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Professor
Jan Scott,
Newcastle
University,
UK
& Visiting
Professor,
NTNU,
Trondheim,
Norway.
NEUROPSYCHIATRY &
CHRONOBIOLOGY:
RHYTHM & BLUES
DISCLOSURES OF INTEREST
Interest Name of organization
Past honoraria/advisory
boards
AstraZeneca; BMS-Otsuka; Eli Lilly; GSK; Janssen-
Cilag; Lundbeck, Sanofi-Aventis
Recent grants Medical Research Council, UK;
RfPB, UK;
NHS Good Ideas (Darzi) Fund, UK;
MDF-Searle Legacy, UK;
Stanley Foundation, USA;
Independent Investigator Awards-
AstraZeneca; Janssen-Cilag; Johnson & Johnson Intl
Collaborators
contributing to this
presentation..
Alison Jackson, Colin Espie, UK
Geoffroy, Etain, Bellivier (Diderot), Paris
Ian Hickie et al, Brain & Mind Centre, Sydney,
Gunnar Morken & FRIENDS, NTNU
MY PROFESSORSHIP IN TRONDHEIM HAS
INCREASED MY PERSONAL INTEREST IN
CIRCADIAN RHYTHMS (CR)!
Trondheim 3 A.M. in the morning!!
Trondheim 3 P.M. in the afternoon!!
1. Circadian System.
2. Sleep- Wake Cycle.
3. Normal variations.
4. Sleep disturbances (circadian) & mental disorders (mood disorders).
5. Current project: identifying young people ‘at risk’ of mood disorders.
OUTLINE: FOCUS ON ‘HEADLINES’
NB: The slide set will be available by email
GENERATION OF CR & THEIR ROLE IN THE
REGULATION OF PHYSIOLOGY ( JAG ANNATH ET AL , 2 01 3 )
BIOLOGICAL TIME KEEPING….
The master clock is in the SCN
Communicate & entrain
peripheral clocks around the
body….
….Co-ordinated rhythmic
physiological outputs…
(~24 hour cycle)
(CBT core body temp.)
SCN=Suprachiasmatic Nuclei
SCN
CR: KEY FEATURES….AN OPEN SYSTEM
Evidence of misalignment e.g. sleep disturbance
is observed in ‘jet lag’ & shift workers…..many illnesses
Process C:
Endogenous self-
sustaining
pacemaker
Photic information
via the retina
Open system:
entrained by
environmental cues
TIMING & STRUCTURE OF THE SLEEP-WAKE CYCLE: 2 PROCESSES
Process S:
Sleep-wake
dependent aspect of
sleep regulation
Regulates duration &
structure of sleep
(e.g. stages 1-4)
Sleep pressure
increases during
wakefulness,
dissipates with sleep
Processes C & S normally operate in synchrony to maintain
wakefulness during the day & consolidate sleep at night.
HEALTHY: both circuits strong & self-stabilising.
During wakefulness (a), the monoaminergic nuclei
(red) inhibit the VLPO (which promotes sleep).
During sleep (b), VLPO neurons (GABA) inhibit
monoaminergic cell groups, (thereby reversing
their own inhibition). Orexin stabilizes the switch.
Direct mutual inhibition VLPO & monoaminergic
neurons= a classic flip-flop switch…producing
sharp transitions in state.
Homeostatic & Circadian systems influence switch.
The same principle applies to the circuitry controlling
transitions between REM & NONREM.
VLPO cell loss associated with sleep disturbances ORX orexin, VLPO ventrolateral preoptic nucleus,
LC, locus coeruleus; TMN, tuberomammillary nucleus.
Circadian alerting system
Homeostatic sleep drive
Circadian ‘hypnotic’ signal
THE FLIP FLOP SWITCH ( S LEEP - WA K E ; REM - NO NREM )
WAKE CENTRE INHIBITS SLEEP CENTRE (VICE VERSA)
HOURS SPENT IN WAKING, REM, & NREM STATES: VARIES WITH AGE
75 38 1
awake
awake
sleep
REM
NREM NREM
REM
sleep
sleep
NREM
REM
awake
years
2002 Allyn & Bacon, Baron et al
ACTIVITY ANALYSIS BY AGE (WITH PERMISSION MERIKANGAS ET AL, 2014)
Minute-to-minute activity
across 24 hours, averaged
across a 2 week period
Younger people are less active
on waking & more active later
in the day
DIFFERENT SLEEP-WAKE CYCLE
PATTERNS ARE OFTEN REFFERED
TO AS CHRONOTYPES…
MORNINGNESS/EVENINGNESS
(Languid/Rigid)
GEOFFROY…SCOTT ET AL 2014: SYSTEMATIC
REVIEW OF SEASONAL AFFECTIVE PATTERNS
51 studies:
32 of admissions, 6 of SAD, & 13 of symptom
dimensions.
