““Bright Nights”Bright Nights”

Seasons and Reasons:Seasons and Reasons:New Perspectives on Seasonal New Perspectives on Seasonal

Affective Disorder (S.A.D.)Affective Disorder (S.A.D.)

John F. Greden, M.D.John F. Greden, M.D.Rachel Upjohn Professor of Psychiatry and Clinical Rachel Upjohn Professor of Psychiatry and Clinical

NeurosciencesNeurosciencesChair, Department of PsychiatryChair, Department of Psychiatry

Executive Director, Comprehensive Depression CenterExecutive Director, Comprehensive Depression CenterResearch Professor, Molecular and Behavioral Research Professor, Molecular and Behavioral

Neurosciences InstituteNeurosciences Institute

January 30, 2007January 30, 2007Depression Center and Depression Center and Ambulatory Psychiatry Ambulatory Psychiatry

Disclosure StatementDisclosure StatementJohn F. Greden, M.D.John F. Greden, M.D.

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

There are no perceived conflicts of interest in this presentation

Agenda and TimetableAgenda 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 MichiganComprehensive

Depression Center

ParticipantsParticipants

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!

Other names for S.A.D.Other names for S.A.D.

Winter DepressionSeasonal DepressionMajor Depression with a Seasonal

PatternChronobiological abnormality

OverviewOverview

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

Simple illustration of our clocksSimple illustration of our clocks

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

Symptoms of S.A.D. (Seasonal Symptoms of S.A.D. (Seasonal Affective Disorder)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

Features and Mechanisms of S.A.D. 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

Features and Mechanisms of S.A.D. 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

Features and Mechanisms of S.A.D.:Features and Mechanisms of S.A.D.:Special ProblemsSpecial Problems

Travel across time zonesChanging from day to night shiftsCo-occurring disorders

– Alzheimer’s – Bipolar Disorder– Diabetes?

TreatmentsTreatments

Phototherapy (Bright Lights)Antidepressant MedicationsExerciseMoving?

Phototherapy Treatment of S.A.D.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

Minor side effects and precautions of Minor side effects and precautions of PhototherapyPhototherapy Eye strain Headache Irritability Insomnia Rarely, hypomania

or mania

Phototherapy Treatment and Phototherapy Treatment and Prevention of S.A.D.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

Antidepressant medication Rx for Antidepressant medication Rx for S.A.D.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

Major Depressive Disorder (MDD) Major Depressive Disorder (MDD) and S.A.D.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

Consider light therapy as first-line Consider light therapy as first-line whenwhen

Depression is mildAntidepressants failGood compliance, able to make time

commitmentMedications not wanted, e.g.,

pregnancy, breast feedingCost variables: Greater initial cost but

insurance may be a variable

Consider medications as first-line Consider medications as first-line whenwhen

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

Bipolar Disorder, disturbed rhythms, Bipolar Disorder, disturbed rhythms, and S.A.D.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.

New Advances in S.A.D.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

Your QuestionsYour Questions

Additional SlidesAdditional Slides

“Advances”– We can discuss if time permits

Selected ReferencesSample questions

New Advances in S.A.D.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

Are S.A.D., Weight Gain, Insulin Receptors, Are S.A.D., Weight Gain, Insulin Receptors, and Spring Birth Related Genetically? and Spring Birth Related Genetically? (Levitan et al, 2006)(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!

Are S.A.D., Weight Gain, Insulin Are S.A.D., Weight Gain, Insulin Receptors, DRD4 Gene and Spring Receptors, DRD4 Gene and Spring Birth Related Genetically? (Levitan et al, Birth Related Genetically? (Levitan et al, 2006)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.

Vision: A National Network of Depression Vision: A National Network of Depression Centers will help us study large samples to better Centers will help us study large samples to better understand S.A.D. and other disordersunderstand S.A.D. and other disorders

Cancer Center Network

A National Network of Depression Centers:

Founding Members to Date

University of Michigan (Organizing Center)University of Texas Southwestern Duke UniversityJohns Hopkins UniversityUniversity of California San FranciscoUniversity of WashingtonUniversity of CincinnatiStanford UniversityCornell UniversityMassachusetts General Hospital(Brown University)(Columbia University)

Topics for discussionTopics 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?

Topics for discussionTopics 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?

ReferencesReferences 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.

ReferencesReferences 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 fostering

research, 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