The presentation reviews the basics of sleep neurobiology and covers some aspects of insomnia diagnosis and management.

1. Sleep Neurobiology and
Insomnia
Dr. Pramod Krishnan, M.D, D.M
Consultant Neurologist and Epileptologist,
Sleep Medicine Specialist,
HOD Neurology
Manipal Hospital, Bengaluru

2. Introduction
• All organisms from virus to complex mammals have periods of activity
and inactivity.
• Such a pervasive finding suggests that sleep is basic to life.
What is sleep?
• Sleep is defined behaviorally as a reversible state of perceptual
disengagement from and unresponsiveness to the environment.
• Sleep is physiologic, necessary, temporary, reversible, and cyclic.

3. • A role for the brain in sleep-wake
behavior was first indicated in 1916, when
Baron Constantine von Economo studied
encephalitis lethargica.
• Lesions at the junction of the midbrain
and posterior hypothalamus (diagonal
hatching) caused hypersomnolence.
• Lesions of the basal forebrain and
anterior hypothalamus (horizontal
hatching) produced profound insomnia.
• Lesions between these two sites (arrow),
which included the lateral hypothalamic
area, caused narcolepsy.
O, optic nerve; VE, third ventricle; Hy, hypothalamus; Th, thalamus; V4, fourth
ventricle; Aq, cerebral aqueduct; K, oculomet, oculomotor nerve.

4. Hypothalamus
Wakefulness is maintained by the combined excitatory influence of forebrain-projecting noradrenergic (locus
coeruleus), histaminergic (tuberomammillary nucleus), serotoninergic (dorsal raphe), and cholinergic (not
shown) cell groups located at or near the mesopontine junction. The cerebral cortex and medullary brainstem
also contain subpopulations of GABA-ergic sleep-active neurons. The pineal gland, located in the
epithalamus, produces melatonin, a hormone thought to function as a hypnotic signal.

5. Sleep is initiated and maintained by neurons in the median preoptic (MnPO) and ventrolateral preoptic (VLPO)
nuclei. Hypocretin (orexin) neurons located in the lateral hypothalamus reinforce activity in the brainstem arousal
pathways and also stabilize both sleep and wakefulness. The suprachiasmatic nuclei (SCN) determine the timing
of the sleep-wake cycle and help to “consolidate” these behavioral states.

6. Wakefulness
“Waking is induced and maintained by multiple redundant neuronal
systems localized from the medulla oblongata to the forebrain”.

7. Ascending arousal system consists of:
1. Noradrenergic (NE) neurons of the
ventrolateral medulla and locus coeruleus.
2. Cholinergic neurons (ACh) in the
pedunculopontine tegmental/laterodorsal
tegmental (PPT/LDT) nuclei.
3. Serotonergic (5-HT) neurons in the dorsal raphe
nucleus.
4. Dopaminergic neurons (DA) of the ventral PAG.
5. Histaminergic neurons (His) of the
tuberomammillary nucleus (TMN).
6. Glutamatergic neurons of the parabrachial
nucleus.
These systems produce cortical arousal via two pathways:
1. Dorsal route through the thalamus
2. Ventral route through hypothalamus and BF.
• The latter pathway receives contributions from the
hypocretin (ORX) and melanin-concentrating hormone
(MCH) neurons of the lateral hypothalamic area (LHA)
as well as GABA-ergic or cholinergic neurons of the BF.

8. NREM Sleep
“NREM sleep is induced and maintained by GABAergic neurons of
the VLPO system by inhibitory projections to the different
populations of waking neurons”.

9. • The median preoptic nucleus and
ventrolateral preoptic nucleus (VLPO)
contain sleep-active cells, which contains the
inhibitory neurotransmitters GABA and
galanin (Gal).
• The VLPO projects to all the main
components of the ascending arousal
system.
• Inhibition of the arousal system by the
VLPO during sleep is critical for the
maintenance and consolidation of sleep.
• There is a node of GABAergic neurons in
the parafacial zone of the rostral medulla
that are also sleep active.
BF, basal forebrain; LC, locus coeruleus; LDT, laterodorsal tegmental nuclei; PPT, pedunculopontine;
SN, substantia nigra; TMN, tuberomammillary nucleus; VTA, ventral tegmental area.