Seasonal peaks observed:
Mania peaks spring/summer (2nd peak in autumn)
MDD peaks in early winter (2nd peak in summer)
Mixed episodes peak early spring or summer.
Seasonal Pattern ~15% Mania; ~25% Depression
Seasonal fluctuations mood & behaviour:
BD > UP > HC.
Some evidence of influence of climatic fluctuations
Longer Insolation/
More Sunshine Longer Day
Length
Higher Humidity/
Rainfall Higher
Temperature
Higher Barometric
Pressure
Total Sudies N=9 N=9 N=7 N=9 N=3
Findings 6+;2NS;1− 5+; 3NS;1− 4-; 3NS 7NS; 2+ 3NS
POTENTIAL LINKS TO NEUROPSYCHIATRY: KEY
PARAMETERS & INTER-RELATED SYSTEMS
Circadian Rhythms Phase Period Amplitude
Sleep Sleep stages Sleep latency
Hormones Cortisol
Neurobehavioral Function Subjective alertness & mood Objective performance (eg memory)
Phase
HEALTH CONSEQUENCES OF DISRUPTED
RHYTHMS & SLEEP
Health-related consequences of abnormal
entrainment or lack of synchronicity are
evident in ~80% of congenitally blind people,
jet-lag, & shift workers.
Loss of alertness, gastric distress, sleep & mood changes…
NB: SHIFT WORKERS
Metabolic & Coronary diseases…
Cancers…
Sleep disturbances &
mental disorders….
EPIDEMIOLOGY OF INSOMNIA: ASSOCIATIONS WITH
PHYSICAL & MENTAL HEALTH. THE HUNT-2 STUDY
(SIVERTSEN ET AL, 2009)
Od
ds R
ati
o (
log
ari
thm
ic s
ca
le)
ASSOCIATION MENTAL > PHYSICAL DISORDERS
ASSOCATION EXISTS FOR OTHER TYPES OF SLEEP PROBLEM…
U.S. NATIONAL COMORBIDITY SURVEY
(ROTH….KESSLER, 2006) Odds Ratio (95% CI)
Major Depression (MDD) 3.5 (2.8-4.4)
BD (I & II) 3.8 (2.6-5.4)
Any Mood Disorder 4.0 (3.2-5.1)
LARGE SCALE STUDIES OF SLEEP &
NEUROPSYCHIATRIC DISORDERS
Benca et al (1992): Meta-analysis of 177 studies (N>7000): sleep & mental disorders.
Changes in : sleep onset latency (SOL), total sleep time (TST),
sleep efficiency (SE), & REM/NREM in MDD.
Pigeon et al (2012): Meta-analysis of 39 studies (N~148,000): sleep disturbance
associated with x2 relative risk of suicidal behaviours (ideation,
attempts, suicide). Depression did NOT moderate association.
Stage 4 early,
REM later.
CR, SLEEP & DEPRESSION
Depression: REM
earlier (i.e. sleep
looks like control with
later sleep onset)
CR, SLEEP & DEPRESSION
ACTA PSYCH SCAND 2015
CLINICAL ASSESSMENT OF SLEEP; N>500
CR DISRUPTION & MANIC SYMPTOMS
IN BD (GONZALEZ ET AL, 2014)
Correlation: CR
& YMRS item
r p
Sleep –.68 <.001
Elevated mood –.13 .43
Increased motor activity & energy –.37 .015
Speech (rate & amount) –.39 .01
Language & thought disorder –.31 .05
Disturbances of thought content –.36 .02
Abbreviation: YMRS = Young Mania Rating Scale.
Correlation between CR (quotient) & YMRS score
SLEEP IN REMITTED BD: A META ‐ANALYSIS OF
ACTIGRAPHY STUDIES (GEOFFROY, SCOTT…ET AL, 2014)
LONGER: SOL & DURATION
INCREASED WASO
REDUCED SLEEP EFFICIENCY
PRODROMES OF MOOD DISORDERS
Prodrome: Early signs of an impending relapse (or 1st episode)– any behavioral, cognitive, & affective change that precedes an illness episode
Systematic review which critically examined all previous studies (Jackson, Cavanagh & Scott, JAD 2003):
Depression 82% <14
days
Sleep= the
commonest,
most
recognized
prodromal
symptom Mania 97%
>21
days
MOST CIRCADIAN PHENOTYPES OBSERVED
IN BD ARE HERITABLE
BD phenomenology
(?? aetiology)
major disruptions of circadian rhythms
most abnormalities seem heritable
underpinned by susceptibility genes
genes encoding proteins that are involved in these chronobiological processes
= putative candidate genes for BD
TRAIT ABNORMALITIES IN MELATONIN PATHWAY: RELATIVELY FEW STUDIES BUT CONVERGENT FINDINGS
For example:
Decreased serum melatonin
BD group < UP Depression & Controls (Lam, 1990; Kennedy, 1996)
BD-I:
(1) significantly lower melatonin levels during the night,
at baseline and following light exposure
(2) later peak time for melatonin at night (Nurnberger, 2000)
Normal melatonin secretion
Mela
ton
in
noon noon midnight
Controls
BD cases
ASMT mRNA
ASMT activity
( altered catabolism ?)
