Cortisol and Seasonal Changes in Mood and Behavior

Whoever wishes to pursue the science of medicine in a direct manner must first investigate the seasons of the year and what occurs in them." --Hippocrates¹

Since ancient times, people have been aware of seasonal changes in mood and behavior.^1-3 Poets have described the sense of sadness, loss, and lethargy that can accompany the shortening days of fall and winter.¹ Many cultures and religions have winter festivals associated with candles or fire. These festivals represent attempts to raise spirits in a season when the days are short.

Historical background

The concept of seasonal mood disorders dates back to the dawn of medicine.^2,3 Seasonal depressions were described by the Greek physician Hippocrates circa 400 bc.⁴ About 2000 years ago, the Greek philosopher Posidonius wrote that "melancholy occurs in autumn, whereas mania in summer."⁵ In the second century, Greco-Roman physicians were treating depression and lethargy with sunlight directed toward the eyes.^6,7 In 1894, explorer Frederick Cook linked seasonal loss of sunlight to a mood disorder.⁸ Cook described a syndrome characterized by a loss of sexual desire and energy, fatigue, and a profoundly depressed mood. The French neurologist Esquirol⁹ and the German psychiatrist Kraepelin¹⁰ both described seasonal changes in mood in books published in the years 1845 and 1921, respectively.

Characteristics of seasonal affective disorder

In 1984, Rosenthal and associates¹¹ described the syndrome of "seasonal affective disorder" (SAD), a condition in which depression in fall and winter alternates with nondepressed periods in spring and summer. It was suggested that in order for a diagnosis of SAD to be made, the following criteria must be met: a history of a major affective disorder; at least 2 consecutive previous years in which depression developed during fall or winter and remitted by the following spring and summer; absence of any other Axis I psychiatric disorder; and absence of any clear-cut, seasonally changing psychosocial variables that would account for the seasonal variability in mood and behavior.¹¹

Later, an opposite pattern--depression in the summer and nondepressed periods in the winter ("summer SAD")--was described.¹² These 2 types of SAD probably represent a subset of a variety of seasonal behavioral disorders. SAD has been included in DSM-III-R and DSM-IV as having a "seasonal pattern," an adjectival modifier of any form of seasonally recurrent mood disorder.^13,14

The onset of winter SAD usually occurs between the age of 20 and 30 years, but affected people often do not seek psychiatric help for some time.^3,15 Many patients with SAD report disliking winter since their teenage years, although the problem usually becomes severe only in adulthood. Sadness, anxiety, irritability, decreased activity, difficulties at work, social withdrawal, changes in appetite, decreased libido, and changes in sleep are characteristic symptoms of winter SAD.¹¹ Most patients with winter SAD have atypical depressive symptoms such as increased sleep duration, increased appetite, weight gain, and carbohydrate craving. Depressive episodes are generally mild to moderate, but some patients need hospitalization.

The neurovegetative symptoms of subsyndromal SAD are similar to those of SAD, but major depression is absent.¹⁶ Patients with winter SAD may experience a reversal of their winter symptoms in summer, including mild hypomania; elevated mood; increased libido, social activity, and energy; and decreased sleep requirements, appetite, and weight.³ Most episodes of SAD occur within unipolar major depressive disorder, a substantial minority have accompanying hypomanic episodes (bipolar II disorder), and very few are associated with manic episodes. Patients with summer SAD usually report typical vegetative symptoms such as insomnia and loss of appetite and weight.¹²

The degree to which season changes affect mood, energy, sleep, appetite, food preference, or desire to socialize with others has been called "seasonality."^1,16 Seasonality can manifest in different degrees in different individuals. It can be viewed as a dimension ranging from the absence of seasonal changes to the occurrence of extreme seasonal changes (eg, some people experience only very mild seasonal changes while others are severely affected).

Children with SAD usually present with fatigue, irritability, difficulty in getting out of bed in the morning, and problems in school.¹⁷ Sadness and changes in appetite have also been observed in children with SAD. Children with winter SAD tend to blame the external world (parents, teachers, etc) for treating them poorly.

