Sleep and Psychiatric Disorders: Your Molecular Clock is Ticking

Transcription

1 Sleep and Psychiatric Disorders: Your Molecular Clock is Ticking (page 281 in syllabus) Stephen M. Stahl, MD, PhD Adjunct Professor, Department of Psychiatry University of California, San Diego School of Medicine Honorary Visiting Senior Fellow, Cambridge University, UK Sponsored by the Neuroscience Education Institute Additionally sponsored by the American Society for the Advancement of Pharmacotherapy This activity is supported solely by the sponsor, Neuroscience Education Institute.

2 Individual Disclosure Statement Faculty Editor / Presenter Stephen M. Stahl, MD, PhD, is an adjunct professor in the department of psychiatry at the University of California, San Diego School of Medicine, and an honorary visiting senior fellow at the University of Cambridge in the UK. Grant/Research: AstraZeneca, BioMarin, Dainippon Sumitomo, Dey, Forest, Genomind, Lilly, Merck, Pamlab, Pfizer, PGxHealth/Trovis, Schering-Plough, Sepracor/Sunovion, Servier, Shire, Torrent Consultant/Advisor: Advent, Alkermes, Arena, AstraZeneca, AVANIR, BioMarin, Biovail, Boehringer Ingelheim, Bristol-Myers Squibb, CeNeRx, Cypress, Dainippon Sumitomo, Dey, Forest, Genomind, Janssen, Jazz, Labopharm, Lilly, Lundbeck, Merck, Neuronetics, Novartis, Ono, Orexigen, Otsuka, Pamlab, Pfizer, PGxHealth/Trovis, Rexahn, Roche, Royalty, Schering-Plough, Servier, Shire, Solvay/Abbott, Sunovion/Sepracor, Valeant, VIVUS, Speakers Bureau: Dainippon Sumitomo, Forest, Lilly, Merck, Pamlab, Pfizer, Sepracor/Sunovion, Servier, Wyeth

3 Learning Objectives Recognize the relationship between circadian rhythms and psychiatric disorders Understand the pharmacological basis of circadian rhythms in depression Review the clinical evidence of therapeutic approaches to resetting circadian rhythms in depression and thus improve the symptoms of depression

4 Pretest Question 1 Anne is a 34-year-old patient with major depressive disorder. Currently, her chief complaint is that she is not sleeping well. Patients with depression often have altered circadian rhythms, as is evident by: 1. Sleep-wake phase changes 2. Altered melatonin levels 3. Altered body temperatures 4. Changes in neurogenesis 5. Altered cortisol levels 6. All of the above

5 Pretest Question 2 Michael is a 45-year-old patient with bipolar disorder. Genetic testing would likely reveal polymorphisms or abnormal expression of which clock genes? 1. Per 2. Cry 3. Both of the above

6 Pretest Question 3 Sasha is a 58-year-old patient with a history of depression. She is currently taking agomelatine and is undergoing estrogen replacement therapy for perimenopausal symptoms. At the present time, she is relatively free of depressive symptoms, likely due in part to: 1. Binding of agomelatine to melatonin receptors in the SCN 2. Binding of agomelatine to 5-HT 2C receptors in the SCN 3. Binding of estrogen to estrogen receptors in the SCN 4. All of the above

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11 Zeitgebers External cues to synchronize circadian rhythms Light Melatonin Eating and drinking patterns Social interactions Van Someren EJW et al. Sleep Med Rev 2007;11(6):

12 Suprachiasmatic Nucleus (SCN) Retinohypothalamic Tract

13 Suprachiasmatic Nucleus (SCN) Pineal Gland (melatonin) Retinohypothalamic Tract

14 Suprachiasmatic Nucleus (SCN) Pineal Gland (melatonin) Retinohypothalamic Tract

15 Receptors Expressed in the SCN Melatonin receptors 5-HT 2C receptors Estrogen receptors Carlson LL et al. Endocrinol 1989;125(5):2670-6; Weaver DR et al. NeuroRep 1996;8(1):109-12; Moyer RW et al. Neurosci Lett 1999;271(3):147-50; Kruijver FPM, Swaab DF. Neuroendocrinol 2002;75:

16 Expression Levels Circadian Rhythmic Expression of MT 1 and 5-HT 2C Receptors Expression Levels MT 1 5-HT 2C Masana MI et al. J Pineal Res 2000;28(3):185-92; Holmes MC et al. J Neurosci 1997;17(11):

17 Melatonin Excretion 5-HT 2C Receptors Affect Melatonin Release 5-HT 2C antagonist Control noon 6 pm midnight 6 am noon 6 pm midnight 6 am Kennaway DJ et al. Brain Res 2001;897(1-2):36-43.