MELATONIN:
decreased amplitude
later peak
lower amount
Rare variations (3% BD v HC)
Frequent promoter variants in
Acetyl Serotonin Methyl Transferase gene (ASMT; 8 enzymes)
Carriers men, early onset, & +ve family history
TIMELESS
GSK3β
DBP
BHLHB 2-3
PPARGC1A
Benedetti
(2003,
2007)
Shi (2008)
Mansour
(2006)
Nievergelt
(2006)
Nievergelt
(2006)
Benedetti
(2008)
Kripke (2009)
Mansour et al
(2006)
Shi et al (2008)
Kishi (2008)
Kripke (2009)
Severino (2009)
Interaction
Shi (2008)
Benedetti (2004,
2005)
Szczepankiewicz
(2006)
Lachman (2007)
(Adapted from Ko et al., 2006; Bellivier, Scott et al, 2015)
CIRCADIAN GENES, BD &/or UP (e.g. CLOCK mRNA & Depression)
TIMELESS ‘TT/TC’ genotype correlates with
CSM-Evening type (b=-3.4, p =0.02)
CTI-Languid type (b=3.0, p =0.005)
RORA ‘GG’ genotype correlates with
CTI-Rigid type (b=-3.0, p =0.01)
Etain et al. 2013
TIMELESS & RORA GENOT YPES AND EVENING,
RIGID & LANGUID CHRONOT YPES
less diurnal alertness, more lethargic after reduced sleep
difficulties sleeping at irregular hours or going to bed early
Adapted from Harvey, Am J Psych, 2008
TIMELESS &
RORA variations
Evening, Rigid,
& Languid
(Lethargic)
Chronotypes
ASMT gene
variations
lower ASMT
activity
(& melatonin
dysregulation?)
MODEL OF INTERACTION BETWEEN CR,
SLEEP & MOOD DISORDERS
Links from CR disturbances &
Mood disorders….other health
consequences
INTERACTION BETWEEN CIRCADIAN CLOCK
GENES & METABOLIC GENES
(ALENGHAT ET AL, NATURE, 2004 )
Chromatin- complex of macromolecules; consists of DNA, protein (histones) & RNA. Functions incl. control of gene expression.
DISEASE PROGRESSION IN GENERAL
MEDICINE: CLINICAL STAGING MODELS
STAGE 0 STAGES 1a & 1b STAGE 2 STAGE 3 STAGE 4
Diagnostic
Threshold
Clinico-pathological boundaries between the stages
Biomarkers;
Intermediate
Phenotypes;
Genotypes
DEVELOPMENTAL TRAJECTORY OF BD…
(Clinical Staging, BJP, Scott et al, 2013)
STAGE 0 STAGE 1a STAGE 1b STAGE 2 OFTEN IDENTIFIED
AS OFFSPRING OF
BD PARENTS
Childhood Adolescence Early Adulthood
3 key findings:
• Even offspring of BD parents do not usually present with BD
• BD usually (but not always) evolves through non-specific childhood problems
(anxiety etc..) to mood symptoms, depression then to hypo(mania)
• Not all individuals who develop non-mood problems continue to the next ‘stage’
Diagramme adapted from Duffy et al, (2009)
DIM LIGHT MELATONIN ONSET IN SUB -SYNDROMAL (STAGE
1B) & SYNDROMAL (STAGE 2) MOOD DISORDERS IN YOUTH
0
5
10
15
20
25
30
35
40
45
50
-6.0 -5.5 -5.0 -4.5 -4.0 -3.5 -3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0 +0.5 +1.0 +1.5 +2.0
Sa
liva
ry m
ela
ton
in (
pic
oM
ola
r)
Time relative to habitual sleep time (hours)
Stage 1b
Stage 2+
Graph demonstrating reduced salivary melatonin data for
patients with Stage 1b (n=28) vs Stage 2 (n=16)
Naismith et al, Translational Psychiatry, 2013
Note: Habitual sleep onset is expected to occur at sample 0.
