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BRAIN & MIND RESEARCH INSTITUTE
Using Circadian-based assessments and interventions to enhance treatments for mood disorders in young people
PROF IAN HICKIE AM MD FRANZCP FASSA PROFESSOR OF PSYCHIATRY | NHMRC Senior Professorial Research Fellow
Ian.hickie@sydney.edu.au
Disclosures: IH
› Health Services Innovations and Research (headspace) funded by the Australian Government
› Educational Seminars supported by Servier, Pfizer, AstraZeneca
› Research Supported by NHMRC, Private Foundations and Servier, Pfizer
› Work is also supported by Private Philanthropy, Private Foundations (Meers Foundation)
› Member of the Headspace Consortium (2006 - ) then Director of Headspace (independent company 2008-2012)
› University of Sydney, through the BMRI, operates two headspace sites – central sydney, campbelltown and is partner to central coast NSW
Depressive Disorders: highly heterogeneous, Multiple needs and complexities
› DSMness – major controversies re current categorical approach as basis for treatment selection
- Low reliability of DSM-5 category - Differential trajectories – age, stage, causation
› Major patient/user needs
- Daytime fatigue and function, good sleep - PREVENTING RECURRENCE
› Sequencing of Treatments and combinations of therapies
- Unrealistic expectations of single psychological or pharmacological therapies
Adolescent onset of major disorders
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Victorian State Government. Victorian Burden of Disease Study: Mortality and morbidity in 2001. Accessed 1/3/2010 http://www.health.vic.gov.au/healthstatus/bodvic/bod_current.htm
Twin modeling of adolescent onset of depression and anxiety
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Developmental
Circadian
Anxiety
Clusters & Dimensions Within Mood Disorders: Public success of major depression vs causal/ treatment specificity
Hypothetical Trajectories/Pathways to Adolescent-Onset Depressive Disorders
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The 24-hour light-dark cycle is the primary
environmental time cue that entrains the circadian system
we have adapted
(almost) to live on a 24-hour planet
Characteristics of a functioning clock Till Roenneberg ‘Internal Time’ 2012
› 1. Our body’s internal day is controlled by its own biological clock;
› 2. Since the biological clock is not 24 hours in length it must be periodically re-set to match the external world;
› 3. The biological clock varies from individual to individual (AND BY DISEASE STATE)!;
› 4. We feel best when all of our bodily functions oscillate in synchrony.
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24 hour sleep-wake and circadian system: studying mood and metabolic outcomes
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Circadian Systems drive health and behaviour
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Normal entrainment"
Circadian-based mood disorders
› 1. Disruption of the 24-hour sleep-wake and circadian systems as the fundamental biology
› 2. About 25-30% of clinical cases in young people
› 3. Novel Assessment Techniques – actigraphy, melatonin-onset assays
› 4. Targeted Interventions for depression – behaviourally on sleep-wake and pharmacologically on melatonin-analogues or arousal systems
› 5. Relevance of traditional medications – notably lithium (lengthens the circadian period)
› 6. Exploration of effects of other modalities on circadian periods (anticonvulsants and other mood stabilizers, modafinil etc)
Circadian-Depression:
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Phase Changes and Internal Desynchrony Hickie & Rogers, Lancet August 2011
Stereotypic Phenomena from disturbed circadian function
› Non-restorative sleep › Daytime fatigue (early morning prior to activity, daytime napping)
› Impaired cognition › Depressive symptoms – ‘atypical’ › Irritability › Light sleep, nightime ‘sweats’ › Musculoskeletal pain
Circadian-based Mood Disorder Phenotypes
› 1. MANIA – HYPOMANIA: HIGH ACTIVITY STATE
Secondary phenomena : ELEVATED MOOD DECREASED SLEEP – WEIGHT LOSS
› 2. FATIGUE – DEPRESSION; LOW ACTIVITY STATE
Secondary Phenomena: LOW MOOD/FATIGUE SLEEP WEIGHT GAIN
SWITCHING FROM ONE STATE TO ANOTHER UNDER A VARIETY OF CIRCUMSTANCES:
- 1. SEASONAL (LIGHT PERIODS) - 2. MEDICATION (STIMULANTS, ANTIDEPRESSANTS) - 3. OTHER CIRCADIAN OR SLEEP DISRUPTING STRESSORS (INFECTION,
SLEEP DEPRIVATION, SHIFT WORK, TRANSMERIDIEN TRAVEL)
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Mania-fatigue construct
A circadian-dysfunction model of age-dependent phenotypes leading to adolescent-onset mood disorders:
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Brain clock(s) - SCN develops with age
Genetic Effects: Chronotype stability,
switch sensitivity
Environmental effects: Varying with age & periods of activity & light exposure
Probable continuity of underlying genetic vulnerabilities
Multiple phenotypic expressions that also vary with age and development
1. Infancy: difficulty developing regular sleep or feeding patterns
2. Primary: difficulty with regularising sleep patterns, attentional issues, chaotic activity patterns
3. Early Adolescent: Emergence of persistent fatigue-oversleep, atypical mood disturbance, irritability, overeat-weight gain, periods of (nighttime) hyperactivity, insomnia, musculoskeletal pain, cognitive effects
4. Late Adolescent / Early Adult: Persistent fatigue / hypersomnia, atypical depression, hypomania / mania, weight gain / insulin resistance, chronic insomnia, cognitive deficits
Cohorts and Methodologies to test concepts
› 1. Informative Population Samples - Brisbane Longitudinal Study of Adolescent Twins (n=3500+) - NCS-A – Merikangas et al. (10,000+) - Young & Well CRC – tracking by technology
› 2.Family Studies: USA (Merikangas), Swiss (Presig)
› 3. Clinical Cohorts of Interest: BMRI-Based:
- Broad Phenotypes (2000+), Neurobiological Cohort (800+) › Sydney/Melbourne – Transitions study (850+), Fish oils
› 4. Reverse translation in relevant animal models
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Persistent fatiuge and depression in US adolescents
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DSM DISORDER Heritability (se) MANIA .79 (.09) *** Major Depression Disorder .58 (.20) *** Atypical Subtype .51 (.12) *** Non Atypical .19 (.05) * HYPOMANIA .31 (.07) *** TRAITS Negative Affectivity .58 (.09)*** Global Functioning .47 (.03)***
Heritability of Mood Disorders and Traits (Merikangas et al, Mol Psychiatry, in press)
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** p < .01 * p < .05
Brisbane Longitudinal Study of Adolescent Twins (from 1992, Ages 12-30, n= 3500)
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› Nick Martin & Naomi Wray – QIMR & QBI
Evaluating physical activity across species: Genetic & environmental effects, behavioural & pharmacological manipulations
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International Collaborations led by NIMH
BMRI
expertise
Recruiting young people – measuring clinical phenotypes, actigraphy and melatonin patterns
› 1. Preventing Progression to more Severe/Enduring Syndromes (Mania, Psychosis, Persistent Depression)
› 2. Enhancing Social, Economic and Education Participation › 3. Reducing Accidental Injury, Self-Harm & Suicidal Behaviour › 4. Reducing Alcohol and Other Substance Misuse, › 5. Enhancing Physical Health
- Smoking prevention and cessation
- Reducing Metabolic risk
- Enhancing physical activity
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Improving Outcomes for Young People with mood disorders who present for care
New Cohort Baseline Publications on these key issues
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Testing our Research Model of Pathways to Illness
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B) Treatment trials: 1. Treatment Response 2. Efficacy trials 3. Stepped care trials A) Longitudinal Assessment: By stage, by pathophysiology and by markers
Joe Takahashi – 1. What makes a good (robust) clock and 2. a good clock therapy? (ACNP-2012; and March, 2013)
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› 1. Robust Clock: Entrainment and Restoration after disturbance
› Non-entrainment and variability of young unipolar-bipolars (Robilliard et al JAD, 2013)
› 2. Good Circadian Therapy a. Behavioural Entrainment
0 5
10 15 20 25 30 35 40 45
5am to
6am
6am to
7am
7am to
8am
8am to
9am
9am to
10am
10am to
11am
11am to
12pm
12pm to
1pm
1pm to
2pm
2pm to
3pm
Control Unipolar Bipolar
Rest Offset Time
%
b. Pharmacology to reduce the variability in the timing of sleep-wake switch Lithium – lengthens period Melatonin/agomelatine to set offset Anti-orexins to end activation 50
60 70 80 90
100 110 120
Ctrl 1a 1b 2+
Varia
bilit
y in
Sle
ep
Offs
et T
ime
(SD
; min
)
Delayed Sleep Phase in Young People with unipolar and Bipolar Disorders
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Percentage (%) of individuals with sleep onset (left panel) and sleep offset (right panel) falling within specific 2-hour time intervals scores in healthy controls (Black, n = 20), patients with affective disorders emerging towards the unipolar (Blue, n = 48) or the bipolar (Red, n = 29) subtype.
