsych

[email protected]

About Me

I am a consultant in adult psychiatry in West London Mental Health Trust.

MSc in Behavioural Sleep Medicine from Glasgow University.

Clinical experience at Guy’s and St Thomas’ Sleep Disorders unit and the National Neuropsychopharmacology Clinic UK

Aims, Objectives & Overview

1. To provide a conceptual framework for understanding sleep, it’s function, it’s structure and it’s control.

2. To provide a clinical framework for approaching Insomnia.

3. To provide a guide to prescribing for insomnia.

Sleep

The function of sleep

The structure of sleep

The control of sleep

Lets begin with a basic statement about sleep…. Sleep can be used as a good measure of mental health. Clearly that is not it’s purpose but it tells us something about sleep.

The function of sleep

Attempts to Define Mental Health

Freud is said to have defined mental health as having ‘the ability to love and to work.’

My working yard stick to assess mental health is the patient’s ability to sleep …

In terms of easy to use

definitions……

I was thinking of taking my hat off to Freud because my definition is more complex.

My defining measure of an individuals mental health is the ability to sleep well, but there is a caveat.

My rule can only be used for individuals who have

An adequate sleeping environment

A patent airway

Legs and arms that don’t twitch or kick

Individuals who aren’t jetlagged, working night shifts,

Don’t have joint pain, GORD etc, etc, etc.

Sleep as a marker of Mental

Health

The truth is however that if you don’t have

An adequate sleeping environment

A patent airway

Or you do have legs and arms that twitch or kick

Are jetlagged, do work night shifts,

Do have joint pain, GORD etc, …

Your mental function will eventually suffer.

So - it’s a two way process

We have essentially stated that poor

mental health affects one’s sleep but also

that…

Poor sleep affects one’s mental health.

Why is this the case?

What is the purpose of sleep and what is

it’s relationship with mental well being?

Function of Sleep: it’s timing

In terms of the sleep wake cycle operating as it does in relation to the external day night cycle – we can understand that; In humans (and other mammals) who require vision,

for example to avoid predators, to grow crops and for other purposes it makes evolutionary sense to be awake during day light hours.

Rodents on the other hand, that rely on touch and smell can do this best at night, away from daytime predators.

But why do we need to sleep at all?

What we know about the

function of Sleep

It is thought that sleep has some effect on immune function – the body’s ability to fight off infections.

Glucose metabolism is thought to be adversely affected in sleep deprivation.

Studies have shown that rats that are sleep deprived actually die after a few days.

We understand therefore that sleep serves a physiological restorative function.

What about higher function though?

Higher Function & Sleep

It is known that higher function – things like decision making, vigilance and attention are adversely affected by sleep deprivation.

We also know that sleep assists with emotional processing, particularly sleep that is associated with dreaming. Other aspects of learning are also consolidated by sleep.

But why the significant two way relationship between sleep and mental health, sleep and higher function?

I’m going to leave you with that question.

Let’s turn to sleep structure and control

before returning to the question of sleep

function

Sleep Structure & Control

Sleep Wake Cycle Control

Circadian Rhythm

Process S/ homeostatic sleep

drive

Physiological rhythms

FSH/LH – 28 day rhythm

Circadian rhythm denotes physiological

parameter that cycles over a “24 hour

period.”

Circadian Rhythm

Body temp

Cortisol

Growth Hormone

Sleep wake cycle

Sleep Wake Cycle

The master clock for circadian rythms, is based in an

area called the suprachiasmic nucleus(SCN),in the hypothalamus.

There is input from photic cells in the retina – cells sensitive to light - that entrain the circadian rhythm to the external environment, which is characterized by periods of light and dark, or day and night. Morning light is the main circadian entrainer.

Recent research has suggested that there are also food related circadian entrainers.

Sleep Wake Cycle

These cycles actually run in humans over slightly longer than 24 hours.

If you were to place a human in an environment where there were no external cues to suggest it was night or day then the circadian rhythm would run for longer then 24 hours and slowly drift away from the 24 hour clock so that one was going to sleep and waking later each day.

Free running Circadian Rhythm

Disorder – blind person.