18 Melatonin Excretion 5-HT 2C Receptors Affect Melatonin Release 5-HT 2C antagonist Control noon 6 pm midnight 6 am noon 6 pm midnight 6 am Kennaway DJ et al. Brain Res 2001;897(1-2):36-43.

19 Melatonin Excretion 5-HT 2C Receptors Affect Melatonin Release 5-HT 2C antagonist Control noon 6 pm midnight 6 am noon 6 pm midnight 6 am Kennaway DJ et al. Brain Res 2001;897(1-2):36-43.

20 Melatonin Excretion 5-HT 2C Receptors Affect Melatonin Release 5-HT 2C antagonist Control noon 6 pm midnight 6 am noon 6 pm midnight 6 am Kennaway DJ et al. Brain Res 2001;897(1-2):36-43.

21 A Broken Circadian Clock Phase changes Changes in neurogenesis Altered body temperature Altered melatonin Altered cortisol Depression and Other Mood Disorders Bechtold DA et al. Trends Pharmacological Sci 2010;31(5):191-8.

22 Desynchronization of the Molecular Clock

23 Desynchronization of the Molecular Clock Shift work

24 Desynchronization of the Molecular Clock Shift work Clock genes Period ROR 9 3 CLOCK 6 REV-ERB Bmal1 Cry

25 Desynchronization of the Molecular Clock Shift work Mutated Clock genes

26 Desynchronization of the Molecular Clock Shift work Neurotransmission prefrontal cortex 12 NE DA 9 3 NE GABA interneurons DA 6 5-HT 5-HT Mutated Clock genes 5-HT brainstem neurotransmitter centers

27 Desynchronization of the Molecular Clock Shift work Impaired Neurotransmission prefrontal cortex 12 NE DA 9 3 NE GABA interneurons DA 6 5-HT 5-HT Mutated Clock genes 5-HT brainstem neurotransmitter centers

28 Diseases Linked to a Broken Clock 12 Cancer Schizophrenia 9 3 6

29 90% of Depressed Patients Complain of Poor Sleep Quality Healthy Control Depression Phase Delay sleep sleep 7 am 11 pm 7 am 11 pm 7 am Stahl SM. Stahl s Essential Psychopharmacology. 3rd ed. Cambridge University Press 2008; Dallaspezia S, Benedetti F. Neurother 2011;11(7):

30 HAMD Score Severity of Depression Correlates With Severity of Phase Delay Severity of Phase Delay r s = 0.61, P=0.01 Emens J et al. Psychiatry Res 2009;168(3):259-61; Lewy AJ et al. J Biol Rhythms 1999;14(3):

31 Neurogenesis Circadian Rhythm of Neurogenesis Hippocampal neurogenesis Learning and memory 6 am noon 6 pm midnight 6 am noon Aimone JB et al. Trends Cognitive Sci 2010;14(7):325-37; Holmes MM et al. J Neurosci Res 2004;76(2):

32 Decreased Neurogenesis in Depression Brain-derived neurotrophic factor (BDNF), a protein that increases neurogenesis, is decreased in patients with depression Hippocampal volume is decreased in patients with depression Patients with depression exhibit prominent deficits in memory Cognitive capacity depends on the function of the hippocampus Chronic or severe stress is strongly associated with depression and correlates with the disruption of hippocampusdependent memory Acheson A et al. Nature 1995;374(6521):450-3; Warner-Schmidt JL, Duman RS. Hippocampus 2006;16(3):239-49; Zakzanis KK. Neuropsychiatry, Neuropsychol, Behav Neurol 1998;11(3):127-35; Squire LR et al. Annu Rev Neurosci 2004;27: ; Pittenger C, Duman RS. Neuropsychopharmacol 2008;33(1):

33 Melatonin (pg/ml) Cortisol (ng/ml) Body Temperature ( C) Physiological Measurements of Circadian Rhythms Are Altered in Depression Healthy Depression am noon 6 pm midnight 6 am noon Souȇtre E et al. Psychiatry Res 1989;28(3):

