Sleep Wake Cycle in Depression

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1 Sleep Wake Cycle in Depression Constantin R. Soldatos Professor of Psychiatry & Founder of Sleep Study Center Eginition Hospital University of Athens Lecture in Suzdal School, 20/04/2013

2 SLEEP WAKE CYCLE IN DEPRESSION LECTURE OUTLINE I. BASICS OF SLEEP-WAKE CYCLE PHYSIOLOGY II. IMPORTANCE OF SLEEP WAKE CYCLE IN DEPRESSION III. IV. SLEEP ARCHITECTURE & CIRCARDIAN ABERRATIONS IN DEPRESSION TREATMENT CONSIDERATIONS FOR SLEEP & WAKEFULNESS IN DEPRESSION

3 SLEEP WAKE CYCLE IN DEPRESSION PART I BASICS OF SLEEP-WAKE CYCLE PHYSIOLOGY

9 Modigliani

10 STUDING SLEEP & WAKEFULNESS SLEEP WAKEFULNESS/ALERTNESS POLYSOMNOGRAM (PSG) MULTIPLE SL TEST (MSLT) CLINICAL SCALES CLINICAL SCALES PITTSBURG (PSQQ) SLEEPINESS (EPWORTH) ATHENS (AIS) FATIGUE (FACIT)

14 PINEAL GLAND LIGHT/DARK SCN MELATONIN h h TEMPERATURE h SLEEP/WAKEFULNESS h CORTIZOL CIRCADIAN RHYTHMS

15 CICARDIAN RHYTHMS: SUBSTRATES MASTER BIOLOGICAL CLOCK IS THE SUPERCHIASMATIC NUCLEUS (SCN) SCN IS SYNCHRONIZED TO THE LIGHT-DARK CYCLE (VIA RETINA) NOCTURNAL SYNTHESIS OF MELATONIN IN THE PINEAL IS DRIVEN BY THE SCN OTHER CIRCADIAN RHYTHMS ARE DRIVEN BY OTHER BIOL. CLOCKS INFLUENCED BY OTHER SUNCHRONIZERS (e.g. food intake for the liver)

16 SLEEP- WAKE CYCLE : HOW IS IT DRIVEN? ENDOGENOUS (FREE RUNNING) CICARDIAN RHYTHM ABOUT 24HOUR PERIOD NATURAL (SYNCHRONIZED) EVERY 24 HOURS UNDER THE INFLUENCE OF TIME-GIVERS MAIN ONE DAY/NIGHT, i.e. LIGHT/DARKNESS ACTUAL (COMPLEX CONTROL) TWO PROCESS MODEL {PROCESS C PROCESS S} OTHER MODELS

19 SLEEP WAKE CYCLE IN DEPRESSION PART II IMPORTANCE OF SLEEP WAKE CYCLE IN DEPRESSION

22 DEPRESION & POOR SLEEP SLEEP COMPLAINTS IN MAJORITY OF DEPRESSED PATIENTS (50-90%) MOST COMPLAINTS OF INSOMNIA, SOME OF HYPERSOMNIA, OR BOTH MANY INSOMNIACS ARE FOUND TO BE DEPRESSED (>20%)

23 INSOMNIA AS A RISK FACTOR FOR PSYCHIATRIC DISORDERS Insomnia No Insomnia Depression Anxiety Alcohol Abuse Drug Abuse

24 CLINICAL COURSE OF DEPRESSION: VALUE OF SLEEP DISTURBED SLEEP CORRELATED WITH a) NEW-ONSET OF MAJOR DEPRESSION b) PERSISTENCE OF DEPRESSIVE SYMPTOMS c) RECURRENCE OF DEPRESSION FOLLOWING SUCCESSFUL RX

25 DEPRESSION : WAKEFULLNESS SYMPOMS ENERGY 94% CONCENTRATION 84% FATIGUE 73% SLEEPINESS 18%

26 DAYTIME SLEEPINESS IN DEPRESSION : CONSEQUENCES FEELINGS OF DYSPHORIA WORK EFFICIENCY SOCIAL FUNCTIONS USE OF CAFEINE / NICOTINE QUALITY OF LIFE RESPONSE TO TREATMENT COMPLIANCE TO TREATMENT RELAPSE RATE