Robillard R, Naismith SL, Rogers NL, Ip TKC, Hermens DF, Scott E, Hickie IB. Delayed sleep phase in young people with unipolar or bipolar affective disorders. Journal of Affective Disorders (2012)
Of the ‘bipolar’ group, 62% had a delayed sleep phase, a proportion significantly higher than that observed in the ’unipolar’ (30%, χ2 = 6.0, p = 0.014) or the control (10%, χ2 = 11.2, p < 0.001) groups
0
5
10
15
20
25
30
35
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9pm
9pm to
10pm
10pm to
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12am to
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1am to
2am
2am to
3am
3am to
4am
4am to
5am
Rest Onset Time
%
0
5
10
15
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25
30
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5am to
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11am to
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12pm to
1pm
1pm to
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2pm to
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Control Unipolar Bipolar
Rest Offset Time
%
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Clinical Staging – Neurobiological Evidence
Circadian Disturbances in Unipolar vs Bipolar Depression
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0
2
4
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17:30 18:00 18:30 19:00 19:30 20:00 20:30 21:00 21:30 22:00 22:30 23:00 23:30 0:00 0:30 1:06 1:30 2:00
Saliv
ary
Mel
aton
in (p
g/m
L)
Clock Time
Unipolar Bipolar
Threshold
Mean melatonin concentrations across the 8-hour protocol. Time points are averaged separately for each group: unipolar group (light grey; n=18) and bipolar group (dark grey; n=14).
Dim Light Melatonin Onset (DLMO)
Compared to the unipolar group, the bipolar group had: • Later DLMO (t = -2.2, p = 0.039) • Smaller melatonin AUC (U = 72.0, p = 0.040)
DLM
O
DLM
O
Two invited reviews of the key concepts: BMC Med 2013
31
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Stronger Evidence-base for selection of sequences of care: 1. Psychological/behavioural; 2. Pharmacological, 3. experimental
Depression Type Psychological / Behavioural Pharmacological Experimental
CBT, IPT, Problem-Solving SSRIs, SNRIs DCS
Oxytocin
Behavioural, Physical Activity Melatonin Fish Oils
Sleep-Wake Cycle Circadian-CBT Melatonin analogues Stimulants
Sleep Deprivation Therapy Lithium Modafinil
Anticonvulsants TMS/DBS
Ketamine
Problem-Solving Atypical Antipsychotics Oxytocin
Social Skills Training Stimulants Novel Neuropeptides
Cognitive Remediation Anticonvulsants Glutamate Regulation
Educational Fish Oils Dopamine Regulation
3. Developmental / Psychosis
1. Anxious-Depression
2. Circadian-Fatigue / Depression
1. Specific Response to treatment trials within types: do the nominated behavioural or pharmacological approaches reduce symptoms AND, concurrently change the key biometric measure of that type (typically n=50)?
Actigraphy and DLMO assay
BMRI Guide to Depression Management: Restoring Your Sleep-wake (Circadian) Cycle
Linking daily activity to the clock
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" has immediate effects on alertness and performance " suppresses nocturnal melatonin secretion " elevates core body temperature " increases alertness " increases neurobehavioural performance levels " has effects on the circadian system seen on subsequent days " shifts the timing of the circadian system " good to get bright light when wake up-tell the body it is ‘morning’ " try and avoid bright light before bedtime
light administration
Stabilising circadian rhythms and depression
Pharmacological Melatonin (not an an1depressant/no an1depressant ac1vity)1,2
Agomela1ne: agonist MT1/MT2 and antagonist 5-‐HT2C3
Helps resynchronise circadian rhythms in pa1ents with depression1,3,4-‐9
Lithium – lengthen period, inter-‐episode effects S1mulants and other vigilance agents Roles of other an1depressants – posi1ve or nega1ve Other Mood Stabilizers ???
1. Hickie I B & Roger N L The Lancet 2011;378:621-31 2. Srinivasan V et al World J Biol. Psychiatry 2006;7:138-151 3. Valdoxan Approved Product Information 4. Leproult R et al Clin Endocrinol. 2005;63:298-304 5. Kasper S et al Clin Psych. 2010;71(2):109-120 6. Lemoine P et al J Clin Psy ch. 2007;68:1723-1732 7. Redman J et al J Biol. Rhythm 1998;13:39-51 8. Armstrong S et al Pharm Biochemistry & Behav 1993;46:45-49 9. Boivin DJ et al Psych Neurosci. 2000:25:446-58
Melatonin Analogues
Conclusions – I
› 1. Clinical phenotypes (depressed mood/persistent fatigue) characterised by low activity, phase delay, later DLMO – though also considerable variability - “less robust”
› 2. The clinical subtype is particularly important in adolescents and young adults – in terms of likely prediction of illness progression to more severe adult phenotypes (including bipolar) and physical health complications
› 3. The childhood phenotypes that precede adolescent-onset depressed mood and fatigue are likely to be those of disrupted unstable sleep-wake cycles and inattention rather than anxiety.
› 4. Continuing to characterize the ways in which various pharmacologic (melatonin, melatonin analogues, lithium) or environmental interventions (circadian-based behaviour therapies) can be used to re-set, resynchronize or stabilize (i.e. make less sensitive to repeated disruption) these circadian-based phenomena
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