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

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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

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Clinical Staging – Neurobiological Evidence

Circadian Disturbances in Unipolar vs Bipolar Depression

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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

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Two invited reviews of the key concepts: BMC Med 2013

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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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