Google images

Sleep Wake Cycle

Circadian Rhythm

Process S

Process S

Also known as the homeostatic sleep drive. This

works with an increased drive for sleep, in direct

relation to how many hours of wakefulness have

passed.

During the day the circadian rhythm promotes

wakefulness counteracting the homeostatic

sleep drive that is accumulating over the course

of a day of wakefulness.

Process S

In the evening when circadian driver for alertness drops, the homeostatic sleep drive induces sleep.

As the homeostatic sleep drive wears off at night, the circadian driver for alertness drops to its lowest level, ensuring continued sleep till the early morning hours have passed.

Most adult humans will therefore have about 8 hours of sleep occurring at night and 16 hours of wakefulness during the day.”

Circadian rhythm & Process S

Google images

Sleep Stages - EEG correlates

Google images

Terminology

R&K AASM REM/NREM Fast /Slow Voltage

Stage 1 N1 NREM Fast Low

Stage 2 N2 NREM Fast Low

Stage 3 N3 NREM Slow High

Stage 4 N3 NREM Slow High

REM

REM

REM

REM

Low

Normal Adult Sleep

Sleep begins with NREM sleep.

NREM sleep and REM sleep alternate in a cycle lasting approximately 90 minutes (ultradian rhythm).

SWS predominates in the first third of the night and is linked to the initiation of sleep and the length of time awake.

REM sleep predominates in the last third of the night and is linked to the circadian rhythm of body temperature.

Normal Adult Sleep

Wakefulness in sleep usually accounts for less than 5% of the night.

Stage 1 sleep generally constitutes up to 5% of sleep.

Stage 2 sleep generally constitutes up to 55% of sleep.

Normal Adult Sleep

Stage 3 sleep constitutes up to 8% of sleep.

Stage 4 sleep constitutes up to 15% of sleep.

NREM sleep constitutes up to 80% of sleep.

REM sleep constitutes up to 25% of sleep.

Normal Sleep

Hypnogram (Wikipedia)

REM Component

1. Let’s wrap up objective 1.

The purpose of sleep - ?

The structure of sleep - √

The control of sleep - √

The Function of Sleep

I am going to make some statements about sleep.

These come from my readings on the subject, thinking on the subject, clinical and personal experience.


Humans are primed to survive.

Maslow – spoke of a hierarchy of needs

that drive us.

Google images


When we are awake our brains are constantly

evaluating incoming information to assess

threats and opportunities relevant to meeting our

innate and learnt needs.

Current theories on sleep suggest that when we

sleep we integrate our new experiences with

older ones to provide an updated data set with

which to evaluate life with.


NREM sleep quantity and quality is said to

correlates well with subjective reports of

restorative sleep in terms of executive

function and fatigue levels.

In fact in the sleep hierarchy NREM sleep

trumps REM sleep.

Once NREM sleep needs are met in a

sleep deprived individual, REM sleep can

occur.


REM sleep it is suggested (by Finnish psychologist

Antti Revonsuo) occurs when the brain simulates

scenarios, whilst the body is paralysed

and rehearses the correct response to an

imagined threat.


My sense is that through sleep, and alongside other

metabolic and immunological restorative processes, our

minds work through the days experiences, sifting

through the meaning of the data and integrating it with

the memory bank of previous experiences.

Sleep can thought of as a higher function digestive

process, where neuroplasticity occurs and learning

occurs and we break down and integrate experiences so

as to develop new paradigms with which to interpret

ourselves and our environment.

Bringing it together…..

Humans operate across different levels of

arousal ranging from hyper vigilance, (verging

on psychotic) through to deep sleep.

There are various neurobiological mechanisms

in place that govern sleep and wake onset.

A flip flop switch acts to shift from being alert to

being asleep and vice versa, as cross over

states are disadvantageous.


Primed to survive and having evolved to

pursue the gratification of our basic and

more complex needs, we cycle through

period of full arousal when we have control

of our striated muscle, when we can

interact with our environment, and respond

to opportunities and threats, so as to meet

our needs.


These periods occur daily alongside sedate

states when safe in the knowledge that it is night

and that predators are not around, our brains

have evolved to digest new experiences,

integrating them with existing data so that we

are placed in a maximally advantageous position

to interpret our environment the following day.