CIRCADIAN DISTURBANCES IN EMERGING AFFECTIVE
DISORDERS: ACTIGRAPHIC RECORDINGS OF SLEEP
ONSET & OFFSET ( RO B ILLARD … … … HIC K IE , 2 01 2 )
DELAYED SLEEP PHASE: 14% Control (n=20), 30% Unipolar (n=48), 62% BD (n=29)
TOTAL SLEEP TIME BD>UP>HC
Exaggerations of patterns in adolescents [worse in MALES]
0
5
10
15
20
25
30
35
40
45
8pmto
9pm
9pmto
10pm
10pmto
11pm
11pmto
12am
12amto
1am
1amto
2am
2amto
3am
3amto
4am
4amto
5am
Rest Onset Time
%
0
5
10
15
20
25
30
35
40
45
5amto
6am
6amto
7am
7amto
8am
8amto
9am
9amto
10am
10amto
11am
11amto
12pm
12pmto
1pm
1pmto
2pm
2pmto
3pm
Control
Unipolar
Bipolar
Rest Offset Time
%
IDS- Depressive Sx
CIRCADIAN RHYMTHICIT Y (SLEEP- ACTIVIT Y) IN YOUNG PEOPLE
WITH RECENT ONSET UP & BD (GRIERSON…..SCOTT, 2016)
Cases complete all
questionnaires
independent of diagnosis
CIRCADIAN RHY THMICIT Y (SLEEP - ACTIVIT Y) IN YOUNG PEOPLE
WITH RECENT ONSET UP & BD (GRIERSON…..SCOTT, 2016)
SUMMARY: INDICATORS OF CR
DYSREGULATION
Body Temperature
Endocrine Regulation
Autonomic Regulation
Metabolism
Melatonin
Sleep-Wake Cycle
Mood State
Psychomotor Activation
Sensori-motor Integration
Attention
Memory
MDD=phase advance; SAD= phase delay
SYMPTOMS
Rhythmicity
Diurnal Variation
Cyclicity
Rapid Cycling
SYNDROME
Periodicity
Recurrence eg Seasonal Affective Disorder
UNIPOLAR & BIPOLAR DISORDERS & CR
1. Endogenous self-sustaining pacemaker
2. System entrained to environmental cues/synchronizers
3. Process C & S in harmony.
4. FLIP FLOP switch.
Changes in mood, activation, attention...
THE TIMING & STRUCTURE OF THE SLEEP-WAKE CYCLE
Thank you
If you would like the slide
set please email:
Mental Disorders= Chronic Illnesses of Young People
PEAK AGE AT ONSET= 15-25 years
CHRONIC DISEASES ACCORDING TO AGE
STROKE &
DEMENTIA
CANCER
IHD
CR DYSREGULATION:
PREDISPOSING & PRECIPITATING FACTORS
FACTORS BIOLOGICAL PSYCHOLOGICAL
PROXIMAL
(Precipitating
Factors)
Season
Maturation/Aging
Hormonal status
Internal dysregulation: Physical illness
Primary sleep disorder
Changes in Temporal Order: Trans-meridian air travel (Jet lag)
Shift work
Social Rhythm Disrupting (SRD) Events:
Family, social, work disruptions
Breakdown/loss of social interactions, relationships
DISTAL
(Predisposing
Factors)
Genetic
Perinatal factors
CR Pacemaker: Abnormal period
Abnormal entrainment
Altered sensitivity &/or
response to Zeitgebers
Developmental: Repetitive early life stress
Negative &/or chaotic emotional environment
Increased sensitisation to negative life
events &/or personality style: High premorbid neuroticism
Learned helplessness
SCN Thalamus
Hypo-thalamus
REPRESENTATION OF CONNECTIONS
BETWEEN CR & OTHER SYSTEMS
Basal
Forebrain
Attention
Memory
Psychomotor
performance
Sensori-motor
integration
Emotion
Endocrine Regn
Body temperature
Autonomic Regn
Metabolism
Sleep-wake cycle
Melatonin
SCN=Suprachiasmatic Nuclei
CR & MOOD DISORDERS (MCCLUNG, 2013)
Correlations between age and sleep onset time
SLEEP-WAKE PATTERNS ACROSS EARLY STAGES OF NEUROPSYCHIATRIC
DISORDERS
Correlations between age and sleep offset time
SLEEP-WAKE PATTERNS ACROSS EARLY STAGES OF NEUROPSYCHIATRIC
DISORDERS
M E N TA L H E A LT H P R O B L E M S I N A D O L E S C E N T S W I T H D E L AY E D S L E E P P H A S E :
R E S U LT S F R O M A L A R G E P O P U L AT I O N ‐B A S E D S T U DY I N N O R WAY ( J S L E E P
R E S E A R C H , 2 01 4 )
Lifespan/Development
CIRCADIAN SYSTEM: IMPORTANT ELEMENTS
The circadian clock regulates sleep and other cognit ive functions, such as
memory and mood, in a sleep -dependent and sleep-independent manner.
