Depression Center and Ambulatory Psychiatry

1. “Bright Nights”Seasons and Reasons:New Perspectives on Seasonal Affective Disorder (S.A.D.)John F. Greden, M.D.Rachel Upjohn Professor of Psychiatry and Clinical NeurosciencesChair, Department of PsychiatryExecutive Director, Comprehensive Depression CenterResearch Professor, Molecular and Behavioral Neurosciences InstituteJanuary 30, 2007 Depression Center and Ambulatory Psychiatry

2. Scientific Advisory Functions During Past Two Years Cyberonics Eli Lilly and Co. GSK Neuronetics Pfizer Wyeth Society Advisory Boards and Foundations DBSA (Depression and Bipolar Support Alliance) American Foundation for Suicide Prevention No corporate contracts or research projects supported by pharmaceutical companies Stock Holding: Originus Disclosure StatementJohn F. Greden, M.D. There are no perceived conflicts of interest in this presentation

3. Agenda and Timetable • Chronobiological Rhythms: What are they? • Symptoms of S.A.D. • Treatments • How to tell S.A.D. from other disorders • New Research • Discussion with panel The University of Michigan Comprehensive Depression Center

4. Participants • John F. Greden, M.D. • Neera Ghaziuddin, M.D. • Todd Arnedt, Ph.D. • Bruce Gimbel, M.D. • The Ann Arbor District Library • Melvin McInnis, M.D. • Trish Meyer • YOU! Thank you!

5. Other names for S.A.D. • Winter Depression • Seasonal Depression • Major Depression with a Seasonal Pattern • Chronobiological abnormality

6. Overview • We have biological clocks • Influenced by rotation of earth and tilting of earth • Our biological clocks are not perfect, and sometimes get “broken” • Our day is 24 hours and 11 minutes (Czeisler, 1999) • Some of us get clinical symptoms (Seasonal Affective Disorder or S.A.D.) • “Broken clocks” can be more serious, linked with depression and bipolar (manic-depression) disorders

7. Simple illustration of our clocks

8. Suprachiasmatic Nucleus of Hypothalamus in the brain is the major biological clock for mammals, set by our genes and environment

9. Symptoms of S.A.D. (Seasonal Affective Disorder) • Predictable onset (September-October) and offset (March-April) with absence of symptoms in summer • Carbohydrate/sweet craving, weight gain • Hypersomnia (sleeping too much) • Fatigue, “heavy limbs,” no energy • Sadness, loss of pleasure, depression • Irritability, more alcohol use • Decreased libido, interest in sex

10. Features and Mechanisms of S.A.D. BMJ 1998;317:1704-1707 Hastings: The brain, circadian rhythms, and clock genes • How common? • 4 - 6 % with “full-blown” SAD • 10 – 20 % of Americans have some symptoms • 75% are women • Peak between ages 18 – 30; can occur in children and adolescents • Where? • More frequent as we get closer to the poles • Rare within 30 degrees of equator • Light exposure is important

11. Features and Mechanisms of S.A.D. Hastings: The brain, circadian rhythms, and clock genes BMJ 1998:317:1704-1707 • Decreased exposure to sunlight makes biological clocks run more slowly • Sleep and hormone cycles may get delayed, run more slowly in winter • Neurotransmitters (chemical messengers) changed by light • Serotonin • Norepinephrine • Dopamine • Explains why both light and medications help

12. Features and Mechanisms of S.A.D.:Special Problems • Travel across time zones • Changing from day to night shifts • Co-occurring disorders • Alzheimer’s • Bipolar Disorder • Diabetes?

13. Treatments • Phototherapy (Bright Lights) • Antidepressant Medications • Exercise • Moving?

14. Phototherapy Treatment of S.A.D. • Phototherapy: White fluorescent light tubes • Plastic screen blocks ultraviolet rays • Light intensity at least 10,000 Lux for 30 minutes in the morning • Don’t look directly at light • 1 to 2 feet away • No tanning booths! • Improvements in 4 to 21 days • Symptoms come back if phototherapy stopped • Get Ophthalmology consult if you have eye problems

15. Minor side effects and precautions of Phototherapy • Eye strain • Headache • Irritability • Insomnia • Rarely, hypomania or mania

16. Phototherapy Treatment and Prevention of S.A.D. • Start using light box in October • Go outside! • Sit by windows when possible • Regular sleep pattern • Limit alcohol • Ask your family or friends to help monitor severity of your symptoms • If more severe than S.A.D. and into episode of depression or mania, see your clinician

17. Antidepressant medication Rx for S.A.D. • Sertraline [Zoloft] (N = 187) and fluoxetine [Prozac] (N = 68) both shown effective • Bupropion XL [Wellbutrin] (N = 1042) shown effective and approved by F.D.A. in 2006 • Allows use for the prevention of major depressive episodes in adult patients with a history of seasonal affective disorder (SAD). • 3 placebo-controlled clinical trials • 150-mg once daily in the morning and titrated to 300 mg/day (target dose) after 1 week if tolerated. • Start in autumn

18. Major Depressive Disorder (MDD) and S.A.D. • MDD often gets worse in winter • This is NOT just S.A.D. • M.D.D. should be treated with medications and C.B.T or I.P.T. • Phototherapy may be used to help seasonal flare-ups but light therapy should not replace other needed treatments • Consult your clinician

19. Consider light therapy as first-line when • Depression is mild • Antidepressants fail • Good compliance, able to make time commitment • Medications not wanted, e.g., pregnancy, breast feeding • Cost variables: Greater initial cost but insurance may be a variable

20. Consider medications as first-line when • More severe depression • Depression episodes during summer, don’t end in spring • Suicidal • No response to light therapy • Relative contraindications to light therapy (e.g., retinal disease, photosensitizing drug) • Cost variables

21. Bipolar Disorder, disturbed rhythms, and S.A.D. • Bipolar patients with S.A.D. should receive mood stabilizers • Lithium (and valproic acid) likely fixes broken body clocks in bipolar disorder • Blocks an enzyme (GSK-3ß) and stabilizes a receptor( Rev-erbα) that leads to the rhythmic turning-on of the protein Bmal1, which fixes the clock cycle • A version of the GSK-3ß gene has been linked to a milder, more easily treatable form of bipolar disorder. Yin l, Wang J, Klein PS, Lazar MA, Nuclear receptor rev-erbα is a critical lithium-sensitive component of the circadian clock. Science, Vol. 311. no. 5763, pp. 1002 - 1005.