Seasonality of mood and behavior is common throughout the US population.^16,18-20 Surveys suggest that the prevalence of SAD in the United States increases with increasing latitude--ranging from 1.4% in Florida to 9.7% in New Hampshire.¹⁹ A survey in the Washington, DC, area found that about 4% of the population have winter SAD and over 10% more have subsyndromal features of SAD.¹⁷ Twenty-seven percent of respondents reported that changes in the seasons were a problem for them, 66% reported seasonal changes in energy level, 64% reported some seasonal changes in mood, and 49% reported seasonal changes in weight. Another survey, in New York City, indicated that about 6% of the population had seasonal impairment equivalent to that of patients with SAD, 18% reported milder symptoms that were bothersome, and 35% noted symptoms but did not complain.²⁰

Many clinical studies report that winter SAD mainly affects women.^3,15 However, the high proportion of women seen in research clinics may be a result of selection bias. Blazer and colleagues²¹ suggested that SAD with major depressive episodes is more frequent among men, whereas women more commonly experience minor depression with a seasonal pattern.

Identification of a seasonal pattern can only be made if both the patient and physician actively look for it.^1,3 Clinicians should ask the following questions when SAD is suspected. When the seasons change, do you:

• Feel down or depressed?
• Have less energy than usual?
• Feel less productive or creative?
• Need more sleep?
• Have less control over your appetite?

If physicians fail to ask these questions, many patients with SAD may be labeled as having a nonseasonal depressive disorder.

HPA function

Various hypotheses related to the pathophysiology of SAD have been proposed.^1,3,22,23 One of these hypotheses suggests that abnormalities of hypothalamic-pituitary-adrenal (HPA)-axis function may contribute to the pathogenesis of SAD. The HPA axis controls the secretion of corticotropin-releasing hormone (CRH), corticotropin (adrenocorticotropic hormone), and cortisol.^24,25 CRH is secreted from the paraventricular nucleus of the hypothalamus as well as from extrahypothalamic sites. It acts on the anterior pituitary gland to cause the release of corticotropin into the bloodstream, where it acts on the adrenal cortex to cause the production and release of cortisol into the bloodstream.

Cortisol has diverse and widespread actions throughout the body and brain. It secondarily inhibits corticotropin and CRH release via negative feedback, although it may augment CRH release in the amygdala. Feedback inhibition is mediated via low-affinity glucocorticoid receptors (GRs) and high-affinity mineralocorticoid receptors (MRs). In the brain, MRs are located primarily in the hippocampus; GRs are more widely distributed in the hypothalamus, pituitary, cortex, and elsewhere. Species from humans to the most ancient organisms share components of the HPA axis.

Cortisol and the circadian rhythm

Release of CRH from the hypothal- amus is influenced by stress, blood levels of cortisol, and the sleep-wake cycle.^26-28 In healthy persons, levels of cortisol rise rapidly after waking, reaching a peak within 30 to 45 minutes. They then gradually diminish over the day, rising again in late afternoon. Cortisol levels fall in late evening, reaching a trough during the middle of the night. The circadian pattern of cortisol release is controlled by the suprachiasmatic nucleus (SCN) of the hypothalamus, also known as the "body clock." Nerve signals from the SCN cause the paraventricular nucleus of the hypothalamus to release pulses of CRH roughly once per hour, resulting in HPA-axis activation and cortisol release. There are also direct links between the SCN and the adrenal gland itself (bypassing the HPA axis) through sympathetic nerve fibers, causing the adrenal gland to become more sensitive to corticotropin stimulation during the morning and further adding to the circadian pattern of cortisol release throughout the day.