Ageing is associated with reduced activity of the circadian system.
This can contribute to ageing & changes in sleep quality, memory and mood.
CIRCADIAN CLOCK REGULATES SLEEP,
COGNITIVE FUNCTIONS, MOOD, ETC
CIRCADIAN CLOCKS, BRAIN FUNCTION,
& DEVELOPMENT (FRANK ET AL, 2013)
EDGAR & MCCLUNG 2015
CIRCADIAN PHENOTYPES AS POTENTIAL
TRAIT MARKERS OF BD (BELLIV IER….SCOTT, 2015)
Early symptoms
Range of sample size
% Cases identifying
early symptoms
Median (%)
MDD
Mood change
Psychomotor symptoms
Increased anxiety
Sleep disturbance
Appetite change
Other
20-40
20-40
20-40
20-40
20
20
10-88
10-86
18-59
17-57
10-53
14-29
48
41
36
36
24
22
Mania Sleep disturbance
Psychotic [extreme behrs]
Mood change
Psychomotor symptoms
Other
Appetite change
Increase anxiety [arousal]
20-206
20-206
20-206
20-206
20
20-206
20-40
53-90
7-80
14-100
10-100
20-35
12-67
11-20
77
47
43
34
30
20
16
Data from: Molnar et al. (1988), Sclare & Creed (1990), Smith & Tarrier (1992), Lam & Wong (1997), Wong & Lam (1999)
SYSTEMATIC REVIEW (JACKSON, CAVANAGH & SCOTT,
2003): PRODROMAL SYMPTOMS
Median duration
<14 days
________
>21 days
82%
97%
• Symptoms that precede an illness episode, prevalence & duration
Early symptoms
(self-ratings)
% individuals
(median)
Bipolar
depression
Mood change
Psychomotor symptoms
Increased anxiety
Appetite change
Suicidal ideas/intent
Sleep disturbance
Other
48
41
36
36
29
24
22
Mania
Sleep disturbance
Psychotic [extreme behrs]
Mood change
Psychomotor symptoms
Other
Appetite change
Increase anxiety [arousal]
77
47
43
34
30
20
16
Data from: Molnar et al. (1988), Sclare & Creed (1990), Smith & Tarrier (1992), Lam & Wong (1997), Wong & Lam (1999)
SYSTEMATIC REVIEW OF PRODROMES JACKSON, CAVANAGH & SCOTT( JAD, JUNE 2003)
82%
97%
Median
Duration
<14
days
>21
days
APPROACHES TO CORONARY ARTERY DISEASE /
IHD…
Increased Risk: Family
history (clinical
examination, genetic
tests)
STAGE 0
(LATENCY OR ‘AT RISK’
STAGE)
Try to minimize risk, encourage
diet & exercise
Obesity, Smoking,
High Cholesterol
STAGE 1 Diet & Exercise plus STATINS
Increased Blood Pressure STAGE 2 Use ANTI-HYPERTENSIVES:
beta blockers
Angina STAGE 3 Use ANTI-ANGINA MEDICATIONS:
GTN
Heart Attack (Myocardial
Infarction)
STAGE 4
(LATE STAGE OR
END STAGE)
Surgery to insert Cardiac Stents
(to bypass damaged arteries)
Mesman et al, 2012
Follow-up of children of BD parents-
Latest publication examined course of illness in
adolescents up until early adulthood…
Repeated prospective assessment….
DEMONSTRATES DEVELOPMENTAL
TRAJECTORIES…
ONLY 1 CASES WHO DEVELOPED BD HAD NO
PRIOR DIAGNOSIS…….