Perhaps we have evolved so that the simple flip

flop wake sleep switch is responsive to levels of

threat.


If we are concerned there is a sabre tooth

tiger in the neighbourhood, then it is not

evolutionary advantageous to sleep –

arousal, fear, worry will therefore prevent

the onset of sleep.

Getting technical but keeping it

simple.. The areas involved in the promotion of sleep (releasing

GABA) and the area involved in the promotion of

alertness (releasing histamine) reciprocally inhibit each

other.

Melatonin release controlled by the SCN tips the balance

in favour of sleep promotion and the onset of sleep

should begin.

Insomnia is now thought to represent the inability of the

alertness promoting centre to turn off despite the sleep

promotion switch being turned on. This occurs when

arousal levels are too high.

Insomnia

This can occur in the context of an acute stressor.

Heightened levels of arousal prevent sleep onset despite

sleep being promoted as directed by melatonin release.

Chronic insomnia can occur when there is learnt anxiety

around the process of falling asleep with conscious

attempts being made to initiate sleep resulting in further

arousal and further prevention of sleep onset.

Sleep onset is an involuntary event that should happen

without conscious effort in the context of a relaxed state

of mind. (Espie)

Sleep & Anxiety

What happens if generalised anxiety is present

during the day - will an individual experience

periods of arousal through the night that disturb

the sleep cycle?

Sleep & Depression

In depression there is a spiralling inability to

problem solve and navigate ones way through

perceived and actual threats and opportunities.

During waking hours capacity to problem solve

is overwhelmed. Might this correlate with more

REM in a brain effort to problem solve? Will this

increased REM get in the way of restorative

NREM sleep?

Sleep & PTSD

Is it possible that in simulating and trying to process

a significant life threatening trauma during sleep, the

brain struggles to calculate any kind of response

that does not trigger a flight or fight response?

Will triggering a full blown flight or fight response be

so arousing as to wake a person out of sleep?

Sleep & Substance Misuse

Do many individuals try to manipulate their arousal

levels through the use of stimulants or depressants?

Mood and Sleep

Is mood a risk stratification system?

It is 11 am. A hunter gatherer spots a nice animal in the

bushes on the other side of a fast moving stream. At that

time in the day a cost benefit analysis would suggest it

better to wait for an animal on the same side of the river

then risk killing yourself in the fast moving water.

At 9pm when there is still no food the same situation

might warrant a different approach - trying to ford the

stream to get the animal.

Mood and Sleep

Perhaps it is advantageous to have a mood that

subtly shifts as the day goes on with a

propensity towards more energy, more optimism

and more risk taking as the day goes on with

sleep is the rest mechanism.

Diurnal mood variation is recognised in a severe

depression as sleep has a depresogenic effect.

Sleep deprivation is efficacious but short lived

antidepressant therapy.

In Summary….

Sleep, mood and arousal are closely

related.

They need to be looked at in tandem when

thinking about insomnia occurring in

isolation and in the context of other

disorders.

A Clinical Framework for

approaching Insomnia

Insomnia

Difficulty with;

Sleep onset,

Sleep maintainence,

Early morning wakening

Or unrestorative sleep

With adequate time and environment for sleep.

Must have day time symptoms.

The ICSD 2 of the American Sleep

Association The ICSD 2 of the American Sleep Association (2005), formulates

six broad categories of sleep disorder. These are;

1. Insomnia

2. Sleep related breathing disorder

3. Hypersomnias of central origin

4. Circadian rhythm disorders

5. Parasomnias

6. Sleep related movement disorders.

Each of these categories in turn includes many different, carefully delineated conditions. (ICSD2; American Academy of Sleep Medicine 2005)

There is now a third edition with a seventh category of “Other Sleeping Disorder”

Sleep Disorder Dx Requires

Night time Symptoms

Day time Symptoms

Sleep Disorder Symptoms

At night. For example…

Insomnia

Sleep related movement disorders

Sleep related breathing disorders

Parasomnias

Hallucinations

Sleep Disorder Symptoms

During the day. For example….

