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
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
SLEEP WAKE CYCLE IN DEPRESSION PART I BASICS OF SLEEP-WAKE CYCLE PHYSIOLOGY
Modigliani
STUDING SLEEP & WAKEFULNESS SLEEP WAKEFULNESS/ALERTNESS POLYSOMNOGRAM (PSG) MULTIPLE SL TEST (MSLT) CLINICAL SCALES CLINICAL SCALES PITTSBURG (PSQQ) SLEEPINESS (EPWORTH) ATHENS (AIS) FATIGUE (FACIT)
PINEAL GLAND LIGHT/DARK SCN MELATONIN 12 0 12h 12 0 12h TEMPERATURE 12 0 12h SLEEP/WAKEFULNESS 12 0 12h CORTIZOL CIRCADIAN RHYTHMS
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)
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
SLEEP WAKE CYCLE IN DEPRESSION PART II IMPORTANCE OF SLEEP WAKE CYCLE IN DEPRESSION
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%)
INSOMNIA AS A RISK FACTOR FOR PSYCHIATRIC DISORDERS 18 16 Insomnia No Insomnia 14 12 10 8 6 4 2 0 Depression Anxiety Alcohol Abuse Drug Abuse
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
DEPRESSION : WAKEFULLNESS SYMPOMS ENERGY 94% CONCENTRATION 84% FATIGUE 73% SLEEPINESS 18%
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
SLEEP WAKE CYCLE IN DEPRESSION PART III SLEEP ARCHITECTURE & CICARDIAN ABERRATIONS IN DEPRESSION
Normal hypnogram awake movement REM stage 1 stage 2 stage 3 stage 4 0 1 2 3 4 5 6 7 8 REM latency 72min hours Sleep efficiency 95% (Actual sleep / time in bed)
Depressed patient Many awakenings awake REM stage 1 stage 2 stage 3 stage 4 baseline 0 1 2 3 4 5 6 7 8 9 Shortened REM latency More SWS in 2nd cycle S. Wilson, 2004
PSG FINDINGS IN DEPRESSION: I. SLEEP QUANTITY INDECES PROLONGED SLEEP LATENCY AWAKENINGS DURING THE NIGHT EARLY FINAL AWAKENING DECREASED TOTAL SLEEP TIME
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
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 4 0 10 20 30 Minutes 10 20 30 Mean SWS (Sleep stage 3 + 4) Quera Salva et al. Int J Neuropsychopharmacol. 2007; 10:691-696
Delta sleep EEG delta power units EEG delta power units 40 35 30 25 20 15 10 5 0 40 35 30 25 20 15 10 5 0 A B 0 60 120 180 240 300 360 420 480 minutes of sleep 0 60 120 180 240 300 360 420 480 minutes of sleep Wilson & Argyropoulos, 2004
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
Circadian Rhythms in Depression MELATONIN LEVELS (pg/ml) BODY TEMPERATURE ( C) CORTISOL LEVELS (ng/ml) 100 80 Ύπνος 37.2 37.0 Ύπνος 220 170 Ύπνος 36.8 60 36.6 120 40 36.4 70 36.2 20 6 9 12 15 18 21 24 3 6 9 36.0 7 9 11131517192123 1 3 5 7 9 1113 20 6 9 12 15 18 21 24 3 6 9 Ώρα controls Depressed Pts Adapted from Souetre et al., 1988, 1989
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
Bipolar vs. Unipolar Depression No significant differences in PSG recorded sleep parameters
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
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
SLEEP WAKE CYCLE IN DEPRESSION PART IV TREATMENT CONSIDERATIONS FOR SLEEP & WAKEFULNESS IN DEPRESSION
Sleep deprivation temporarily improves mood in depressed patients 30 25 Sleep deprivation Recovery sleep 20 Ham-D score 15 10 N=21 5 0 8.30am 8.30am 2.00pm 10.00pm 8.30am Day 1 Day 2 From Neumeister et al 1998 Arch Gen Psychiatry 55:167-172
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)
Effects of antidepressants on sleep early in treatment REM time REM latency Sleep efficiency TCAs or MAOIs SSRIs SNRIs Nefazodone - - Mirtazapine / - / -
DAYTIME SLEEPINESS (ANTIDEPRESSANTS VS PLACEBO) Physician s Desk Reference 2001 : Difference in prevalence of complaints (AD)
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
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 4 0 10 20 30 Minutes 10 20 30 Mean SWS (Sleep stage 3 + 4) Quera Salva et al. Int J Neuropsychopharmacol. 2007; 10:691-696
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 4 0 10 20 0 Cycle 1 Cycle 2 Cycle 3 Cycle 4 30 Minutes 10 20 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; 10:691-696
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