(arrow from the white circle to the red circle…)
FOLLOW-UP YEAR
AGE OF ONSET OF BIPOLAR DISORDERS
0
5
10
15%
20
25
30%
PRE-
PUBERTAL <14 15-19 20-24 >=25 > 29
Age (years)
~50% onset
15-25 yrs
Can we predict
risk of early
onset
Stage 0 Increased risk but NO symptoms
Stage 1a Mild or non-specific symptoms; mild functional change or decline
Stage 1b Ultra high risk : moderate but sub-threshold symptoms (specific mood symptoms), and functional
decline
Stage 2 First episode of severe mood disorder (BD=MANIA)
Full threshold disorder with moderate to severe symptoms, possible neurocognitive deficits and
established functional decline
Stage 3 Incomplete remission from first episode of care
Recurrence or relapse
Multiple Recurrences
Stage 4 Severe, persistent or unremitting illness
HEURISTIC STAGING MODEL FOR MOOD DISORDERS:
SPLITTERS VS CLUMPERS ( M C G O R RY….BERK…. .H I C K I E…K A P Z I N S K I…DUFFY…. . . SCOTT….B R E I T Z K E . . )
CAUSE
or CONSEQUENCE
or COMPENSATORY
Sz=Schizophrenia; BD=Bipolar Disorder; MD=Major Depression
KNOWLEDGE
GAP
(McGorry, with
permission)
schizophrenia
EVOLUTION OF ‘ADULT’ BD – EARLY STAGES
ARE SIMILAR TO OTHER SEVERE MENTAL
DISORDERS….
Sleep
Disruption
Anxiety
Behaviour
Disruption
Depression
Childhood & Pre-pubertal Age groups ….
1. Presenting syndromes/problems show heterotypic continuity
2. Non-specific prediction of young adults with problems…
PUBERTY & ADOLESCENCE….risk syndromes have more predictive
validity
Staging Model of Selected Cancers: Tumour, Node, Metastasis… NOT just about post-onset duration…it captures extension within & across systems
STAGE TUMOR NODE METASTASIS
0 To No MO
IA T1 No MO
IB T2 No MO
II T3 No MO
IIIA T4 No MO
IIIB Any T No MO
IIIC Any T N1 MO
IVA Any T Any N MO
IVB Any T Any N M1
EXTENSION
SEVERITY
AT RISK
SLEEP ABNORMALITIES IN EPISODE= STATE MARKER
? TRAIT MARKER
Do sleep parameters differentiate-
‘At risk’ individuals from general population
Euthymic cases from healthy controls
• ? PREDICT EPISODE ONSET
Are sleep changes identified in the prodrome
i.e. precede episode onset
Are specific sleep parameters (type/severity) the key component of the relapse signature
i.e. precede onset of other prodromal symptoms
RELATIONSHIP BETWEEN MOOD
DISORDER & SLEEP
SELECTION OF STUDIES
DIAGNOSTIC CRITERIA-
At Risk Population: measures used in range of studies
Clinical Population: DSM IV criteria for BP
HEALTHY CONTROLS-
No personal or family history of ANY major mental disorders
MATCHED for age & gender with cases
ANALYSIS-
Instability is proposed to be a core vulnerability in BP
Studies estimated Group Means (SD) for sleep parameters &
intra-individual variability
KEY SLEEP PARAMETERS
Acti-watch worn for 7 consecutive days
Sleep Onset Latency
Sleep Duration
Sleep Efficiency
Sleep Fragmentation
Night Waking Time
SAMPLE
18-22 yrs- Hypomanic Personality Scale (Eckblad & Chapman, 1986)
High-scorers: elevated risk of BP & mood symptoms (Kwapil et al, 2000)
31 ‘AT RISK’ individuals v 24 ‘CONTROLS’ matched for age & gender
AT RISK POPULATION ANKERS & JONES (J CL PSYCHOL, OCT, 2009)
SLEEP
PARAMETERS
(Actigraphy)
HIGH RISK GROUP
(n=31)
Mean SD
CONTROLS
(n=24)
Mean SD
SIGNIF
(p)
7-DAY AVERAGE
Duration 6.8 hours 0.75 7.5 hours 0.6 0.01
Fragmentation 38% 11% 34% 9%
Efficiency 84% 7% 89% 4%
VARIANCE
Duration 1.5 hours 0.6 1.2 hours 0.5 0.01
Fragmentation 13% 6.5% 9% 5% 0.05
Efficiency 8% 7% 4% 2.5% 0.05
AT RISK POPULATION- KEY FINDINGS ANKERS & JONES (J CL PSYCHOL, OCT, 2009)
KEY SLEEP PARAMETERS
Established Self-Ratings eg Pittsburgh Scale, Internal State Scale
Acti-watch worn for 5 consecutive days & Self-Ratings-
Sleep Onset Latency
Sleep Duration
Sleep Efficiency
Sleep Fragmentation
Night Waking Time
SAMPLE
19 DSM IV cases of BP I disorder, euthymic > 3 months
19 ‘CONTROLS’ matched for age & gender
ANALYSIS
