Shedding Light on Seasonal Affective Disorder

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DOI: 10.1089/act.2008.14608 • MARY ANN LIEBERT, INC. • VOL. 14 NO. 6DECEMBER 2008

Hippocrates, the noted Greek physician, once said: “It is chiefly the changes of the seasons which produce diseases.”1 And modern scientists also recognize this. Commonly known as winter depression, seasonal affective disorder (SAD) is clas-sified as a mood disorder with a seasonally recurrent pattern.2 The well-known seasonal symptoms of depressed mood, low energy levels, disturbed sleep, overeating, and weight gain were first described in clinical terms in the early 1980s.1 This article discusses the prevalence, diagnosis, treatment options, and eti-ology of this disorder.

Epidemiology

SAD predominantly affects individuals living at northern latitudes where exposure to daylight is low in the fall and winter seasons. The prevalence of SAD in the United States has been estimated to range from about 1% in Sarasota, Florida, to more than 9% in Fairbanks, Alaska. Dark indoor work environments may also contribute to SAD. In addition to depression, symp-toms typically include increased appetite and weight gain. The average age at onset is in the early 20s, and the female-to-male ratio is approximately 3:1.3 The rate of SAD among young-sters ages 9–19 has been estimated at 2%–5.5%.4

What is more, some patients suffer from subsyndromal SAD, “winter blues,” a less-severe form of the disorder.5 Having com-parable symptoms in the summer is a less-common subtype of SAD that is more prevalent in Japan than in the United States1; this “reverse” form of SAD has been found more frequently among African students attending college in Washington, D.C., compared to their African-American peers.6

The typical winter seasonal pattern is not found in some countries far from the equator (e.g., parts of Norway7 and Ice-

land1), as measured by the Seasonal Pattern Assessment Ques-tionnaire (SPAQ). Noting the variability in the seasonality of depression scores found when using the SPAQ , some experts suggest using the instrument as a screening rather than as a diagnostic instrument.8 Other researchers have estimated that, despite patients’ experience of numerous seasonal depressive episodes, nearly 60% of these patients have not been treated for SAD.9

Patients presenting with general complaints of fatigue and lethargy during the autumn and winter months should be evaluated to rule out other types of depression, hypothyroid-ism, hypoglycemia, chronic fatigue syndrome, or mononucleo-sis and other viral infections. Comorbid conditions, including eating disorders, are common, as is a patient history of close relatives with SAD or other mood disorders.3

Treatment Options

Bright-Light TherapyIn addition to being the first to identify SAD as a clinical

entity, psychiatrist Norman E. Rosenthal, M.D., who was a re-searcher at the National Institute of Mental Health at the time (and is currently medical director of Capital Clinical Research Associates in Rockville, Maryland),10 experienced the effects of seasonal differences firsthand and pioneered indoor bright-light therapy for SAD. This type of phototherapy involves patient exposure to a light box containing white fluorescent lights of 10,000-lux intensity,* about 20 times as great as that of ordinary indoor lighting, and a diffuser.

Shedding Light on Seasonal Affective Disorder

Sala Horowitz, Ph.D.

*Earlier use of lower-intensity light therapy for SAD was not found to be as effective. See Ref. 1.

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ALTERNATIVE AND COMPLEMENTARY THERAPIES • DECEMBER 2008

MARY ANN LIEBERT, INC. • VOL. 14 NO. 6

cations may consider applying a sunblocking product prior to light therapy.1 Cases of light therapy–induced suicidal ideation are rare, but suicidal thoughts may occur in any form of depres-sion and require professional help.13 A clinical trial studying a tool to predict which patients might benefit from light therapy is now in progress.14

Because eating disorders often occur in patients with SAD, and both disorders occur predominantly in women, the effects of bright-light therapy have been studied in this patient pop-ulation. A 4-week trial of early morning light exposure (using a standard 10,000-lux fluorescent light box with a UV filter) for 30–60 minutes daily resulted in significant improvement in mood and reduction in the frequency of binges and purges in an open trial of 22 female patients with concurrent SAD and bulimia nervosa. Because the rate of bulimic behavior re-mained high after treatment, the researchers concluded that light therapy may be used most effectively as an adjunctive therapy to psychotherapy and/or medications for comorbid bulimia and SAD.15

