1. 1 Sleep Disorders Medicine In Psychiatry Alan B. Douglass MD, FRCPC, Dip. ABPN, Dip. Amer. Board of Sleep Medicine Asst. Professor, Dept of Psychiatry, University of Ottawa Medical Director, Sleep Disorders Service, Royal Ottawa Hospital

2. 2 Introduction A large proportion of insomnia cases involve elements of: Depression Anxiety Disorder Bipolar Disorder Current diagnostic reference – Internat’l Classification of Sleep Disorders (ICSD) Resembles DSM-IV-TR, but more specific diagnostic criteria

3. DSM-IV-TR

4. Sleep waveform schematic

5. Sleep Stage % by Age

6. Table of Stg. %Table of Stg. % Stg%

7. EEG TypeHz.Sleep Stg. Delta0.5 - 3SWS Theta3 - 7REM Alpha8 - 12Wake Beta16 - 25Wake Spindle12 - 14Stg. 2 - 4 Gamma20 - 50REM, wake EEG Frequencies

8. Table of Stg. %Table of Stg. % Wake => Sleep Transition R & K 1968 Wake => Sleep Transition

9. R & K 1968 Stage 2 Sleep

10. Stage 4 Sleep

11. Onset of REM R & K 1968 REM sleep onset

12. Sleep Histogram RL

13. 24-hr Sleepiness Profile

14. Multiple Sleep Latency Test (MSLT)

15. MSLT Sleep Restriction

16. REM Control Nuclei

17. SCN clock DA (+) Histamine (+) NA (+) 5HT (+) Orexin / Hypocretin Monoamines controlled by Orexin ~

18. REM Paralysis Control (from LDT / PPT)

19. Neurotransmitters in Sleep

20. Normal

21. Sleep Apnea

23. 23 OSA Clinical Symptoms

24. 24 Clinical Applicability – Apnea Sleep apnea and depression share clinical features; apnea can produce secondary depression Serious sleep apnea can cause sufficient sleep impairment to suggest dementia Serious snoring in demented patient could suggest treatable illness Apnea or PLMD can cause sleep deprivation, then relapse of mania or depression

25. Periodic Limb Movement Disorder

26. 26 RLS – PLMD: Sx and Tx SYMPTOMS Late evening / night Legs cramp, squirm, move by themselves Multiple awakenings “Charley Horses” Can’t tolerate legs being immobilized Majority elderly TREATMENT Check Fe, ferritin, B12, folate Dopamine agonists (L-DOPA, ropinirole, pramipexole) Benzodiazepines or opiates now 2 nd line Quinine obsolete

27. 27 RLS – PLMD: neurochemistry Likely due to iron deficiency in basal ganglia (Fe is co-factor in enzymes that synthesize DA). May predict onset of “syn-nuclein- opathies” (REM behaviour disorder, PSP, Parkinson’s, Lewy Body dementia).

28. Narcolepsy: age of onset Silber 2004, p.97.

29. Narcolepsy: night sleep

30. Narcolepsy: MSLT, SOREMs

31. Narcolepsy “Tetrad” True sleep attacks Falls asleep without warning, unusual situations Cataplexy Flaccid muscle paralysis; eyes and diaphragm OK; pt. remains awake but paralyzed. Hypnagogic / Hypnopompic hallucinations “Multimodal” – visual, tactile, auditory, smell. Often highly emotional, sexual, frightening Sleep Paralysis Awakes unable to move anything but eyes. Can’t breathe voluntarily or talk. HH often occur.

32. Narcolepsy Biology HUMANDOG Orexin / Hypo- cretin cells Destroyed by immune system Normal Orexin receptors NormalGenetic abnormality, inactive REM intrusion: (SP, Cataplexy) ++

33. Narcolepsy Treatment SLEEPINESS: Stimulants (noradrenaline receptor agonists): d-amphetamine (Dexedrine), methylphenidate (Ritalin), modafinil (Alertec). CATPLEXY: Antidepressants that increase serotonin and / or noradrenaline and block Ach.

34. Worm in lateral hypothalamus causing narcolepsy. (neurocysticercosis) J. Clin. Sleep Med. 1(1) 2005, p. 41.

35. 35 Polysomnographic Abnormalities In Psychiatric Patients

36. 36 Sleep Abnormalities in Psychiatry Benca, 1992 Meta-analysis of sleep in all major psychiatric disorders showed affective disorders had the largest and most consistent differences from controls. Kaneko, 1981 Extremely short nocturnal REM latency is common to both psychiatric disorders and narcolepsy

37. 37 Psychiatric Sleep Measurements Most polysomnographic measurements are the same as for a clinical study (“epoch”= 30 sec.): Sleep Latency (SL) – sleep onset measured as first three contiguous epochs of Stage 1 sleep REM Latency (RL) – time from sleep onset to first epoch of REM sleep REM Latency Minus Awake (RLMA) – RL subtracting any interposed epochs of wake Eye Movement Density in REM Sleep (REM Density, RD) – the actual number of eye movements divided by minutes spent in REM

38. 38 RL and RLMA REM Latency is shortened by the cholinergic agonists arecoline, pilocarpine, physostigmine Prolonged by anti-cholinergics (benztropine, trihexyphenidyl, diphenhydramine RL correlates inversely with age RLMA – superior statistical properties; smaller variance, more normal distribution

39. 39 MDD Long initial insomnia, early morning wakening Shallow sleep, easily awakened Non-refreshing sleep Antidepressants are REM suppressants Increase neurotransmission in serotonergic and adrenergic monoamine pathways REM is under tonic inhibition by monoamines Monoamine nuclei are under control of OREXIN from lateral hypothalamus

40. 40 MDD (cont) Some powerful sleep mechanism underlies the expression of depression Total sleep deprivation or selective REM deprivation dramatically improves mood of severely depressed patients Benefit lost after one night’s sleep or nap Amount of Non-REM sleep in nap predicts worsening of mood

41. 41 Alcoholism Acute administration of alcohol produces REM suppression, then: Withdrawal after chronic alcohol intoxication Actually REM sleep without physiological paralysis Hallucination – visual, gustatory, tactile dream- like imagery

42. 42 Narcolepsy versus Schizophrenia Narcolepsy Actually Daytime REM sleep intrusion Apparent “Schizophrenic” Hallucinations 90% aassociation of narcolepsy with a DNA fragment (DQB1*0602) allows “inverse” screening of schizophrenics for narcolepsy Narcolepsy is detectable in sleep lab (MSLT) but pt. must be medication-free for at least 3 weeks.

43. 43 Bipolar Disorder vs. Depression Excessive sleeping Crushing fatigue Extreme appetite “Atypical Depression” Actually Depressed Phase of Bipolar Disorder DDX: Narcolepsy, Idiopathic Hypersomnolence

44. 44 Bipolar Disorder (cont) “Switch process” from depression to mania often occurs at night Significantly reduced sleep on that night is often seen REM deprivation may be the key factor in the switch May also explain seasonal cyclicity of some bipolars (shorter sleep in Spring)

45. 45 Bipolar Disorder + Narcolepsy Apparent Schizophrenic Hallucinations Narcolepsy Bipolar Disorder + Actually Hypnagogic Hallucinations Narcolepsy gives mis-Dx: psychotic bipolar, schizo- affective

46. 46 REM Latency (RL) Short RL not specific for depression Seen also in schizophrenia, bipolar disorder, schizoaffective disorder, alcoholism, and borderline personality disorder Puzzle: RL abnormalities not correlated with any shared clinical feature of these illnesses Psychotic bipolar depression has the shortest RL values observed (10 – 40 min.)

47. 47 REM Latency (cont) MDD - Short RL, usually 80 minutes) Short RL predicts eventual successful antidepressant response in MDD Psychotic MDD patients have shorter mean RL than non- psychotic MDD Depression, schizophrenia – RL inversely correlated to symptom severity Bipolar – RL short in depressive phase RL abnormalities exist in relatives of bipolar patients Sleep abnormalities are state rather than trait markers – normalize with treatment

48. 48 Sleep Efficiency (SE) SE in MDD less than normals, but equal to insomniacs 75-150 mg doxepin qHS improves SE; mirtazepine also very effective SE also poor in schizophrenia Normalizes after adequate antipsychotic drug treatment

49. 49 Clinical Applicability Bipolar Mania - Initial insomnia is the most persistent symptom in treated bipolar patients, even when euthymic. Higher levels of mood stabilizer eliminate insomnia without need for sleep lab referral Alcohol Withdrawal DTs - REM rebounds strongly after cessation of drinking Absence of customary REM paralysis allows patient to act out dreams (similar to REM behavior disorder patients)

50. 50 Clinical Applicability Depressed Bipolar patient with hypersomnia (“atypical depression”) can be mistaken for Idiopathic Hypersomnolence, or even narcolepsy. Cataplexy is the key differential symptom – only present in narcolepsy

51. 51 Bipolar Disorder MDD patients typically have reduced night sleep but normal day alertness In depressed phase, Bipolars often have excess of sleep (18 hours/day), with crushing fatigue when awake Accompanied by ravenous appetite Termed “atypical depression” In the extreme, blends into catatonia