Intra-individual variability (& averages) CONTROLLING for MOOD symptoms
EUTHYMIC BP I CASES & CONTROLS MILLER, ESPIE & SCOTT (JAD, FEB, 2004)
SUBJECTIVE
RATINGS-SLEEP
PARAMETERS
BP I CASES (n=19)
Mean SD
CONTROLS (n=19)
Mean SD
SIGNIF (p)
AVERAGE
Duration 474 mins 113 412 mins 56 0.05
Onset Latency 41 mins 45 17 mins 11 0.005
Efficiency 86% 9% 89% 10% NS
VARIANCE
Duration 92 mins 63 56 mins 32 0.03
Onset Latency 31 mins 55 12 mins 14 0.03
Efficiency 12.5% 8.5% 7% 5.5% 0.02
BP I CASES & CONTROLS- KEY FINDINGS MILLER, ESPIE & SCOTT (JAD, FEB, 2004)
CLASSIFICATION: 84%
BP I CASES=15
CONTROLS= 17
MRC STUDY & JACKSON PHD : DAILY
MONITORING OF SYMPTOM VARIABILITY
Outpatients
Advocacy
group
Affective & Lithium Clinic
60 individuals
90 days monitoring &
15 months follow-up
AIMS: Feasibility & Acceptability
• Relationship of variability in symptoms & episodes
• Sequence of change in symptoms
LEVEL OF SLEEP VARIABILITY PREDICTS
ADMISSIONS
Median
days to
Admission
Cumulative
Admissions
Low Variability 1160 29%
High Variability 252 50% Time in days
146010957303650
Cu
mu
lative
Pro
ba
bili
ty o
f S
urv
iva
l
1.2
1.0
.8
.6
.4
.2
0.0
sleep efficiency
high variability
high-censored
low variability
low -censored
LOW HIGH
Sleep Variability
BP v Control
Effect
Size
Night Waking Time (mins) 0.9
Sleep Efficiency (%) 0.7
Fragmentation Index 0.9
Jackson, PhD, University of Glasgow, 2007
-0.3
-0.25
-0.2
-0.15
-0.1
-0.05
0
0.05
0.1
0.15
0.2
8 Nights Before Mood Change
7 Nights Before Mood Change
6 Nights Before Mood Change
5 Nights Before Mood Change
4 Nights Before Mood Change
3 Nights Before Mood Change
2 Nights Before Mood Change
Night Before Mood Change
Night of Mood Change
1 Night After Mood Change
2 Nights After Mood Change
3 Nights After Mood Change
4 Nights After Mood Change
5 Nights After Mood Change
6 Nights After Mood Change
Sleep and Mood Latency
CCF CCF
+2*SE
-2*SE
0
20
40
60
80
100
1 9
17
25
33
41
49
57
65
73
81
89
97
105
113
121
129
137
145
153
161
169
Days of Data
Mo
od
Rati
ng
0
4
8
12
16
20
24
Sle
ep
Du
rati
on
Mood
Sleep
USING CROSS- CORRELATION FUNCTIONS
TO EXPLORE RELATIONSHIPS OVER TIME
SLEEP CHANGE PREDICTED
DEPRESSION ONSET (N=20)
CR disruptions as measured by sleep abnormalities
at risk population
euthymic patients
prodrome of mood episodes
precede onset of other core symptoms
Predictive marker
Can monitor reliably & some factors modifiable
CONCLUSIONS
SLEEP CHANGE PREDICTED
(HYPO)MANIA ONSET (N=17)
CASE EXAMPLE: MOOD (IR)REGULARITY
PRIOR TO AN EPISODE
0
20
40
60
80
100
-60 -50 -40 -30 -20 -10 0 10
Days Before and After Episode
Moo
d
0
20
40
60
80
-60 -50 -40 -30 -20 -10 0 10
Days Before and After Episode
Moo
d
60 Days Before and Start of Depressed Episode
60 Days Before and Start of Manic Episode
Sig diff from equivalent 60 days of euthymia, M >> D
D
M
TIME SERIES PLOT OF ACTIGRAPHY RECORDINGS
OF NIGHT WAKING IN BIPOLAR DISORDER (BP)
Tick marks represent 7 day period
Actigraph estimation (across 82 nights)
Nigh
t wak
ing
in m
inut
es
480
420
360
300
240
180
120
60
0
SLEEP PARAMETERS Odds Ratio
(95% confidence
intervals)
INTER-INDIVIDUAL VARIATION
(Actigraphy)
Duration 0.96 (0.93, 0.99)
AVERAGE (Subjective Ratings)
Onset Latency 0.90 (0.82, 0.99)
Duration 0.98 (0.97, 1.00)
CLASSIFICATION: CASES V CONTROLS- MILLER, ESPIE & SCOTT (JAD, FEB, 2004)
CLASSIFICATION:
84%
BP I CASES=15
CONTROLS= 17
iMonitor Daily Ratings
USING PDAS TO MONITOR DAILY
SYMPTOMS
iMonitor Weekly Chart
0
10
20
30
40
50
60
70
80
90
100
W1 W2 W3 W4 W5 W6 W7 W8 W9 W10 W11 W12
Weeks
% (
0-1
00
VA
S)
Mania
Depression
Activation
Dysfunction
RESULTS vs healthy controls Sleep measures that don’t work for group studies
AVERAGED SLEEP MEASURES (~4 WEEKS):
BIPOLAR DISORDER V HEALTHY CONTROLS
(JACKSON & SCOTT)
Sleep variable Bipolar Disorder
M (SD) 95% CI General Population
M (SD) 95% CI Effect Size
p
Time in bed (min.)