22. New Advances in S.A.D. • We have learned a great deal • Treatments are available • Be persistent • New “Advances” • Clock Genes • Possible linkage between genes, weight gain, and season of birth • Mechanisms of mood stabilizers • We can discuss if time permits

23. Your Questions

24. Additional Slides • “Advances” • We can discuss if time permits • Selected References • Sample questions

25. New Advances in S.A.D. • Clock Genes • Explain many things • E.g., “Larks” vs. “Owls” • Effects of lithium and mood stabilizers in bipolar disorder • Possible linkage between genes, weight gain, and season of birth

26. Are S.A.D., Weight Gain, Insulin Receptors, and Spring Birth Related Genetically? (Levitan et al, 2006) • When periodic famine and loss of food supply occur, weight gain improves survival • Seasonal famines once an issue • When food is constantly available, weight gain produces obesity • Periodic weight gain once adaptive, no longer!

27. Are S.A.D., Weight Gain, Insulin Receptors, DRD4 Gene and Spring Birth Related Genetically? (Levitan et al, 2006) • Spring birth interacts with DRD4 gene • Linked to anticipation of seasonal famines for those in northern latitudes? • DRD4 x Insulin Gene x Birth season interact to promote weight gain, and possibly S.A.D.

28. Vision: A National Network of Depression Centers will help us study large samples to better understand S.A.D. and other disorders University of Michigan (Organizing Center) University of Texas Southwestern Duke University Johns Hopkins University University of California San Francisco University of Washington University of Cincinnati Stanford University Cornell University Massachusetts General Hospital (Brown University) (Columbia University) Cancer Center Network A National Network of Depression Centers: Founding Members to Date

29. Topics for discussion • Where can I get lights? • How can I better regulate my sleep? • Can bright lights be used for children and adolescents? • Do bright lights help Major Depressive Disorder? Bipolar Disorders? • When should medications and bright lights be used together?

30. Topics for discussion • What about chocolate? Caffeine? • Can I build my own light box? • Will we ever have gene therapy to treat S.A.D. • Do mood stabilizers help S.A.D. or seasonal flare-ups of depression or bipolar?

31. References • Rosenthal NE, Sack DA, Gillin JC, et al: Seasonal affective disorder: a description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry 1984; 41:72-80. • Bauer MS, Dunner DL: Validity of seasonal pattern as a modifier for recurrent mood disorders for DSM-IV. Compr Psychiatry 1993;34:159-70.Eastman CI, Young MA, Fogg LF, et al: A placebo-controlled trial of bright light treatment for winter seasonal affective disorder. Arch Gen Psychiatry 1998; 883-9.Gallin PF, Terman M, Reme CE, et al: Opthalmologic examination of patients with seasonal affective disorder, before and after bright light therapy. Am J Ophthalmol 1995; 119:202-10.Kogan AO, Guilford PM: Side effects of short-term l0,000-lux light therapy. Am J Psychiatry 1998; 155:293-294.Lam RW (ed.): Seasonal Affective Disorder and Beyond. Light Treatment for SAD and Non-SAD Conditions. Washington DC, American Psychiatric Press, 1998.Lam RW, Gorman CP, Michalon M, et al: Multicenter, placebo-controlled study of fluoxetine in seasonal affective disorder. Am J Psychiatry 1995; 152:1765-70.

32. References • Lewy AJ, Bauer VK, Cutler NL, et al: Morning vs. evening light treatment of patients with winter depression. Arch Gen Psychiatry 1998;55:890-6.Moscovitch A, Blashko C, Wiseman R, et al: A double-blind, placebo-controlled study of sertraline in patients with seasonal affective disorder. New Research Abstracts, 151st Meeting of the American Psychiatric Association, 1995.Tam EM, Lam RW, Levitt AJ: Treatment of seasonal affective disorder: a review. Can J. Psychiatry 1995; 40:457-66.Terman M, Terman JS, Ross DC: A controlled trial of timed bright light and negative air ionization for treatment of seasonal affective disorder. Arch Gen Psychiatry 1998; 55:875-82.Terman M, Terman JS, Quitkin FM, McGrath PJ, Stewart JW, Rafferty B: Light therapy for seasonal affective disorder. A review of efficacy. Neuropsychopharmacology 1989; 2: 1-22. • INFORMATION RESOURCES FOR SAD • Society for Light Treatment and Biological Rhythms (SLTBR). • SLTBR is an international, not-for-profit society dedicated to fosteringresearch, professional development and clinical applications in the fieldsof light therapy and biological rhythms. • Contact: Stephanie Argraves, Executive Director, SLTBR842 Howard Avenue, New Haven, CT, USA 06519e-mail: sltbr@yale.eduweb site: http://www.websciences.org/sltbr/(includes a list of Corporate Members that manufacture and distribute lightSevices) • University of Michigan Depression Center www.mail.med.umich.edu