Light-Emitting Diode Light TherapyAdvances in light-emitting diode (LED) technology have

enabled researchers to test the effectiveness of light of different wavelengths. In a randomized study of 24 patients completing 45 minutes of morning light treatment daily for 3 weeks, nar-row bandwidth/short wavelength blue light at 607 microW/cm2 outperformed dimmer red light at 654 nanometers (nm) at 34 microW/cm2 (the placebo) in reducing patients’ scores on the Structured Interview Guide for the Hamilton Depression Rating Scale–SAD version.16

In a study of the Litebook LED treatment device (The Lite-book Company Ltd., Alberta, Canada), 26 participants ages 18–65 with SAD were randomly assigned to exposure to the device, which delivers 1350-lux white light at a distance of 20 inches, or to an inactivated negative ion generator (see the fol-lowing section), also at 20 inches, for 30 minutes per day upon awakening prior to 8 am. After 4 weeks, subjects who received

While some people pre-fer full-spectrum fluores-cent light boxes that mimic the spectral distribution of sunlight, Dr. Rosenthal does not believe that such lights offer any therapeutic advantage over cool-white fluorescent lights. He ad-vises against using any light fixture without an ultra-violet (UV) light filter, as UV light poses a potential danger to the eyes and skin. Light therapy is consid-ered to be safe for pregnant women and persons with seizure disorders (modern fluorescent light fixtures minimize flickering),1 and effective for pediatric patients.11

Although light boxes are available without a prescription, they should be used under medical supervision, according to Dr. Rosenthal.1 Some professional organizations have en-dorsed the use of light boxes for treating SAD, but the Food

and Drug Administration (FDA) has not officially approved them as medical devices despite years of successful, clinically validated use.12

In Dr. Rosenthal’s protocol, which is tailored to individual needs, patients are typically instructed to sit about 45 cm away from a light box, slanted at a 45º-angle toward the face, for 30 minutes each morning. Light exposure may be increased to 45 minutes in the morning plus 30 minutes in the eve-ning during the winter months, with a gradual decrease and discontinuation with the approach of spring. Patients may resume therapy as a preventive measure in the early fall to avoid relapse. Some positive response should be expected by the third or fourth week of treatment. With no consensus on whether a morning or evening protocol is optimal, Dr. Rosenthal recommends a schedule most conductive to pa-tient adherence.3

Mild side-effects of this therapy include headaches, eyestrain, irritability, hypomania activation, and insomnia (especially with evening treatments). Symptoms related to overstimula-tion can be overcome by decreasing the duration of treatment or having the patient sit further from the light source. Patients with fair skin and those taking photosensitivity-causing medi-

Example of bright light therapy using Bio-Light device. Photo courtesy of Enviro-Med Company, Vancouver, WA.

Mild side-effects of bright-light therapy include headaches,

eyestrain, irritability, hypomania activation, and insomnia.

Norman E. Rosenthal, M.D., Photo courte-sy of Capital Clinical Research Associates.

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psychiatry at Oregon Health & Science University in Portland, recommends administering low-dose supplemental melatonin in the morning and light therapy in the evening.24 Dr. Lewy prescribes a maximum daily dose of 0.3–0.5 mg of melatonin, in divided doses, if patients get sleepy right after taking medi-cation (personal communication, October 2, 2008).