Excessive daytime sleepiness

General malaise, irritability

Sleep phase timing

Cataplexy

Sleep paralysis

Somnolence

Sleep Related Breathing Disorder

When considering a sleep related

breathing disorder, one should ask about a dry mouth and headache in the mornings

(indicating mouth breathing),

snoring and cessation of breathing when asleep

leading to arousals, noticeable to the sleeping

partner at night. (American Academy of Sleep

Medicine 2005)

Hypersomnias of Central Origin

Narcolepsy

Narcolepsy is a hypersomnia of central origin. This can present with excessive daytime sleepiness (EDS) and occurrences of somnolence,

hypnopompic and hypnogogic hallucinations,

cataplexy (a loss of voluntary muscle control resulting in collapse often experienced in sufferers in response heightened emotional experiences) as well as

sleep paralysis (feeling unable to physically move despite having woken from sleep). (American Academy of Sleep Medicine 2005)

Other Hypersomnias of Central

Origin

Hypersomnia of central origin can be behaviorally induced by insufficient sleep, so it will be important to establish if the patient is allowing himself an adequate amount of time to sleep. There are other causes of central origin hypersomnia as well.

Sleep Related Movement Disorders

Periodic limb movement disorder will often only be noticed by a bedtime partner. The partner might have noticed kicking legs at night which can disturb the patients sleep without fully awakening them but clearly evident to the partner.

Sleep Related Movement Disorders

They can occur in the context of restless leg syndrome (RLS) which tends to come on in the evening and is described as a generally non-painful but irritating desire to move the legs to avoid a deep feeling of discomfort in them which otherwise accumulates.

Both periodic limb movement disorder and RLS can result in poor sleep and daytime fatigue, by fragmenting sleep architecture at night.

Parasomnias

NREM

Sleepwalking

Confusional arousal

Sleep Terror

REM

REM Sleep Behaviour Disorder

Nightmare Disorder

Circadian Rhythm Disorders

Patients can present with symptoms such as

late bedtimes and delayed waking time in the

mornings, associated with a genetically linked

delayed phase syndrome, whereby their

circadian rhythm, runs later than most with

reference to the 24 hour day/night cycle,

resulting in a delayed drive for sleep in the

evening and delayed wakefulness in the

morning.

Secondary Sleep Disorders

Thought should also be given to any

medical conditions,

psychiatric conditions

medication,

drug or alcohol use that can affect sleep at

night with a subsequent effect on alertness

during the day.

Sleep Assessment

Once arriving at a possible differential

diagnosis based on the history elicited,

attempts can be made to refine or confirm

the diagnosis through the use of various

instruments.

Sleep Assessment scales

Investigations

Sleep Scales

Epworth Sleepiness Scale –assesses

propensity to fall asleep in different

situations. Very high score suggestive of

severe sleep related breathing disorder or

Hypersomnia of central origin.

Sleep Investigations

These might include

Sleep diaries or Actigraphy.

Polysomnography (PSG), +/-

videotelemetry,

Multiple Sleep Latency Test (MSLT)


These might include

immobilization test (SIT) to establish the

presence of RLS,

cerebrospinal fluid Hypocretin level testing to

rule out narcolepsy,

or other blood tests and imaging studies to

establish the presence of medical conditions.


Sleep Diaries

Sleep diaries can be useful in documenting sleep patterns over a sustained period of time and is useful to capture poor sleep hygiene and circadian rhythm disorders which can often be strikingly evident when recorded over a period of 1-2 weeks.

(Following treatment it is also possible to repeat this exercise to assess response to treatment.)


Actigraphy

This involves the use of a wrist worn device given to the patient that detects movement.

It is able to differentiate between periods of active wakefulness and periods of rest and correlates fairly well with periods of wakefulness and sleep.

It is particularly helpful again at picking up on circadian rhythm disorders when plotted against a 1-2 week time line, as it is then fairly easy to identify delayed sleep phase disorders.

Google images


Polysomnography

The gold standard investigation if presenting with symptoms suggestive of RLS, PLMD, Sleep related breathing disorder,

Parasomnias or hypersomnias of central origin

Multiple Sleep Latency Test

Daytime testing can include the multiple sleep latency test (MSLT) which should be carried out if a diagnosis of narcolepsy is suspected.