10. REM Sleep
“REM sleep is generated by neurons located in the brainstem’.
However, recent studies suggest that hypothalamic neurons control REM sleep
by descending projections.

11. • GABA-ergic ventrolateral PAG (vlPAG) neurons fire during NREM states to inhibit entry into REM sleep.
• During REM sleep these neurons are inhibited by a population of GABAergic REM sleep–active neurons in the
sublaterodorsal region (SLD) and pre coeruleus (PC).
• This mutually inhibitory relationship produces a REM-NREM flip switch, promoting rapid and complete
transitions between these states.
• The core REM sleep switch is, in turn, modulated by other neurotransmitter systems.

12. Noradrenergic neurons in the locus coeruleus (LC) and serotonergic neurons in the dorsal raphe (DR) inhibit
REM sleep by exciting REM-off neurons and inhibiting REM-on neurons. During REM sleep, they are
silent. Cholinergic neurons (blue) promote REM sleep by having opposite actions on the same two neuronal
populations. The orexin neurons inhibit entry into REM sleep by exciting neurons in the REM-off
population, whereas the VLPO neurons promote entry into REM sleep by inhibiting this same target.
-
-
- -
+
+

13. • During REM sleep, glutamatergic
neurons in the SLD (red) activates a
series of inhibitory interneurons in the
medulla and spinal cord, which inhibit
motor neurons and produce the atonia
of REM sleep.
• Withdrawal of tonic excitatory input
from the REM-off regions may also
contribute to atonia.
• Ascending projections from
glutamatergic neurons in the
parabrachial (PB) nucleus and pre-
coeruleus (PC) area activate forebrain
pathways that drive EEG
desynchronization and hippocampal
theta rhythms (typical of REM sleep).
+
+
+
+
-
-
-

14. Hypocretin/ Orexin system

15. • Orexin A and Orexin B are
cleaved from prepro-orexin1
• Orexin A binds OX1R and OX2R1
• Orexin B binds OX2R1 only
• Activation of OX1R/OX2R is
responsible for the transition of
respective sleep states to a state
of wakefulness1-3 Promotes
wakefulness
OX1R OX2R
Promotes
wakefulness
Orexin A Orexin B
Pro-hormone
Peptide
Prepro-orexin
N
C
GKR GRR
Via regulation of
neurons involved in
REM sleep
Via regulation of neurons
involved in REM + NREM
sleep
Fundamental role of orexin in sleep-wake
regulation
NREM=non-rapid eye movement; OX1R=orexin receptor type-1; OX2R=orexin receptor type-2; REM=rapid eye movement 1. Equihua AC et al. Front Pharmacol. 2013;4:163. 2. Beuckmann CT et al. J Pharm Mol Ther. 2017;362(2):287-295.
3. Willie JT et al. Neuron. 2003;38(5):715-730

16. The first glimpse of Orexin. An in situ hybridization
autoradiography showing Orexin expression in the
hypothalamic region of the rat brain.

17. Fundamental Role of Orexin in Sleep-Wake
Regulation
Firing rate of orexin neurons across sleep-wake states
Firing
rate
(a.u.)
100
50
0
aW qW tSWS SWS tPS PS
• Preclinical studies have
demonstrated the fundamental role
of orexins in gating and sustaining
wakefulness.
• Orexin neuronal activity is highest
during active wakefulness and
lowest during sleep.
• This diurnal pattern of orexin
activity regulates the sleep-wake
cycle and normal sleep architecture.
a.u.=arbitrary units; aW=active wakefulness; PS=paradoxical sleep; qW=quiet wakefulness; SWS=slow-wave sleep; tPS=transition to paradoxical sleep; tSWS=transition to slow-wave sleep
Azzez IA, et al. Front Pharmacol. 2018;9:1061

18. Hypocretin neurons in the lateral hypothalamic area innervate all the ascending arousal
systems as well as the cerebral cortex, and are excitatory.
BF, basal forebrain; LC, locus coeruleus; LDT, laterodorsal tegmental nuclei; PPT, pedunculopontine; SN,
substantia nigra; TMN, tuberomammillary nucleus; VTA, ventral tegmental area.

19. Sleep homeostasis
• The networks for wake, NREM and REM sleep are well known.
• However, the mechanisms at the origin of the switch between states remains
to be fully understood.

20. • VLPO and MnPO inhibit the components of the ascending arousal pathways in both the hypothalamus and the
brainstem.
• This interaction between the VLPO and MnPO and components of the arousal system is, mutually inhibitory and
analogous to an electronic “flip” switch/circuit.
• The lateral hypothalamic orexin neurons likely play a stabilizing role for the switch and reduce transitions during
both sleep and wakefulness. VLPOex, extended ventrolateral preoptic nucleus; VLPOc, core ventrolateral preoptic
nucleus.

21. CIRCADIAN RHYTHM
“The Suprachiasmatic nucleus in the anterior hypothalamus is an
endogenous clock entrained by excitatory projections arising from
specialized light-sensitive neurons of the retina”.

22. Photic information reaches the suprachiasmatic nucleus (SCN) from the retina via the retinohypothalamic
tract (RHT). Melatonin is released from the pineal gland at night, and its output is regulated by the SCN via
the superior cervical ganglion (SCG). In addition to its ability to synchronize circadian rhythms, melatonin
can also promote sleep. Integrated timing information from the SCN is transmitted to sleep-wake centers.

23. Two-process model: the SCN promotes wakefulness by stimulating arousal networks. SCN activity appears to
oppose the homeostatic sleep drive. The propensity to be awake or asleep at any time is related to the
homeostatic sleep drive and the opposing SCN alerting signal. At normal bedtime, both the alerting drive and
the sleep drive are at their highest level. The SCN has at least two types of melatonin receptors, MT1 and MT2,
involved in the regulation of sleep. Stimulation of MT1 receptors is believed to decrease the alerting signal from
the SCN, whereas MT2 stimulation is thought to be involved in synchronizing the circadian system.

24. The Two-Process Model of Sleep-Wake
Regulation: Working in Unison

25. The Two-Process Model of Sleep-Wake Regulation:
The Homeostatic Process (Process S)
A homeostatic process is
represented by the buildup
of sleep pressure and
consists of a rising phase
during wake and a declining
phase during sleep.1,2
EEG=electroencephalograph; REM=rapid eye movement
1. Kryger MH et al. Principles and Practice of Sleep Medicine. 6th ed. Philadelphia, PA: Elsevier; 2017. 2. Borbély AA et al. J Sleep Res.
2016;25(2):131-143.

26. The Two-Process Model of Sleep-Wake Regulation:
Adenosine Levels Correlate With the Buildup of Sleep Pressure
• Adenosine levels increase over
duration of wake-time activity
during the day, correlating
with a buildup of sleep
pressure.1,2
• Adenosine levels gradually
increase in arousal-promoting
areas such as the reticular
activating system of the brain
stem; with higher
concentrations, adenosine
inhibits arousal and induces
sleepiness.2
1. Kryger MH et al. Principles and Practice of Sleep Medicine. 6th ed. Philadelphia, PA: Elsevier; 2017. 2. Bjorness TE, Greene RW. Curr
Neuropharmacol. 2009;7:238-245

27. The Two-Process Model of Sleep-Wake Regulation:
The Circadian Process (Process C)
The dimming of environmental light
at dusk triggers the release of
melatonin by the pineal gland via
input from the suprachiasmatic
nucleus (circadian pacemaker),
promoting the onset of sleep.2
1. Kryger MH et al. Principles and Practice of Sleep Medicine. 6th ed. Philadelphia, PA: Elsevier; 2017. 2. Arendt J. J Biol. Rhythms.
2005;20(4):291-303.

28. The Two-Process Model of Sleep-Wake Regulation:
Melatonin Induces Release of Preoptic GABA Signaling at Night
• The rise in melatonin production
coincides with increased GABA
signaling from the ventrolateral
preoptic area, and induces onset
of sleep.1,2
• Preoptic GABA activity is elevated
during sleep and inhibited during
daytime wake behavior.1
GABA=gamma aminobutyric acid; SCN=suprachiasmatic nucleus
1. Kryger MH et al. Principles and Practice of Sleep Medicine. 6th ed. Philadelphia, PA: Elsevier; 2017. 2. Arendt J. J Biol. Rhythms.
2005;20(4):291-303

29. Fundamental Role of Orexin in Sleep-Wake Regulation
GABA=gamma aminobutyric acid; NREM=non-rapid eye movement; REM=rapid eye movement
1. Equihua AC et al. Front Pharmacol. 2013;4:163. 2. Azzez IA, et al. Front Pharmacol. 2018;9:1061
Preclinical studies have
shown that orexin neuronal
activity follows a diurnal
fluctuation pattern – highest
during active wake behavior,
decreases during non-active
wake and sleep behaviors,
and lowest during NREM
Stage 3 sleep.1,2

30. Summary of Sleep and
Wakefulness

32. EEG, EOG, EMG and neurotransmitter dominance in wakefulness, NREM and REM sleep:
Neuromodulator activity is primarily cholinergic during wake and REM sleep. Wake is supported by
activity of monoamines, histamine and hypocretin/ orexin. In sleep, monoaminergic systems, including
norepinephrine and serotonin are attenuated, and are silent in REM sleep. Dopamine levels do not
change dramatically across the sleep wake cycle.
Awake NREM Sleep REM sleep

33. Retinal inputs
Suprachiasmatic
nucleus
Adenosine build up
during wake period
VLPO
Multiple waking
systems
NREM sleep
Sublaterodorsal
tegmental nucleus
REM sleep
+
+
+
-
-
Tonic, NE
and ACh
GABA
Via A2A
receptors
-
via A1
receptors
vlPAG, LPT
+
-
GABA
-
GABA
Lateral
hypothalamus
Orexin +
Pineal gland
Melatonin
LDT/ PPT
Glutamate
ACh

34. Normal sleep and its
functions

35. Sleep-Wake Changes With Age
NEWBORNS
• Sleep is intermittently
distributed across the day
and night
• Infants sleep ~16 to 18
hours within a 24-hr
period
• Greater than 50% of
sleep is spent in REM
sleep
• The transition between
sleep and wake is
achieved through REM
sleep during the first year
of life
Sleep-wake cycles and sleep architecture show distinctive changes with age.
CHILDREN
• Children between the ages
3 and 5:
• Total sleep time decreases
to 10-12 hours/day
• Sleep is composed
predominantly of SWS
ADOLESCENTS:
• Require 8 to 10 hours of
sleep per night
• SWS duration decreases
by ~40%
ADULTS
• Sleep duration is ~8
hours per night
• Those with normal sleep
enter sleep through
NREM sleep and
transition to REM sleep
within ~90 min
• NREM and REM sleep
then alternate throughout
the night in ~90-min
epochs
• Sleep efficiency
decreases with age
LATE LIFE
• Sleep efficiency and total
sleep time diminish
• Sleep is broken up,
lighter, and associated
with many nighttime
arousals
• Deep sleep diminishes

36. Proportion of the night spent in the various sleep stages in adults. Wakefulness in sleep usually makes up less
than 5% of the night. Stage N1 sleep generally makes up 2% to 5% of sleep; stage N2, 45% to 55%; and stage
N3, 3% to 15%. Non–rapid eye movement sleep is therefore usually 75% to 80% of sleep. Stage R sleep is
usually 20% to 25% of sleep and occurs in three to six discrete episodes.

38. Sleep Architecture

39. Age-related changes in sleep stages in healthy men.

41. Sleep Is Essential
Chronic sleep loss is linked to:
Depression
Anxiety
Compromised immune system function
High blood pressure
Cardiovascular disease
Diabetes
Obesity
Lack of sleep is associated with:
Memory impairments
Reductions in cognitive abilities
Mood lability
Suggested physiological roles for sleep:
• Replenish energy reserves
• Modulate metabolism and body temperature
• Facilitate learning and memory
• Removal of metabolic waste products
Sleep is essential for daily function and survival

42. INSOMNIA

43. Insomnia Can Manifest at Different Times of the Sleep
Cycle and Cause Daytime Impairments
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Washington, DC:
American Psychiatric Association; 2013. 2. Misra AK et al. J Assoc Physicians India. 2017;65(4):43-47
The goal of insomnia therapy is to allow patients to fall asleep, stay asleep, wake, and function well
Timing of Insomnia Symptoms
Daytime Impairments (Wake Behavior):
• Fatigue
• Daytime sleepiness
• Impairment in cognitive performance
• Mood disturbances
• Depressive or anxiety symptoms
Get in bed / Lights off
24-hour
Sleep/Wake
Behavior
Get out of bed / Lights on
Waking too early
Problems staying asleep
Problems falling asleep

44. Epidemiology: Prevalence
of adults experience
symptoms of insomnia
33%
~
Population-based studies
Insomnia is one of the most prevalent sleep disorders

45. Epidemiology: Socio-demographics
Insomnia disorder affects
people of all ages and
backgrounds, but certain
populations tend to have a
higher rate.
S O C I O D E M O G R A P H I C FA C T O R S A F F E C T I N G T H E
P R E VA L E N C E O F I N S O M N I A D I S O R D E R
Gender Diagnosis more common in women
Shift hours
Patients with irregular shifts at work are more likely to
report symptoms of insomnia
Disability
Higher odds of diagnosis in patients who report
having a disability
Race Increased risk in racial minorities.
Age Greater risk in older patients
Socioeconomic
status
Greater risk in patients with a lower socioeconomic
status
Comorbidities
Increased risk in patients with concurrent medical
and/or mental disorders

46. Risk factors for insomnia disorder are multifaceted, as the development of this condition can involve an
interplay among a variety of factors.
Insomnia
Risk Factors and Potential Causes
Environmental Behavioral Physiological Pharmacological
o Temperature
o Amount of light in
the bedroom
o Level of noise in
the bedroom
o Mattress state
o Alone/bedpartner
o TV on/off
o Excessive worry
about sleep
o Diet/exercise
o Daytime activities
(e.g., napping)
o Pre-bedtime
activities (e.g.,
computer use,
exercise)
o Increases in basal
heart rate and
metabolism
o Irregular brain
metabolism
o Age-related
changes
in brain function
o Antidepressants
o Sedatives
o Antihypertensives
o Steroids
o Decongestants
o Antihistamines
o Adrenergic
agonists

47. Approximate distribution of types of insomnia. Those with primary insomnia
make up only a small portion of the population of people with insomnia.

48. Spielman’s 3-P model for insomnia. Insomnia develops and is a function of predisposing
and precipitating factors and is sustained over time by perpetuating factors.

49. Steps in the evolution of Insomnia

50. Models for Insomnia Disorder
A number of models have been proposed to explain the
etiology and underlying pathophysiology of insomnia disorder.
Behavioral Models:
Insomnia disorder is
due to behaviors that
preclude sleep (e.g.,
spending too much
time in bed)
Cognitive Models:
Thoughts, feelings, and
beliefs underlie
insomnia disorder
(e.g., excessive
worrying)
Physiological Models:
Insomnia disorder is
due to aberrant
physiological processes
(e.g., dysfunctional
sleep-wake regions in
brain)

51. Symptoms must have lasted for ≥3 months at a frequency of ≥3 times per week
despite adequate opportunity and circumstances to sleep.
Dissatisfaction with sleep quantity or
quality with one or more of the following:
• Difficulty initiating sleep.
• Difficulty maintaining sleep,
characterized by frequent awakenings.
• Early morning awakening with inability
to return to sleep.
Not better explained by/occur solely during the
course of another sleep-wake disorder.
The sleep disturbance causes clinically significant
distress or impairment in daytime functioning, as
evidenced by one of the following:
o Fatigue or low energy
o Daytime sleepiness
o Impaired attention, concentration or memory
o Mood disturbances
o Behavioural difficulties
o Impaired occupational or academic function
o Impaired interpersonal or social function
o Negative effect on caregiver or family
functioning
DSM-5 Definition of Insomnia Disorder

52. ICSD 3 criteria for chronic insomnia disorder
Criteria A to F must be met
A. The patient reports, or the patients parent or caregiver
observes one or more of the following:
Difficulty initiating sleep.
Difficulty maintaining sleep.
Waking up earlier than desired.
Resistance to going to bed or appropriate schedule.
Difficulty sleeping without parent or caregiver intervention.
B. The patient reports, or the patients parent or caregiver
observes one or more of the following:
Fatigue/ malaise
Attention, concentration or memory impairment
Impaired social, family, occupational or academic
performance.
Mood disturbance/ irritability.
Daytime sleepiness.
Behavioural problems (eg. Hyperactivity, impulsivity,
aggression)
Reduced motivation/ energy/ initiative.
Proneness for errors/ accidents.
Concerns about or dissatisfaction with sleep.
C. The reported sleep/ wake complaints cannot be
explained purely by inadequate opportunity or inadequate
circumstances for sleep.
D. The sleep disturbance and associated daytime
symptoms occur at least 3 times/week.
E. The sleep disturbance and associated daytime
symptoms have been present for at least 3 months.
F. The sleep/ wake difficulty is not explained more clearly
by another sleep disorder.

53. Insomnia Disorder: More Than Just Insomnia Symptoms
(1)Inclusion of 3-month duration criterion, with 3 times per week as the minimum frequency.
(2)Elimination of the distinction between “primary” and “secondary” insomnia diagnoses, recognizing that it
is often impossible to reliably determine directionality or causality between insomnia and comorbid
conditions.
(3)ICSD-3 collapses “primary insomnia” subtypes into a single diagnosis, given poor reliability and
discriminant validity of these subtypes.
Key Revisions From Earlier Criteria
Diagnostic Criteria for Insomnia (DSM-5/ICSD-3a)
Symptoms Impairment Chronicity
+ +

54. Clinical Evaluation
The American Academy of Sleep Medicine (AASM) published a guideline for the
evaluation and management of chronic insomnia disorder.
The AASM recommends that the diagnosis of insomnia disorder rely primarily on a
clinical evaluation.
What are key components of a clinical evaluation for insomnia disorder?
Sleep history.
Other history: (e.g., medical and psychiatric history, medication use,
family/social/occupational history).
Physical and mental health status.

55. Examples of Tests and Tools That Aid in the Diagnosis of Insomnia Disorder
T E S T O R T O O L D E S C R I P T I O N
A A S M
R E C O M M E N DA T I O N
Sleep-wake diaries
Daily records in which the patient tracks bedtime, length
of time to fall asleep, length of sleep, number of
nighttime awakenings, length of nighttime
sleeplessness, and quality of sleep.
Consensus-based
Insomnia questionnaires
Self-report surveys that assess either sleep quality,
sleepiness, psychological issues, or quality of life.
Consensus-based
Actigraphy
Noninvasive method using a portable device worn on the
wrist that monitors physical activity to gauge rest and
activity cycles.
Optional
Polysomnography
A test involving an overnight stay at a sleep center that is
used to identify medical causes of insomnia (e.g., sleep
apnea, restless legs syndrome)
Only when indicated.
Multiple Sleep
Latency Test
Used to identify suspected hypersomnolence disorders
or narcolepsy that may present with symptoms of
insomnia.
Only when indicated.

56. Management of insomnia
• Hypnotic medications used
judiciously is the mainstay of
treatment.
• For few nights to a maximum of 4
weeks.
• Most commonly used are BZD
receptor agonists.
• Melatonin and melatonin receptor
agonists for sleep onset insomnia.
• Cognitive behavioural therapy, sleep
hygiene.
• Judicious use of hypnotics.
Acute, transient, short term insomnia Chronic insomnia

57. Different Approaches to Insomnia Management
CNS=central nervous system; GABA=gamma aminobutyric acid; OTC=over-the-counter 1. Morin CM et al. Sleep. 1999.;22(8):1134-56. 2. Atkin T et al. Pharmacol Rev. 2018;70(2):197-245

58. Technique Involves Addresses
Sleep hygiene
education
Review of diet, exercise, alcohol, and environmental
factors that may help or interfere with sleep;
importance of regular bedtime and set time and the
negative effects of long naps.
Lifestyle and behaviors that are
hurdles to good quality sleep.
Stimulus control Teach patient to go to bed only when sleepy; get out
of bed when unable to sleep; and when sleepy, stop
all sleep-incompatible activities (e.g., television
viewing while in bed, using electronic devices before
bedtime).
The learned associations of the
bed with wakefulness.
Sleep restriction Emphasize the importance of reducing time in bed
to actual sleep time.
Disrupted and fragmented
sleep related to too much time
in bed.
Relaxation Teach patient to reduce muscle tension with
relaxation techniques and to reduce thoughts that
will not shut off by using imagery training and
meditation.
Increased hyperarousal
(physiologic, cognitive,
emotional).
Cognitive Correct inaccurate beliefs and attitudes about
insomnia.
Incorrect information and
misconceptions that are
perpetuating the problem.
Components of Cognitive Behavioural Therapy in Insomnia

59. Cognitive behavioural therapy for insomnia (CBTI) produces durable improvements in sleep-onset
latency, wake after sleep onset, and total sleep time 6 months after treatment is discontinued.

60. GABA-A Agonists Drugs
Generation Representative Issues
Barbiturates 1900
GABAA receptor positive allosteric
modulator
barbital
pentobarbital
breathing depression, memory
deficits, motor deficits,
dependency, tolerance
Benzodiazepines 1960
GABAA receptor positive
allosteric modulator
temazepam
triazolam
flurazepam
memory deficits, motor
deficits, dependency, tolerance,
rebound insomnia
Non-Benzodiazepines 1985
GABAA receptor positive
allosteric modulator
zolpidem
zaleplon
zopiclone
memory deficits, motor
deficits, dependency, tolerance,
rebound insomnia (in general,
side effects are milder)

61. Effects of the approved treatment options on Sleep Architecture
• Majority of available sleep medications are associated with suppression of
REM sleep
1. MacFarlane, J. (2019). The Effects of Psychotropic and Neurotropic Medications on Sleep. Sleep Review Mag.
2. Rosenberg R, et al. (2005). An Assessment of the Efficacy and Safety of Eszopiclone in the Treatment of Transient Insomnia in Healthy Adults. Sleep Med. 2005;6:15-22.
3. Moline, M. et al. Effect of Lemborexant on Sleep Architecture in Older Adults with Insomnia Disorder. Poster presented at 33rd Annual Meeting of the APSS; June 8-12; San Antonio, TX
4. Data on File Eisai Limited.
% SWS % REM Sleep
Benzodiazepines (BZDs) ↓↓ ↔↓
Non-BZD Receptor Agonists ↔↑ ↔
Tricyclic Antidepressants (TCAs) ↔↑ ↓
↓ : REM Suppressant
↔: REM Neutral

62. American Academy of Sleep Medicine Clinical Practice Guideline for the
Pharmacologic Treatment of Chronic Insomnia in Adults
aAASM guideline suggested use of medication by clinicians for treatment of sleep onset and/or sleep maintenance insomnia versus no treatment. All recommendation categories in gray [including Direction (“For” / “Against”), Quality of Evidence (Very low, Low, Moderate, High, and Very High), and Strength (“Strong” / “Weak”)] based on GRADE approach;
for GRADE approach details, refer to Morgenthaler et al. J Clin Sleep Med. 2016; bThese uses may be different than FDA-approved indication; cFDA-approved for treatment of insomnia .
AASM=American Academy of Sleep Medicine; FDA=Food and Drug Administration Adapted from Sateia MJ et al. J Clin Sleep Med. 2017;13(2):307-349

63. Unmet Needs in Insomnia Treatment
Availability of Additional New Drugs: Lack of additional new drugs in the
market which are of good quality and address both sleep onset and sleep
maintenance.
Long-Term Efficacy: Drugs which can be used for long periods without
concerns of dependency or side effects.
Fewer Side Effects: Current drugs are addictive or cause dependence. Need
drugs which could lower cognitive impairment.
Next-Morning Impact: Limited or absence of next-morning impact or
behavioral concern.

64. THANK YOU