In a study of patients who were partial or nonresponders to phototherapy, 1 g of l-tryptophan, a serotonin precursor, 3 times daily for 2 weeks produced a good clinical response in 9 of 16 patients.25 Several controlled studies have found a mood-elevating effect for vitamin B1 (thiamine) at a dose of 50 mg per day.1

While 5-hydroxytryptophan (5-HTP), a metabolite of tryptophan, omega-3 fish oil supplements, and S-adenosyl-l-methionine (SAMe) have been useful for treating general depression, their efficacy in treating SAD specifically has not been researched. According to Dr. Rosenthal, taking Hyperi-cum perforatum (St. John’s wort) in tandem with light therapy for SAD is contraindicated because of patient complaints of increased sensitivity to light and eye pain.1

Lifestyle Approaches Self-help techniques, including getting regular exercise, at-

tending a support group, keeping a daily mood log to increase awareness of symptoms and conditions that reduce them, and taking winter vacations in sunnier locations may be helpful. Alcohol, with its well-known depressant effects, should be avoided. Restricting hours of sleep can also have a salutary ef-fect on mood and energy level.1 Based on research indicating that patients with SAD have a more acute olfactory sense,26 it has been suggested that aromatherapy may be worth trying.27

Cognitive Behavioral Therapy Psychotherapy, particularly cognitive behavioral therapy

(CBT), for depression has been beneficial by itself or as an ad-junct to light therapy and/or antidepressants. In an anti-SAD CBT program at the Uniformed Services University of the Health Sciences in Bethesda, Maryland, patients in a group setting were taught to educate themselves about SAD, themes in their negative thinking, and how their thoughts contributed to their symptoms; and to challenge their negative thinking.1

The first controlled trial of psychotherapy for SAD com-pared CBT tailored for 61 patients with SAD (1.5 hours, twice-weekly group therapy), standard light therapy for SAD (90 minutes daily with time of administration individually ad-justed), and a combination of the two treatment modalities, compared with a wait-list control over a 6-week period. The 73% remission rate for patients receiving both light therapy and CBT was a clinically meaningful improvement over the 53% observed in patients receiving light therapy solely.28

AntidepressantsAntidepressants are often prescribed alone or in conjunc-

tion with light therapy, and may prevent relapse following a course of light therapy that is stopped too soon.29 Bupropion HCL (Wellbutrin XL) was the first drug approved by the

the active intervention had significantly lower scores on the Hamilton Depression Rating Scale scores for SAD, and a great-er proportion of these patients attained remission of SAD.17

Dawn SimulationFor patients who find standard light therapy inconvenient

or who experience sleep problems, an alternative form of light therapy is naturalistic dawn simulation. This therapy in-volves gradually increasing light output for a preset time be-fore awakening. One controlled study found light simulation (from 4:30 am to 6 am, peaking at 250 lux) to be superior to bright-light therapy for 30 minutes in the early morning or placebo (a dim red light) for 95 patients,18 while another study found the two types of light therapy to have compa-rable antidepressant effects.19

Negative Air IonizationThe indoor environment can also be therapeutically en-

hanced in the winter months to simulate outdoor summer conditions by negative air ionization. A study was conducted with 99 patients (77 women, 22 men) who had a winter–sea-sonal pattern of major depressive disorder, which was assessed via the Structured Interview Guide for the Hamilton Depres-sion Rating Scale–SAD version. The patients were exposed to high-intensity negative air ionization produced by negative ion generators for 30 minutes each morning for a week. The researchers noted that negative air ionization was as good as standard light therapy functioning as a naturalistic antide-pressant. The same results were obtained when patients slept on a grounded sheet attached to a high-density negative ion generator. But low-density ion flow produced results no better than a placebo.19

Dietary SupplementationExposure to sunlight, and therefore vitamin D, is at a mini-

mum in the winter months at northern latitudes. A literature review of peer-reviewed research on serum vitamin D levels and mood in women revealed an association in 4 of 6 stud-ies between low 25-hydroxyvitamin D (25OH-D) levels and a higher incidence of mood disorders including SAD.20 In a study of 15 patients with SAD, subjects randomized to receive a one-time megadose of 100,000 international units (IU) of vitamin D (25OH-D) had greater improvement in depression scale scores than subjects assigned to broad-spectrum light therapy after 1 week.21

However, a study of whether vitamin D supplementation with 800 IU of the vitamin daily could prevent or reduce SAD symptoms in women ages 70 and older did not result in any marked difference in the mental health scores of women in the intervention group (n = 912) compared with the control group (n = 1205).22 Maureen Williams, N.D., who practices in Quechee, Vermont, advises patients with SAD to take 1000 IU of vitamin D per day, especially patients who live in northern latitudes in the winter.23