34 Transcription Factors Involved in the Molecular Clock ROR 9 3 CLOCK 6 Period Cry REV-ERB Bmal1 DNA Promoter Gene

35 9 3 6 E E CLOCK (circadian locomotor output cycles kaput) BMAL1 (brain and muscle ARNT-like-1) E PER (period) CRY (cryptochrome) E REV-ERB ROR (retinoic acid-related orphan receptor) E Box response element ROR/REV-ERB response element RRE

36 9 3 6 E E CLOCK (circadian locomotor output cycles kaput) BMAL1 (brain and muscle ARNT-like-1) E PER (period) CRY (cryptochrome) E REV-ERB ROR (retinoic acid-related orphan receptor) E Box response element ROR/REV-ERB response element RRE

37 E E CLOCK (circadian locomotor output cycles kaput) BMAL1 (brain and muscle ARNT-like-1) E PER (period) CRY (cryptochrome) REV-ERB RRE ROR (retinoic acid-related orphan receptor) E E Box response element ROR/REV-ERB response element

38 Clock Genes Associated With Psychiatric Disorders Clock Gene Disorder References Bmal Bipolar Mansour et al. 2006; Nievergelt et al Clock (or its homolog, NPAS) Bipolar Benedetti et al. 2003; Soria et al Cry Depression Soria et al Schizophrenia Takao et al Seasonal affect disorder Johansson et al. 2003; Partonen et al Depression Soria et al Per Bipolar Nievergelt et al. 2006; Artioli et al. 2007; Mansour et al Depression Artioli et al Schizophrenia Mansour et al Seasonal affect disorder Partonen et al Rev-erb Bipolar Kripke et al. 2009; Severino et al

39 Clock Genes Are Altered in Depression Healthy Control Patient With Depression Gouin JP et al. J Affective Disord 2010;126(1-2):161-6.

40 % of Control Fluoxetine Alters Expression of Clock Genes * * * * Per1 Per2 Per3 Clock Bmal1 Cry1 Cry2 * p< 0.05 Uz T et al. Neuroscience 2005;134:

41 Does a Broken Circadian Clock Lead to Depression? Circadian rhythms regulate sleep-wake cycles; altered sleep cycles can be considered phase delayed, and severity of depression correlates with severity of phase delay Circadian rhythms regulate neurogenesis, and there is decreased neurogenesis in depression Master clock genes in the SCN facilitate circadian regulation of physiological processes and are altered in depression MT 1 and 5-HT 2C receptors are expressed in the SCN and oscillate with circadian rhythmicity 5-HT 2C receptors are involved in the modulation of circadian rhythms

42 ANTIDEPRESSANT TREATMENTS THAT TARGET CIRCADIAN FUNCTION Agomelatine Melatonin and agonists TK-301 Neu-P11 Estrogen Chronotherapies

43 Antidepressants and Novel Pharmacology Tricyclic Antidepressants Serotonin Selective Reuptake Inhibitors (SSRI) Antagonism Serotonin Norepinephrine Reuptake Inhibitors (SNRI) Agomelatine Agonism de Bodinat C et al. Nat Rev Drug Discovery 2010;9(8):628-42; Stahl SM. Stahl s Essential Psychopharmacology. 3rd ed. Cambridge University Press 2008.

44 A Multifaceted Approach to Depression Through Resynchronization of Circadian Rhythms Normalization of sleep-wake phase Increasing BDNF and hippocampal neurogenesis Increasing intracellular signaling for neurogenesis and sleep-wake phase Decreasing stress-induced glutamate release Increasing NE in the frontal cortex and the hippocampus and DA in the frontal cortex Low rate of side effects

45 Darkness-Induced Phase Delay Period of activity Days 0 5 Normal phase 10 6 am 6 pm 6 am Light Dark Armstrong SM et al. Pharmacol Biochem Behav 1993;46(1):45-9.

46 Darkness-Induced Phase Delay Period of activity Days 0 5 Normal phase 10 6 am 6 pm 6 am Light Dark Normal light-dark cycles Days 0 5 Phase delay Constant darkness 10 6 am 6 pm 6 am Armstrong SM et al. Pharmacol Biochem Behav 1993;46(1):45-9.