PSG

Google images

Google images


Cerebrospinal Fluid (CSF) Testing

The presence of normal levels of hypocretin in the CSF would rule out narcolepsy as a diagnosis.

Suggested Immobilisation Test

The Suggested Immobilisation Test (SIT) looks at electromyelogram reading and discomfort ratings of a subject asked to lie still for an hour during the daytime. In RLS the subject will have significantly higher levels of discomfort and restlessness than normal subjects.

General Sleep Disorder

Management

Sleep Disorder Treatment

Cognitive Behavioral Therapy. Including….. .

Sleep restriction

Sleep consolidation

Stimulus control

Relaxation therapy

Cognitive approaches such as paradoxical intention.

Sleep Disorder Treatment

Light therapy – timed light exposure/light restriction

Pharmacological interventions Z drugs/ Benzodiazepenes

Sedating Antidepressants

Antihistamines

Melatonin

Anticonvulsants

Sedating Antpsychotics

Stimulant medication (Hypersomnias)

Dopamine agonists/ opiates (PLMD)

Sodium Oxybate (Hypersomnias)

Sleep Related Breathing Disorder

Treatment

Breathing devices

CPAP

Mandibular advancement devices

Surgical intervention e.g. uvuloplasty.

A Guide to Prescribing for

Insomnia

Sleep Neurochemistry

Sleep

wake State

GABA Acetyl

choline

5HT & NA Histamine

(H1)

Dopamine

Awake

+

+++

+++

+++

+++

NREM

+++

+

+

+

+++

REM

+++

+++

_

_

+++

Sleep Disturbing

SSRI

SNRI

NDRI

NRI

MAOI

Stimulants

Affecting Sleep

AD and AP – RLS / PLMD

Muscle Relaxents– OSA

AP/AD – weight gain - OSA

Sleep Promoting GABA A

Alpha 1 sub

unit PAM /

GHB

receptor

VSSC H1

antagonist

NA α 1

antagonist

5HT 2 A/C

antagonist

M1

antagonist

MT1 & MT2

agonist

barbituates Pregabalin Trazodone Trazodone Trazodone Ramelteon

benzodiazep

enes

Gabapentin Mirtazapine Mirtazapine Melatonin

Z-drugs TCA TCA TCA

Sodium

Oxybate

Quetiapine Quetiapine Quetiapine Quetiapine

Clozapine Clozapine Clozapine

Olanzapine Olanzapine Olanzapine Olanzapine

GABA A α subunits GABA A

Alpha sub

unit

Alpha 1 Alpha 2 Alpha 3 Alpha 5

Sedation √

Muscle

Relaxent √ √

Anxiolytic √ √

Cognitive

effect

√

GABA A PAMs

GABA Alpha

sub unit

Alpha 1 Alpha 2 Alpha 3 Alpha 5

Benzo

diazepnes √ √ √ √

Zopiclone √ √ √ √

E-zopiclone √ √ √ √

zolpidem √

Sleep and Mental Health

Always ask about sleep – great barometer,

simple question, huge amount of

information.

If insomnia present screen for

Physical health cause

Mental health cause

Other primary sleep disorders

Brief Sleep Assessment

Take hx by working through work through

24 hr cycle to cover;

Sleep Hygiene

Schedule

Symptoms at night

Symptoms during the day

Closed questions to screen for specific

disorders

Treatment Tips

Investigate/Refer

Treat underlying cause if there is one.

Consider CBTi

Consider medication when appropriate.

Treatment Tips

Think about arousing agents

Target GABA

Anti Histamine

Sedating antidepressant

Sedating antiepileptic

Sedating low dose antipsychotic

Melatonin / MT agonist

Consider medication combination.

Treatment Tips

Think about ;

Patient age

Acute vs Chronic

Comorbidities

Side effects

Addiction /withdrawal/ rebound

Parting Thoughts

Sleep is part of who we are and integral to

physical and higher function

Incorporate sleep into your field of enquiry.

Sleep is your friend, an early warning system,

a target for intervention, is tangible and

measurable and can be addressed to keep

your patients well.

Any Questions?

[email protected]

prescribing for insomnia

Health & Medicine