543 (61) 508-578 499 (45) 467-530 0.8 0.064
Sleep duration (min.)
426 (84) 377-475 427 (33) 403-451 -0.01 0.977
Sleep latency (min.)
36 (26) 21-51 21 (17) 9-32 0.7 0.108
Night waking time (min.)
77 (37) 56-98 47 (24) 30-64 0.9 0.036
Sleep efficiency (%)
78 (12) 71-84 86 (6) 82-90 -0.7 0.047
Fragmentation index
39 (17) 29-49 25 (11) 17-33 0.9 0.034
AVERAGED SLEEP MEASURES (~4 WEEKS):
BIPOLAR DISORDER V HEALTHY CONTROLS
(JACKSON & SCOTT)
Sleep variable Bipolar Disorder
M (SD) 95% CI General Population
M (SD) 95% CI Effect Size
p
Time in bed (min.)
543 (61) 508-578 499 (45) 467-530 0.8 0.064
Sleep duration (min.)
426 (84) 377-475 427 (33) 403-451 -0.01 0.977
Sleep latency (min.)
36 (26) 21-51 21 (17) 9-32 0.7 0.108
Night waking time (min.)
77 (37) 56-98 47 (24) 30-64 0.9 0.036
Sleep efficiency (%)
78 (12) 71-84 86 (6) 82-90 -0.7 0.047
Fragmentation index
39 (17) 29-49 25 (11) 17-33 0.9 0.034
Miller, Scott & Espie (2003)- Actigraph variability in sleep duration signif diff (p<0.04)
KAPLAN-MEIER ANALYSIS OF ADMISSIONS IN
LOW AND HIGH SLEEP EFFICIENCY VARIABILITY
GROUPS (JACKSON, PHD)
Variability in Sleep
Efficiency*
Time to Admission
(days)
Cumulative Admissions
Low variability (N=7)
1126 15%
1240 29%
High variability (N=8)
40 12.5%
247 25%
252 37.5%
315 50%
*Similar result for variability in duration
Time in days
146010957303650
Cu
mu
lative
Pro
ba
bili
ty o
f S
urv
iva
l
1.2
1.0
.8
.6
.4
.2
0.0
sleep efficiency
high variability
high-censored
low variability
low -censored
LOW HIGH
CASE EXAMPLE: MOOD (IR)REGULARITY
PRIOR TO AN EPISODE
0
20
40
60
80
100
-60 -50 -40 -30 -20 -10 0 10
Days Before and After Episode
Moo
d
0
20
40
60
80
-60 -50 -40 -30 -20 -10 0 10
Days Before and After Episode
Moo
d
60 Days Before and Start of Depressed Episode
60 Days Before and Start of Manic Episode
Sig diff from equivalent 60 days of euthymia, M >> D
D
M
BIOLOGICAL TIME KEEPING:
MODEL OF PACEMAKER SYSTEM
Two major elements important for biological timekeeping: 1. Endogenous self-sustaining pacemaker
2. System for entrainment to environmental cue/synchronizer
Entrainment Pathway + Clock Output Pathway
taken from Principles & Practice of Sleep Medicine, 2005
DELAYED SLEEP PHASE
SLEEP
CIRCADIAN PHYSIOLOGY OVERVIEW
~24 hour rhythms are observed in eg.
core body temperature, hormone concentrations, subjective alertness, objective performance & other physiology
Suprachiasmatic Nuclei (SCN) is necessary & sufficient for Circadian Rhythm (CR) expression
Observed rhythms in these functions result from endogenous (circadian) and exogenous (evoked)factors
evoked or masking influences include light levels, meals, activity levels
Symptoms of misalignment are observed in eg.
‘jet lag’, & shift workers (cardiovascular, hormonal, gastro -intestinal & neuro-behavioural abnormalities)