The HPA axis and depression

Over the past 2 decades, there has been a shift from viewing excessive HPA activity in depression as an epiphenomenon to its having specific effects on symptom formation and cognition.^29-31 Studies have demonstrated that hypercortisolism is involved in the pathogenesis of depressive disorders. Researchers have suggested that HPA dys- regulation is involved in the causality of depression and have proposed that antidepressants may act through normalization of pathologic HPA-axis changes.^30-32 The following clinical observations have been made in patients with depression:

• The number of cortisol and corticotropin secretory pulses is increased, which is also reflected in elevated urinary cortisol production rates.
• Levels of CRH in the cerebrospinal fluid are elevated.
• The number of CRH-secreting neurons in limbic brain regions is increased.
• The number of CRH-binding sites in the frontal cortex is reduced as a secondary effect of increased CRH concentration.
• The dexamethasone suppression test (DST), CRH stimulation test, combined DST-CRH stimulation test, and other neuroendocrine function tests indicate the presence of HPA dysregulation.^29-34

The DST showed that a high proportion of patients with various affective disorders have elevated cortisol levels, thus escaping the suppressive effect of dexamethasone.³⁴ After CRH became available for clinical studies, the DST was combined with CRH administration.^30,35,36 In this test, patients are pretreated with a single dose of dexamethasone at 11 pm and receive CRH intravenously at 3 pm the following day. The resulting DST-CRH stimulation test proved to be much more sensitive in detecting HPA system alterations than the DST alone. Several studies showed that depressed patients pretreated with dexamethasone reacted with an exaggerated corticotropin and cortisol response.^30,34,35 A number of studies found that cortisol can affect mood and behavior and disrupt memory and recall.^37-39 For example, cortisol administration in healthy volunteers alters processes associated with prefrontal cortex functions such as inhibitory control, atten- tion regulation, and planning.^38,39

Seasons and cortisol

Most seasonal investigations into cortisol have found the highest levels to be present in winter.⁴⁰ Quarterly measurements of morning and evening cortisol levels were determined in a longitudinal study of healthy male and female volunteers.⁴¹ There was a season-al variation in cortisol levels with significantly higher levels found in winter and fall than in spring and summer. Walker and associates⁴² also reported that in healthy men, winter plasma cortisol levels were significantly higher than summer values. Studies that investigated the circadian profile of cortisol in healthy individuals indicated that circadian rhythm was delayed in winter.^43,44 In an Antarctic study, the circadian rhythm of cortisol showed low am- plitude and a phase advance in summer when compared with other seasons.⁴⁵

The circadian rhythms of cortisol obtained without a "constant routine" (a protocol used in circadian rhythms or sleep studies to minimize exogenous effects such as changes in body position, temperature, and meals) were found to be similar in SAD patients and controls in both phase and amplitude; the rhythms did not change with successful bright light therapy.⁴⁶ Since sleep has a suppressing effect on cortisol,⁴⁷ those cortisol data do not reflect the unmasked endogenous circadian rhythm of cortisol.

Avery and colleagues⁴⁸ assessed cortisol rhythms during a constant routine in patients with winter SAD and in healthy controls. After sleep was standardized for 6 days, the subjects were sleep-deprived and restricted to bed rest for 27 hours while cortisol levels were assessed. The minimum level of the cortisol rhythm was phase-delayed in the SAD group compared with the control group; however, with bright light treatment, the minimum level advanced. Another study reported that SAD patients had normal cortisol and corticotropin levels but their responses to CRH were delayed and significantly reduced.⁴⁶ With bright light therapy, the responses of cortisol and corticotropin to CRH increased significantly.

We have studied the question of whether there are circannual effects on clinical parameters, baseline cortisol and prolactin levels, and cortisol and prolactin responses to fenfluramine hydrochloride administration in subjects with nonseasonal major depression.⁴⁹ We compared subjects experiencing major depressive episodes in fall or spring (the spring/fall group) with subjects experiencing major depressive episodes in summer or winter (the winter/summer group) and found that baseline cortisol levels were significantly higher in the spring/fall group compared with the winter/summer group.

Our observation that baseline plasma cortisol levels were higher in the spring/fall group than in the winter/ summer group suggests that these 2 groups may represent different biologic subtypes of major depression. This hypothesis is supported by the observation by Beck-Friis and associates,⁵⁰ who examined the per-month frequency of patients with one or more depressive episodes registered yearly from first onset of illness. The frequencies--calculated from the patients' previous records--were a percentage of the maximum number of patients and were separated for patients with normal and abnormal results on the DST. The authors demonstrated a trend for higher incidences of depression during spring and fall among the patients with normal DST results, whereas the distribution of depressive periods during the year in the abnormal DST group was more uniform.