47 Agomelatine Promotes Phase Advance Constant darkness Normal light-dark cycles Phase delay 6 am 6 pm 6 am Light Armstrong SM et al. Pharmacol Biochem Behav 1993;46(1):45-9. Dark

48 Agomelatine Promotes Phase Advance Constant darkness Normal light-dark cycles Phase delay Agomelatine promotes phase advance 6 am 6 pm 6 am Light Armstrong SM et al. Pharmacol Biochem Behav 1993;46(1):45-9. Dark

49 Melatonergic Agonist Properties of Agomelatine 12 Suprachiasmatic Nucleus (SCN) Pineal Gland

50 Melatonergic Agonist Properties of Agomelatine 12 Suprachiasmatic Nucleus (SCN) Agomelatine Pineal Gland

51 Brain-Derived Neurotrophic Factor (BDNF) Supports survival of existing neurons Encourages neurogenesis BDNF is decreased in patients with depression Acheson A et al. Nature 1995;374(6521):450-3; Sairanen M et al. J Neurosci 2005;25(5): ; Brunoni AR et al. Int J Neuropsychopharmacol 2008;11(8):

52 BDNF mrna Levels (% Vehicle) Increases in BDNF in the Prefrontal Cortex * p< vehicle agomelatine melatonin 5-HT 2C antagonist agomelatine + melatonin antagonist The unique synergy of melatonergic plus 5-HT 2C antagonism is necessary to increase BDNF. Molteni R et al. World J Biol Psychiatry 2010;11(2):

53 Stimulation Ventral Hippocampal Neurogenesis Neurogenesis * p<0.05 After 3 Weeks of Treatment vehicle agomelatine Soumier A et al. Neuropsychopharmacol 2009;34(11):

54 Cell Survival After 21 Days in Ventral and Dorsal Hippocampi Newly Formed Neurons (% Above Control) Dorsal * *p<0.05 (two-way ANOVA) Ventral * control agomelatine 5-HT 2C antagonist melatonin Soumier A et al. Neuropsychopharmacol 2009;34(11): agomelatine + melatonin antagonist

55 Serotonin Inhibits Dopamine and Norepinephrine Release via 5-HT 2C Receptors NE DA prefrontal cortex NE GABA interneurons 5-HT2C DA 5-HT 5-HT overactivation normal 5-HT baseline hypoactivation brainstem neurotransmitter centers Stahl SM. Stahl s Essential Psychopharmacology. 3rd ed. Cambridge University Press 2008.

56 Agomelatine Releases Norepinephrine and Dopamine in the Frontal Cortex NE release DA release prefrontal cortex NE GABA interneurons 5-HT2C DA Agomelatine overactivation normal baseline hypoactivation 5-HT brainstem neurotransmitter centers Stahl SM. Stahl s Essential Psychopharmacology. 3rd ed. Cambridge University Press 2008; Millan MJ et al. J Pharmacol Exp Ther 2003;306(3):

57 Agomelatine Releases Norepinephrine and Dopamine in the Frontal Cortex NE release DA release prefrontal cortex NE GABA interneurons 5-HT2C DA Agomelatine overactivation normal baseline hypoactivation 5-HT brainstem neurotransmitter centers Stahl SM. Stahl s Essential Psychopharmacology. 3rd ed. Cambridge University Press 2008; Millan MJ et al. J Pharmacol Exp Ther 2003;306(3):

58 Agomelatine Releases Norepinephrine and Dopamine in the Frontal Cortex NE release DA release prefrontal cortex NE GABA interneurons 5-HT2C DA Agomelatine overactivation normal baseline hypoactivation 5-HT brainstem neurotransmitter centers Stahl SM. Stahl s Essential Psychopharmacology. 3rd ed. Cambridge University Press 2008; Millan MJ et al. J Pharmacol Exp Ther 2003;306(3):

59 Proportion Remaining Without Relapse Relapse Prevention Study Agomelatine (n=165) Placebo (n=174) 21.7% P< % Weeks of Treatment Goodwin GM et al. J Clin Psychiatry 2009;70(8)

60 Agomelatine Significantly Decreases Depression as Early as 1 Week Mean HAMD 17 Total Score Placebo Agomelatine (25 mg) * * * * * * At week 1, significance from placebo was p<0.01; it remained at p<0.05 for 8 weeks Week Stahl SM et al. J Clin Psychiatry 2010;71(5):

61 Agomelatine Clinical Studies: Does Resetting the Circadian Clock Treat Depression? Clinical efficacy of agomelatine was demonstrated in 6 studies with placebo Decreased depression Prevented relapse Demonstrated efficacy as early as week 1 Agomelatine shows favorable efficacy in treating depression versus: Venlafaxine Fluoxetine Sertraline Agomelatine has few side effects and no discontinuation symptoms

62 Melatonin as Treatment for Depression Some preliminary data suggest association of SNPs in melatonin MT 2 receptors with depression Melatonin given in late afternoon/early evening Advances circadian clock Earlier falling asleep and waking Melatonin given in the morning Delays circadian clock Later falling asleep and waking Short ½-life Prolonged-release melatonin improves sleep but not depression A preliminary study suggests antidepressant effects of the melatonin agonist ramelteon Quera Salva MA et al. Curr Pharm Des 2011;17(15): ; McElroy Sl et al. Int Clin Psychopharmacol 2011;26(1):48-53; Galecka E et al. Psychiatry Res 2011;Epub ahead of print.