Because of the pivotal role melatonin plays in circadian rhythm alignment, Alfred J. Lewy, M.D., Ph.D., a professor of

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FDA specifically for SAD30; studies indicate that this drug can prevent recurrence when begun before patients experi-ence seasonal symptoms.9 Other antidepressants commonly prescribed for SAD include the selective serotonin reuptake inhibitors (SSRIs). Examples include: fluoxetine (Prozac),31 sertraline (Zoloft),32 and citalopram (Celexa)33; serotonin and norepinephrine reuptake1 inhibitors, such as duloxetine (Cymbalta)34; and modafinil, a wake-promoting agent.35 Ago-melatine, a mood stabilizer that is an analogue of melatonin, is currently being evaluated by the FDA for treating major de-pressive disorder.36,37 The FDA has issued “black box” warning labels on several antidepressants including Wellbutrin, Celexa, and Zoloft because of the increased risk of suicidal ideation and behavior in pediatric and young adult patients.38

According to Dr. Rosenthal, light therapy may reduce the usual therapeutic dosages of antidepressants for SAD and, consequently, their side-effects.1 A study of 98 patients ran-domized to receive standard light treatment (10,000 lux) and a placebo capsule, low-level (200 lux) placebo light, or 20 mg of fluoxetine, yielded comparable quality-of-life measures for subjects who were treated with standard light therapy or the antidepressant after 8 weeks of treatment.39

Pathophysiology

The facts that light therapy, a shift in sleep patterns (general-ly to fewer hours of sleep), and/or antidepressants are often ef-fective in treating symptoms of SAD point to desynchronized circadian rhythms as being causal.40 Bright-light therapy and SSRIs work by restoring balance between the neurotransmit-ter serotonin, which has concentrations at a minimum in the winter, and the light–dark cycle–synchronizing hormone me-latonin that is normally regulated by sunlight.1

The immunomodulatory role of melatonin is also seasonally dependent.41 Melatonin secretion appears to be higher in peo-ple with SAD in the winter than in other people,42 which has prompted speculation that cravings for carbohydrates may be a self-regulatory means of counteracting excess melatonin levels (i.e., excess melatonin decreases energy and lowers body tem-perature, and eating carbohydrates reverses this phenomenon).43 Exercise also suppresses melatonin secretion.44 Melatonin level (as seen in 24-hour urine analysis of 6-hydroxymelatonin) can also be used diagnostically as a marker of circadian-rhythm func-tion and its phase-shifting in SAD.45 Because of their ability to reset circadian rhythms, melatonin and certain antidepressants are known as chronobiotics or resychronizing agents.46

A recent study of seasonal fluctuations in serotonin func-tion identified a previously unknown regulatory mechanism to explain seasonal changes in normal and pathologic bio-rhythms and behavior. Through positron-emission tomog-raphy (PET) scans of the brains of 88 healthy volunteers, researchers found that the values of serotonin-binding trans-porter, which regulates and is inversely related to the intensi-ty and spread of serotonin signals, varies markedly by season and duration of sunlight.47

The potentials of this transporter were significantly higher in the brain regions of individuals tested in the fall and winter months compared to subjects who were tested in the spring and summer. Serotonin levels were at their lowest levels in the lesser-light seasons associated with SAD in vulnerable individuals.47

A genetic factor may account for the vulnerability of some individuals and populations to SAD and their incomplete re-sponses to treatment.48 A variant in the gene for melanopsin, a photopigment in the retina, contributed to an increasing light requirement for normal functioning during winter in a study of 130 subjects with SAD compared to 90 control subjects.49 Ac-cording to the dual-vulnerability hypothesis, different patterns of SAD result from the interaction of independent patient factors for depression and seasonality.5 Such genetic factors may account for the lower-than-expected prevalence of SAD

Resources

Organizations

Center for Environmental Therapeutics (CET) 337 West 20th Street, Suite 4M New York, NY 10013 E-mail list: [email protected] Website: www.cet.org/contact.html

The CET consists of multidisciplinary researchers and clinicians promoting the development and application of environmental therapies for the nonpharmacologic treatment of seasonal affec-tive disorder (SAD) and related conditions. Equipment to treat SAD is available through the Center.