Another study of depressed patients showed a significantly biannual rhythm in the postdexamethasone cortisol values in depressed men, with peaks in June and December and troughs in March and September.⁵¹ The hypothesis that the spring/fall group and the winter/summer group represent different biologic subtypes of major depression is also supported by the observation that the number of binding sites to serotonin receptors during spring and fall is 12% higher than in winter and summer.⁵²

Treatment of SAD

Light therapy is recommended as a first-line treatment for SAD in expert and consensus clinical guidelines.^53-57 It is possible that light therapy reduces HPA-axis abnormalities associated with SAD.

It has also been shown that antidepressants may prevent and treat SAD.^57,58 A recent report suggests that light treatment showed earlier response onset and lower rates of some adverse events relative to fluoxetine, but there were no other significant differences in outcome between light therapy and antidepressant medication.⁵⁷ Another study concluded that it is possible to prevent recurrence of SAD episodes by beginning bupropion treatment early in the season while patients are still well.⁵⁸ Antidepressants may act by normalizing the pathologic changes in HPA function in SAD patients. Also of interest, a recent report suggests that mifepristone,⁵⁹ a steroid antagonist, may be useful for the treatment of SAD.

Increased cortisol secretion caused by major and minor stressful events may contribute to the development of SAD and other depressive disorders in vulnerable individuals.⁶⁰ Therefore, one of the goals of prevention of such stress-related disorders is to help individuals to be more competent in managing their behavior and emotions in reaction to the negative aspects of their environment.

Dr Sher is an associate clinical professor of psychiatry at Columbia University College of Physicians and Surgeons and a research psychiatrist in the department of neuroscience at the New York State Psychiatric Institute in New York City. He reports no conflicts of interest regarding the subject matter of this article.

References:

References:1. Rosenthal NE. Winter Blues: Everything You Need to Know to Beat Seasonal Affective Disorder. Rev ed. New York: Guilford Press; 2006.
2. Wehr TA. Seasonal affective disorder. A historical overview. In: Rosenthal NE, Blehar MC, eds. Seasonal Affective Disorders and Phototherapy. New York: Guilford Press; 1989:11-32.
3. Oren DA, Rosenthal NE. Seasonal affective disorders. In: Paykel ES, ed. Handbook of Affective Disorders. 2nd ed. New York: Guilford Press;1992: 551-567.
4. Hippocrates. Aphorisms. In: Jones WHS, trans-ed. Hippocrates. Vol. 4. Cambridge, Mass: Harvard University Press; 1931:128-129.
5. Roccatagliata G. A History of Ancient Psychiatry. New York: Greenwood Press; 1986.
6. Aretaeus. The Extant Works of Aretaeus, the Cappadocian. Adams F, trans-ed. London: Sydenham Society; 1856.
7. Aurelianus C. On Acute Diseases and On Chronic Diseases. Drabkin IE, trans-ed. Chicago: University of Chicago Press; 1950.
8. Cook FA. Gynecology and obstetrics among the Eskimo. Brooklyn Med J. 1894;8:154-169.
9. Esquirol JE. Mental Maladies. A Treatise on Insanity. Hunt EK, ed. Philadelphia: Lea and Blanchard; 1845.
10. Kraepelin E. Manic-Depressive Illness and Paranoia. Barklay RM, trans, Robertson GM, Livingstone E, Livingstone M, eds. Edinburgh: E&S Livingstone; 1921.
11. 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.
12. Wehr TA, Sack DA, Rosenthal NE. Seasonal affective disorder with summer depression and winter hypomania. Am J Psychiatry. 1987;144:1602-1603.
13. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 3rd ed rev. Washington, DC: American Psychiatric Publishing; 1987:224.
14. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Publishing; 1994: 389-390.
15. Partonen T, Lonnqvist J. Seasonal affective disorder. Lancet. 1998;352:1369-1374.
16. Kasper S, Wehr TA, Bartko JJ, et al. Epidemiological findings of seasonal changes in mood and behavior. A telephone survey of Montgomery County, Maryland. Arch Gen Psychiatry. 1989;46:823-833.
17. Rosenthal NE, Carpenter CJ, James SP, et al. Seasonal affective disorder in children and adolescents. Am J Psychiatry. 1986;143:356-358.
18. Magnusson A. An overview of epidemiological studies on seasonal affective disorder. Acta Psychiatr Scand. 2000;101:176-184.
19. Rosen LN, Targum SD, Terman M, et al. Prevalence of seasonal affective disorder at four latitudes. Psychiatry Res. 1990;31:131-144.
20. Terman M. On the question of mechanism in phototherapy for seasonal affective disorder: considerations of clinical efficacy and epidemiology. J Biol Rhythms. 1988;3:155-172.
21. Blazer DG, Kessler RC, Swartz MS. Epidemiology of recurrent major and minor depression with a seasonal pattern. The National Comorbidity Survey. Br J Psychiatry. 1998;172:164-167.
22. Sher L. Genetic studies of seasonal affective disorder and seasonality. Compr Psychiatry. 2001;42: 105-110.
23. Magnusson A, Boivin D. Seasonal affective disorder: an overview. Chronobiol Int. 2003;20:189-207.
24. Hauger RL, Datzenberg FM. Regulation of the stress response by corticotropin-releasing factor receptors. In: Conn PM, Freeman ME, eds. Neuroendocrinology in Physiology and Medicine. Totowa, NJ: Humana Press; 2000:261-287.
25. Tsigos C, Chrousos GP. Hypothalamic-pituitary- adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2002;53:865-871.
26. Van Cauter E, Turek FW. Endocrine and other biological rhythms. In: De Groot LJ, ed. Endocrinology. Philadelphia: WB Saunders;1995:2497-2548.
27. Van Cauter E, Speigel K. Circadian and sleep control of hormonal secretions. In: Turek FW, Zee PC, eds. Regulation of Sleep and Circadian Rhythms. New York: Marcel Dekker, Inc; 1999:397-425.
28. Jameson DW. Mind-Body Health and Stress Tolerance. Lincoln, Neb: iUniverse;2003.
29. Shatzberg AF, Garlow SL, Nemeroff CB. Molecular and cellular mechanisms of depression. In: Davis KL, Charney D, Coyle JT, Nemeroff C, eds. Neuropsychopharmacology: The Fifth Generation of Progress. Philadelphia: Lippincott, Williams & Wilkins; 2002:1039-1050.
30. Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology. 2000;23: 477-501.
31. Holsboer-Trachsler E, Stohler R, Hatzinger M. Repeated administration of the combined dexamethasone-human corticotropin releasing hormone stimulation test during treatment of depression. Psychiatry Res. 1991;38:163-171.
32. Keeney A, Jessop DS, Harbuz MS, et al. Differential effects of acute and chronic social defeat stress on hypothalamic-pituitary-adrenal axis function and hippocampal serotonin release in mice. J Neuroendocrinol. 2006;18:330-338.
33. Sher L, Oquendo MA, Galfalvy HC, et al. Age effects on cortisol levels in depressed patients with and without comorbid post-traumatic stress disorder, and healthy volunteers. J Affect Disord. 2004;82:53-59.
34. Carroll BJ. Use of the dexamethasone suppression test in depression. J Clin Psychiatry. 1982;43:44-50.
35. Heuser I, Yassouridis A, Holsboer F. The combined dexamethasone/CRH test: a refined laboratory test for psychiatric disorders. J Psychiatr Res. 1994;28: 341-356.
36. Sher L, Cooper TB, Mann JJ, Oquendo MA. Modified dexamethasone suppression-corticotropin-releasing hormone stimulation test. In: Kandel I, Merrick J, Sher L, eds. Adolescence and Alcohol. An International Perspective. London and Tel Aviv: Freund Publishing House. In press.
37. Gold PW, Drevets WC, Charney DS. New insights into the role of cortisol and the glucocorticoid receptor in severe depression. Biol Psychiatry. 2002;52:381-385.
38. Lupien SJ, Gillin CJ, Hauger RL. Working memory is more sensitive than declarative memory to the acute effects of corticosteroids: a dose-response study in humans. Behav Neurosci. 1999;113:420-430.
39. