Abnormal sleep pattern in

a patient with bipolar

disease. Mohan Dutt MD

Type of Potential Conflict Details of Potential Conflict

Grant/Research Support

Consultant

Speakers’ Bureaus

Financial support

Other

1.2.3.

xX

Accreditation Statement

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of The American Academy of Sleep Medicine and The Michigan Academy of Sleep Medicine. The American Academy of Sleep Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Objectives

• Case review

• Review of normal sleep

• Pathogenesis of N24SWD

• Treatment

• Effects of Bipolar disease on sleep cycle

• Case wrap up

Case Presentation - Initial Visit

(2012) • HPI: 51 yo M with complaints of circadian rhythm disturbance for

multiple years.

• Delayed for most of his life

• “Allergic to light”

• Joined army and had to keep set schedule, was miserable

• Has been allowing himself to free run since leaving the army

• Previously tried melatonin to help with sleep, currently taking

Doxepin.

• Lives in basement

Initial Visit

• ESS: 1/24

• Sleep symptoms: Denies snoring, witnessed apneas or

gasping for air. Sleeps for around 6 to 8 hours per night.

Wakes up feeling refreshed.

• PMHx: Depression

• FamHx: Non-Contributory

• Social: No alcohol or tobacco

• Meds: Doxepin, Wellbutrin

Initial Visit- A/P

• Restart melatonin at night

• Light exposure in the morning

• Embletta

• Sleep Logs

Sleep Study Results

• AHI: 9.1 events/hr

• Sleep Latency: 82 minutes

• REM Sleep Latency: 124 minutes

• Sleep Efficiency: 55%

• No PLMs

Follow-up Visit

• Did not believe that he had

sleep apnea

• Sleep log shows free running

• Was using light + melatonin +

Doxepin

• Circadian Cycle: 24.85 h

• Daily advance: 50 minutes

• Average sleep duration: 9h15m

Sleep Log Data

15

18.75

22.5

26.25

30

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Tim

e (

hours

)

Day

Cycle length

0h 0m

120000h 0m

240000h 0m

360000h 0m

480000h 0m

600000h 0m

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Dura

tion

Day

Shift in Midpoint sleep

Follow-up: A/P

• Continue with with light therapy and melatonin

• Discuss with psychiatrist about starting mood

stabilizers due to evidence of manic episodes on

interview

Non 24 Sleep Wake Disorder

• “There is a history of insomnia, excessive daytime

sleepiness, or both, which alternate with

asymptomatic episodes, due to misalignment

between the 24-hour light-dark cycle and the non-

entrained endogenous circadian rhythm of sleep-

wake propensity” (ICSD 3)

Demographics

• Unknown prevalence in sighted individuals

• First case described in 1971 (Elliot et al)

• Over 50% of blind individuals

• Hayakawa et al - Case report of 57 sighted males with N24SWD

• 72% men

• 98% disturbed social function

• 28% with psychiatric disorder

Clinical Features

• Symptoms depend on when individual tries to

sleep based on circadian rhythm

• Sleep onset insomnia

• Daytime sleepiness

• Alternating periods of normalcy

Diagnosis

• Sleep logs or actigraphy- typically 14 days

• Free running pattern

• Tau (τ)

• Phase Angle (ψ)

The Circadian System

• Responsible for temporal organization of majority

of bodies physiologic function

• Controls sleep wake cycle, in coordination with

environmental input.

• In the absence of external cues the endogenous

cycle length (τ) is around 24.15 hours.

• Requires zeitgebers

Biologic Clock • Suprachiasmatic

nucleus=Master clock

• Peripheral tissues have

autonomous clocks

• Clock works through negative

feedback

• Mutations in individual genes

can lead to phase shifts.

• Endogenous cycle length

around 24 hours

Synchronization • Retinohypothalamic Tract

• Photic

• Geniculohypothalamic Tract

• Photic/Non-photic

• Raphe Nucleus

• Non-photic

• Light stimulates PER expression

Output

• Pineal Gland

• Melatonin Production

• Hypothalamic-Pituitary-Axis

• Cortisol

• Body Temperature

Pathogenesis of N24SWD

• Phase angle differences

• Decreased response to light

• Long endogenous period

Phase Angle Differences

Decreased Response

• Blunted response to light induced melatonin

suppression

• Decreased sensitivity of phase response curve

• Photoreceptor abnormalities

Long Endogenous Circadian

Period

• Tau of 24.48 vs 24.17 in controls (Kitamura et al)

• Genetic mutations on core machinery

• Single nucleotide polymorphism in PER3-

rs228697 (Hida et al)

• PER3- rs908078 (Kripke et al)

Treatment

• Light Therapy

• Melatonin

• Melatonin Agonist

Light Therapy

• Self selected light

exposure abnormalities

• Cognitive Behavioral

Therapy

• Light exposure should

be shortly after body

temp minimum to

induce phase advance

Melatonin

• Opposite PRC compared to light

• Phase advance in the evening

• Phase delay in the morning

• Soporific

• Should administered around time of DLMO

Bipolar disorder and circadian

rhythms

• Melatonin

• HPA

• Body temperature

Melatonin

• Advanced peak during mania

• Decreased peak during euthymia and depression

• Overall decrease in melatonin levels

• Increased sensitivity to light melatonin suppression

Bipolar Disease and Core Clock

Mechanism

• Clock

• Per3

• BMAL

• CRY2

• GSK-3B

Mood Stabilizers and Sleep

• Lithium

• Increases phase delay

• increases tau

• inhibits GSK-3B

• Reduces melatonin light sensitivity

• Valproic Acid

• May advance phase

• Increases expression of melatonin receptors

Back to the Case

• Patient was seen by

psychiatrist and trialed on VPA,

Lamictal, and Tegratol.

• Never able to entrain his sleep

cycle

• Lost to follow up for 4 years

4 years later

Sleep Log Data

0.00

8.00

16.00

24.00

32.00

40.00

Hours

Date

Cycle Length

0h 0m

120000h 0m

240000h 0m

360000h 0m

480000h 0m

Sat,Jul 22,2017

Tue,Jul 25,2017

Fri, Jul28,

2017

Mon,Jul 31,2017

Thu,Aug 3,2017

Sun,Aug 6,2017

Wed,Aug 9,2017

Sat,Aug12,

2017

Tue,Aug15,

2017

Fri,Aug18,

2017

Mon,Aug21,

2017

Thu,Aug24,

2017

Phase Delay

Sleep Statistics

Effects of Aripiprazole

• Two previous case reports

• Mechanism of action remains unknown

• Agonist of 5HT1

• Non Photic regulation of cycle

• Increases histamine production

• Wakefullness

• Inhibits GSK 3B

• Activates BMAL

• Reduces Circadian periodicity

Questions?