abnormal sleep pattern in a patient with bipolar disease
TRANSCRIPT
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?