63 TIK-301 Melatonin receptor agonist Also has serotonin 5-HT 2B and 5-HT 2C antagonism Recently finished Phase II clinical trials Quera Salva MA et al. Curr Pharm Des 2011;17(15):

64 Melatonin agonist Also has affinity for: Serotonin 5-HT 1A Serotonin 5-HT 1B Serotonin 5-HT 2B Neu-P11 Rodent studies show: Promotion of sleep Anxiolytic effects Antidepressant effects Quera Salva MA et al. Curr Pharm Des 2011;17(15):

65 Estrogen Estrogen receptors are located in the SCN Estrogen decreases Cry2 mrna levels in the SCN Estrogen increases spontaneous firing frequency (SFF) of SCN neurons This effect is blocked by the ER antagonist ICI Estrogen also modulates serotonin neurotransmission and has been shown to have antidepressant effects Cry2 mrna Fatehi M, Fatehi-Hassanabad Z. Neuropsychopharmacol 2008;33: ; Nakamura TJ et al. Neurosci Res 2001;41(3):251-5.

66 Chronotherapies Controlled exposures to environmental stimuli that act on biological rhythms Bright light therapy Sleep deprivation Sleep phase advance therapy

67 Bright Light Therapy Exposure to light alters circadian rhythms and suppresses melatonin release 10,000 lux (bright light) for 30 min/day Must be timed with patient s circadian phase of melatonin secretion Administer light hrs after evening melatonin secretion Approximation of melatonin secretion can be determined using the Horne-Ostberg Morningness-Eveningness Questionnaire (MEQ) Useful as a non-pharmacological intervention during pregnancy Dallaspezia S, Benedetti F. Expert Rev Neurother 2011;11(7):961-70; Pail G et al. Neuropsychobiol 2009;64:

68 Bright Light Therapy for Depression Rapid onset of antidepressant action Hastens the effects of antidepressant drugs Antidepressant effects mediated through eyes Extraocular administration shows no antidepressant benefits Good for bipolar depression but may precipitate mania Dawn simulation therapy Slow incremental light signal at the end of the sleep cycle Side effects are rare Headaches, eyestrain, nausea, and agitation Dallaspezia S, Benedetti F. Expert Rev Neurother 2011;11(7):961-70; Terman M et al. Biol Psychiatry 1989;25(7):

69 Bright Light Therapy Is Fast and Effective BLT may be as effective as pharmacological antidepressant treatment Kripke DF. J Affective Disord 1998;49(2):

70 Sleep Deprivation Therapy 36 hrs of deprivation Antidepressant effects within hours Decreases activity of 5-HT 2C receptors Response rates are similar to antidepressants (50-80%) Response is influenced by some of the same polymorphisms 5-HTTR (serotonin transporter), 5-HT 2A, COMT, GSK-3 Improvement doesn t last unless combined with: Other chronotherapies Lithium Antidepressants Contraindicated for patients with epilepsy Sleep deprivation increases risk of seizures in patients with epilepsy Dallaspezia S, Benedetti F. Expert Rev Neurother 2011;11(7):

71 Sleep Phase Advance Therapy Advances timing of sleep-wake cycle Synchronizes sleep with other biological rhythms Improves effects of antidepressants Also effective as monotherapy Dallaspezia S, Benedetti F. Expert Rev Neurother 2011;11(7):

72 Summary Many biological processes are regulated by circadian rhythms Circadian rhythm dysfunction has been linked to several psychiatric illnesses, including depression The circadian rhythm involves molecular regulation by clock genes; polymorphisms in these clock genes have been associated with many psychiatric disorders, and their expression is often altered by effective treatments Antidepressants that include modulation of circadian rhythms as part of their mechanisms of action (such as agomelatine) may be most effective Non-pharmacological chronotherapies may also be useful for fast relief of depressive symptoms