Mental Health America (MHA) 2000 North Beauregard Street, 6th floor Alexandria, VA 22209 Phone: (703) 684-7722; (800) 969-6642 toll free Fax: (703) 684-5968

The MHA is an educational, advocacy, and support organiza-tion for all persons concerned about mental health and illness. The Society provides fact sheets on topics including SAD.

Society for Light Treatment and Biological Rhythms (SLTBR) c/o Division of Sleep and Chronobiology Unit of Experimental Psychiatry Department of Psychiatry University of Pennsylvania School of Medicine Philadelphia, PA 19104-6021 Phone: (215) 898-1742 Fax: (757) 336-5777 Website: www.sltbr.org E-mail: [email protected] Contact: Namni Goel, Ph.D., president

The SLTBR fosters research, clinical applications, and profes-sional development in the areas of light therapy and biologic rhythms, and publishes The Journal of Biological Rhythms. Corpo-rate members develop and market therapeutic light devices.

Book for you and your patients

Winter Blues: Everything You Need to Know to Beat Seasonal Affective Disorder, Revised Edition By Norman E. Rosenthal, M.D. New York: Guilford Press, 2006

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12. Mayo Clinic Staff. Seasonal Affective Disorder: Treatment with Light Therapy. Online document at: www.mayoclinic.com/health/seasonal-affec tive-disorder/MH00023 Accessed September 30, 2008.13. Lam RW, Tam EM, Shiah IS, et al. Effects of light therapy on sui-cidal ideation in patients with seasonal affective disorder. J Clin Psychiatry 2000;61:30–32.14. National Institutes of Health. Predicting Effectiveness of Light Treatment for Winter Seasonal Affective Disorder. Online document at: www.clinicaltri als.gov/ct2/show/NCT00742365 Accessed October 7, 2008.15. Lam RW, Lee SK, Tam EM, et al. An open trial of light therapy for women with seasonal affective disorder and comorbid bulimia nervosa. J Clin Psychiatry 2001;62:164–168.16. Glickman G, Byrne B, Pineda C, et al. Light therapy for seasonal affective disorder with blue narrow-band light emitting diodes (LEDs). Biol Psychiatry 2006;59:502–507.17. Desan PH, Weinstein AJ, Michalak EE, et al. A controlled trial of the Litebook light-emitting diode (LED) light therapy device for treatment of seasonal affective disorder (SAD). BMC Psychiatry 2007;7:38.18. Avery DH, Eder DN, Bolte MA, et al. Dawn simulation and bright light in the treatment of SAD: A controlled study. Biol Psychiatry 2001;50:205–216.19. Terman M, Terman JS. Controlled trial of naturalistic dawn simulation and negative air ionization for seasonal affective disorder. Am J Psychiatry 2006;163:2126–2133.20. Murphy PK, Wagner CL. Vitamin D and mood disorders among women: An integrative review. J Midwifery Women’s Health 2008;53:440–446.21.Gloth FM 3rd, Alam W, Hollis B. Vitamin D vs broad spectrum phototherapy in the treatment of seasonal affective disorder. J Nutr Health Aging 1999;3:5–7.22. Dumville JC, Miles JN, Porthouse J, et al. Can vitamin D supplementation prevent winter-time blues? A randomised trial among older women. J Nutr Health Aging 2006;10:151–153.23. Williams M. Can the Sunshine Vitamin Beat the Blues? [Health Con-ditions and Concerns: Mental Health] Bastyr Center for Natural Health. Online document at: http://bastyrcenter.org/content/view/1420/ Accessed October 6, 2008.24. Lewy AJ. Melatonin and human chronobiology. Cold Spring Harb Symp Quant Biol 2007;72:623–636.25. Lam RW, Levitan RD, Tam EM, et al. l-Tryptophan augmentation of light therapy in patients with seasonal affective disorder. Can J Psychiatry 1997;42:303–306.26. Postolache TT, Wehr TA, Doty RL, et al. Patients with seasonal affective disorder have lower odor detection thresholds than control subjects. Arch Gen Psychiatry 2002;59:1119–1122.27. Marshall F, Cheevers P. Positive Options for Seasonal Affective Disor-der (SAD): Self-Help and Treatment. Alameda, CA: Hunter House Pub-lishers, 2003.28. Rohan KJ, Roecklein KA, Tierney LK, et al. A randomized controlled trial of cognitive–behavior therapy, light therapy, and their combination for seasonal affective disorder. J Consult Clin Psychol 2007;75:489–500. 29. Westrin A, Lam RW. Long-term and preventative treatment for seasonal affective disorder. CNS Drugs 2007;21:901–999.30. Food and Drug Administration. FDA News: FDA Approves the First Drug for Seasonal Depression. June 12, 2006. Online document at: www.fda.gov/bbs/topics/NEWS/2006/NEW01388.html Accessed September 30, 2008.31. Lam RW, Levitt AJ, Levitan RD, et al. The Can-SAD study: A ran-domized controlled trail of the effectiveness of light therapy and fluoxetine in patients with winter seasonal affective disorder. Am J Psychiatry 2006; 163:805–812.32. Moscovitch A, Blashko CA, Eagles JM, et al. A placebo-controlled study of sertraline in the treatment of outpatients with seasonal affective disorder. Psychopharm (Berl) 2004;171:390–397.

among some populations. Gender-specific hormonal factors are likely to account for the greater prevalence of SAD among young women.1

A study of 17 patients using brain imaging (PET) tech-niques provided evidence that CBT may help patients with major depression by producing treatment-specific changes in key cortical and limbic sites. They may be learning to “short-circuit” depression-inducing changes in the brain. This cortical pattern was found to differ from that produced with parox-etine (Paxil).50

An experimental model suggested that short photoperiods (i.e., relative day length), in conjunction with a high-carbohy-drate diet in rats, increased total caloric intake and adiposity as it does in patients with SAD.51

Conclusion

Treatment options for SAD include various types of light therapy, negative ion exposure, dietary supplementation, CBT, and/or antidepressants. Further research is warranted on the efficacy of different treatment combinations for indi-vidual patients and the seasonal disorder’s underlying neu-robiologic mechanisms. n

References

1. Rosenthal NE. Winter Blues: Everything You Need to Know to Beat Sea-sonal Affective Disorder, rev. ed. New York: Guilford Press, 2006.2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th rev. ed. Washington, D.C.: American Psychiatric As-sociation, 1994.3. Rosenthal NE. Diagnosis and treatment of seasonal affective disorder. JAMA 1993;270:2717–2720.4. Swedo SE, Pleeter JD, Richter DM, et al. Rates of seasonal affec-tive disorder in children and adolescents. Am J Psychiatry 1995;152: 1016–1019.5. Lam RW, Tam EM, Yatham LN, et al. Seasonal depression: The dual vul-nerability hypothesis revisited. J Affect Disord 2001;63:123–132.6. Guzman A, Rohan KJ, Yousufi SM, et al. Mood sensitivity to seasonal changes in African college students living in the greater Washington D.C. metropolitan area. Sci World J 2007;7:584–591.7. Hansen V, Skre I, Lund E. What is this thing called “SAD”? A cri-tique of the concept of seasonal affective disorder. Epidemiol Psychiatr Soc 2008;17:120–127.8. Mersch PP, Vastenburg NC, Meesters Y, et al. The reliability and validity of the Seasonal Pattern Assessment Questionnaire: A comparison between patient groups. J Affect Disord 2004;80:209–219.9. Modell JG, Rosenthal NE, Harriett AE, et al. Seasonal affective disorder and its prevention by anticipatory treatment with bupropion XL. Biol Psychia-try 2005;58:658–667. 10. Rosenthal NE. Seasonal affective disorder: A description of the syn-drome and preliminary findings with light therapy. Arch Gen Psychiatry 1984;41:72–80.11. Swedo SE, Allen AJ, Glod CA, et al. A controlled trial of light therapy of pediatric seasonal affective disorder. J Am Acad Child Adolesc Psychiatry 1997;36:816–821.

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43. Smith LL, Elliott CH. Seasonal Affective Disorder for Dummies. Hobo-ken, NJ: Wiley Publishing, 2007.44. Weydahl A. Evening melatonin in January after changes in hours of ha-bitual exercise during fall among youths living in the subarctic. Arctic Med Res 1994;53:146–151.45. Lewy AJ, Lefler BJ, Emens JS, Bauer VK. The circadian basis of winter depression. Proc Natl Acad Sci USA 2006;103:7414–7419. 46. Touitou Y. Dysfunctions of biological clocks and their treatment [in French]. Ann Pharm Fr 2008;66:146–157.47. Praschak-Reider N, Wileit M, Wilson AA, et al. Seasonal variation in human brain serotonin transporter binding. Arch Gen Psychiatry 2008; 65:1072–1078.48. Le Strat Y, Ramoz N, Gorwood P. Affective disorders and biological rhythms [in French]. Ann Pharm Fr 2008;66:169–174.49. Roecklein KA, Rohan KJ, Duncan WC, et al. A missense variant (P10L) of the melanopsin (OPN4) gene in seasonal affective disorder. J Affect Disord 2008;Sep 17;epub ahead of print. 50. Goldapple K, Segal Z, Garson C, et al. Modulation of cortical-limbic pathways in major depression: Treatment-specific effects of cognitive behavior therapy. Arch Gen Psychiatry 2004;61:34–41.51. Sinitskaya N, Schuster-Klein C, Guardiola-Lemaitre B, et al. Short day-length increases sucrose consumption and adiposity in rats fed a high-fat diet. Psychoneuroendocrinology 2008;1269–1278.

To order reprints of this article, e-mail Karen Ballen at: [email protected] or call (914) 740-2100.

33. Pirek E, Winkler D, Stastny J, et al. Escitalopram in seasonal affective disorder: Results of an open trial. Pharmacopsychiatry 2007;40:20–24.34. Pirek E, Willeit M, Praschak-Rieder N, et al. Treatment of seasonal af-fective disorder with duloxetine: An open-label study. Pharmacopsychiatry 2008;41:100–105.35. Lundt L. Modafinil treatment in patients with seasonal affective disorder/winter depression; An open-label pilot study. J Affect Disord 2004;81:173–178.36. Pirek E, Winkler D, Konstantinidis A, et al. Agomelatine in the treatment of seasonal affective disorder. Psychopharmacology (Berl) 2007;190:575–579.37. San L, Arrantz B. Agomelatine: A novel mechanism of antidepressant action involving the melatonergic and serotonergic system. Eur Psychiatry 2008;23:396–402. 38. U.S. Food and Drug Administration. FDA Launches a Multi-Pronged Strategy to Strengthen Safeguards for Children Treated with Antidepressant Medications. FDA News: October 15, 2004. Online document at: www.fda.gov/bbs/topics/news/2004/NEW01124.html Accessed October 7, 2008. 39. Michalak EE, Murphy G, Levitt AJ, et al. Quality of life as an outcome indicator in patients with seasonal affective disorder: Results from the Can-SAD study. Psychol Med 2007;37:727–736.40. Monteleieone P, Maj M. The circadian rhythm of mood disorders: Re-cent developments and treatment implications. Eur Neuropsychopharmacol 2008;18:701–711.41. Srinivasan V, Spence DW, Trakht I, et al. Immunomodulation by mela-tonin: Its significance for seasonally occurring diseases. Neuroimmunomodu-lation 2008;15:93–101.42. Wehr TA, Duncan WC Jr, Sher L, et al. A circadian signal of change of season in patients with seasonal affective disorder. Arch Gen Psychiatry 2001;58:1108–1114.

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Shedding Light on Seasonal Affective Disorder