Sleep Medicine

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.
2.
3.
To provide a conceptual framework for
understanding sleep, it’s function, it’s
structure and it’s control.
To provide a clinical framework for
approaching Insomnia.
To provide a guide to prescribing for
insomnia.
Sleep

The function of sleep

The structure of sleep

The control of sleep
The function 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.
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
 Process
drive
Rhythm
S/ homeostatic sleep
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.

The Function of Sleep
Humans are primed to survive.
 Maslow – spoke of a hierarchy of needs
that drive us.

Google images
The Function of Sleep


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.
The Function of Sleep
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.

The Function of Sleep

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.
The Function of Sleep


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.
Bringing it together…..

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.
Bringing it together…..


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.
Bringing it together…..

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.

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.
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
 Sleep

arousal
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
 Investigations
scales
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)
Sleep Investigations

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 Investigations



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.)
Sleep Investigations

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
Sleep Investigations


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
Google images
Google images
Sleep Investigations




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.

Aims, Objectives & Overview
1.
2.
3.
To provide a conceptual framework for understanding
sleep, it’s function, it’s structure and it’s control.
To provide a clinical framework for approaching
Insomnia.
To provide a guide to prescribing for
insomnia.
A Guide to Prescribing for
Insomnia
Sleep Neurochemistry
Sleep
GABA
wake State
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
H1
NA α 1
5HT 2 A/C
M1
MT1 & MT2
antagonist
antagonist
antagonist
antagonist
agonist
Pregabalin
Trazodone
Trazodone
Trazodone
Ramelteon
Gabapentin
Mirtazapine
Mirtazapine
Melatonin
GABA A
Alpha 1 sub
unit PAM /
GHB
receptor
VSSC
barbituates
benzodiazep
enes
Z-drugs
TCA
TCA
TCA
Sodium
Oxybate
Quetiapine
Quetiapine
Quetiapine
Clozapine
Clozapine
Olanzapine
Olanzapine
Quetiapine
Clozapine
Olanzapine
Olanzapine
GABA A α subunits
GABA A
Alpha sub
unit
Alpha 2
Alpha 3
Muscle
Relaxent
√
√
Anxiolytic
√
√
Sedation
Cognitive
effect
Alpha 1
Alpha 5
√
√
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]