27 SLEEP WAKE CYCLE IN DEPRESSION PART III SLEEP ARCHITECTURE & CICARDIAN ABERRATIONS IN DEPRESSION

28 Normal hypnogram awake movement REM stage 1 stage 2 stage 3 stage REM latency 72min hours Sleep efficiency 95% (Actual sleep / time in bed)

29 Depressed patient Many awakenings awake REM stage 1 stage 2 stage 3 stage 4 baseline Shortened REM latency More SWS in 2nd cycle S. Wilson, 2004

30 PSG FINDINGS IN DEPRESSION: I. SLEEP QUANTITY INDECES PROLONGED SLEEP LATENCY AWAKENINGS DURING THE NIGHT EARLY FINAL AWAKENING DECREASED TOTAL SLEEP TIME

31 PSG FINDINGS IN DEPRESSION II. SLEEP STAGES REDUCED SLOW WAVE SLEEP MANY STAGE SHIFTS SHORT REM LATENCY MORE REM EARLY IN THE NT INCREASED REM DENSITY LOWER DELTA ACTIVITY IN THE 1 ST THAN THE 2 ND SLEEP CIRCLE YET, NO SINGLE PSG ABERRATION SPECIFIC FOR DEPRESSION

32 SLEEP ARCHITECTURE IN DEPRESSION Wake REM sleep Stage 1 Stage 2 SWS Stage 3 SWS Stage 4 0 NORMAL CONTROLS Cycle 1 Cycle 2 Cycle 3 Cycle 4 Minutes DEPRESSED PTS Cycle 1 Cycle 2 Cycle 3 Cycle Minutes Mean SWS (Sleep stage 3 + 4) Quera Salva et al. Int J Neuropsychopharmacol. 2007; 10:

33 Delta sleep EEG delta power units EEG delta power units A B minutes of sleep minutes of sleep Wilson & Argyropoulos, 2004

34 DEFICIENCY OF PROCESS S: CONSEQUENCES WEAKNESS OF SW PROPENSITY LEADING TO DECREASED NREM SLEEP AWAKENINGS DURING THE NIGHT & EARLY FINAL AWAKENING ARE DUE TO EARLY EXAUSTION OF NREM SLEEP FAST & SHORT LASTING ANTIDEPRESSANT EFFECT OF SLEEP DEPRIVATION IS DUE TO TEMPORARY BOOST OF SW

35 Circadian Rhythms in Depression MELATONIN LEVELS (pg/ml) BODY TEMPERATURE ( C) CORTISOL LEVELS (ng/ml) Ύπνος Ύπνος Ύπνος Ώρα controls Depressed Pts Adapted from Souetre et al., 1988, 1989

36 MECHANISMS FOR SLEEP ABERRATION IN DEPRESSION: MAJOR HYPOTHESES 1. IMBALANCE BETWEEN MONOAMINERGIC AND CHOLINERGIC SYSTEMS IN CNS 2. INCREASED REM PRESSURE 3. HPA AXIS DUSREGULATION 4. DEFICIENCY OF HOMEOSTATIC PROCESS (S) IN ITS INTERACTION WITH CICARDIAN PROCESS (C) 5. MISPLACEMENT OF THE PHASE AND DECLINE OF AMPLITUDE OF PROCESS C

37 Bipolar vs. Unipolar Depression No significant differences in PSG recorded sleep parameters

38 Sleep disturbance in mania Sleep is difficult to study Sleep is more curtailed than in depression REM sleep abnormalities are similar to depression and equally frequent No reduction of slow wave sleep percentage, however

39 Sleep in Bipolar Disorder: Abnormalities persist REM sleep abnormalities persist in euthymia A high percentage of the euthymic pts. with bipolar disorder exhibit a clinically significant sleep disturbance There is evidence that sleep abnormalities are trait markers of the disorder

40 SLEEP WAKE CYCLE IN DEPRESSION PART IV TREATMENT CONSIDERATIONS FOR SLEEP & WAKEFULNESS IN DEPRESSION

41 Sleep deprivation temporarily improves mood in depressed patients Sleep deprivation Recovery sleep 20 Ham-D score N= am 8.30am 2.00pm 10.00pm 8.30am Day 1 Day 2 From Neumeister et al 1998 Arch Gen Psychiatry 55:

42 NON-PHARMACOLOGICAL TREATMENT OF DEPRESSION MANIPULATIONS OF SLEEP- WAKE CYCLE SLEEP DEPRIVATION SLEEP PHASE ADVANCE BRIGHT LIGHT THERAPY PSYCHOTHERAPEUTIC/ PSYCHOSOCIAL INTERVENTIONS COGNITIVE BEHAVIORAL THERAPY (CBT) INTERPERSONAL SOCIAL RHYTHM THERAPY (IPSRT)

43 Effects of antidepressants on sleep early in treatment REM time REM latency Sleep efficiency TCAs or MAOIs SSRIs SNRIs Nefazodone - - Mirtazapine / - / -

44 DAYTIME SLEEPINESS (ANTIDEPRESSANTS VS PLACEBO) Physician s Desk Reference 2001 : Difference in prevalence of complaints (AD)

45 DRUG Rx OF DEPRESSION: RE TO S/W CYCLE EFFECTIVE ANTIDEPRESANT DRUGS ACT THROUGH CNS NEUROTRANSMITTER SYSTEMS INVOLVED IN S/W REGULATION MOST OF THEM REM SLEEP & REML SOME ARE ENERGIZERS ( INSOMNIA) SOME ARE SEDATIVES ( SLEEPINESS) AGOMELATINE ADVANCES CIRCADIAN PHASE, INCREASING SLEEPINESS AT NIGHT WITHOUT NEXT DAY RESIDUAL EFFECTS NOR ANY COMMON S.E. OF OTHER A/D (MT1 AND MT2 receptor agonist, 5- HT2c receptor antagonist). MOREOVER, THROUGH ITS S/W CYCLE SYNCRONIZING EFFECTS IMPROVES REMISSION & MINIMIZES RELAPSES

46 SLEEP ARCHITECTURE IN DEPRESSION Wake REM sleep Stage 1 Stage 2 SWS Stage 3 SWS Stage 4 0 NORMAL CONTROLS Cycle 1 Cycle 2 Cycle 3 Cycle 4 Minutes DEPRESSED PTS Cycle 1 Cycle 2 Cycle 3 Cycle Minutes Mean SWS (Sleep stage 3 + 4) Quera Salva et al. Int J Neuropsychopharmacol. 2007; 10:

47 SLEEP ARCHITECTURE: EFFECTS OF AGOMELATINE Wake REM sleep Stage 1 Stage 2 SWS Stage 3 SWS Stage 4 NORMAL CONTROLS Minutes DEPRESSED PATIENTS TREATED WITH AGOMELATINE 25mg Cycle 1 Cycle 2 Cycle 3 Cycle Cycle 1 Cycle 2 Cycle 3 Cycle 4 30 Minutes Mean SWS (Sleep stage 3 + 4) 30 Baseline After 6 weeks ** P<0.05 versus Cycle 4 Quera Salva et al. Int J Neuropsychopharmacol. 2007; 10:

48 TAKE HOME MESSAGES 1. SLEEP ARCHITECTURE & SLEEP WAKE CYCLING ARE UNDER NEUROENDOCRINE CONTROL 2. MELATONIN SECRETION DRIVEN BY LIGHT DARK ALTERATIONS PLAYS CARDINAL ROLE IN SLEEP- WAKE CYCLING 3. DISTRURBED SLEEP AND WAKEFULNESS ARE IMPORTANT FEATURES AMONG THE CLINICAL CHARACTERISTICS OF DEPRESSION 4. SLEEP WAKE CYCLE ABERRATIONS MAY BE USEFULL IN UNDERSTANDING THE PATHOPSYSIOLOGICAL MECHANISMS IN DEPRESSION. 5. CHANGES IN SLEEP WAKE CYCLING MAY HAVE THERAPEUTIC IMPLICATIONS IN DEPRESSION 6. ANTIDEPRESSANT DRUGS EFFECTS ON SLEEP WAKE CYCLE ARE USUALLY UNWANTED. 7. AGOMELATINE IS AN EFFICATIOUS ANTIDEPRESSANT AND IT REGULARISES THE SLEEP WAKE CYCLE

Circadian rhythm and Sleep. Radwan Banimustafa MD

Circadian rhythm and Sleep. Radwan Banimustafa MD Circadian rhythm and Sleep Radwan Banimustafa MD Homeostasis Maintenance of equilibrium by active regulation of internal states: Cardiovascular function (blood pressure, heart rate) Body temperature Food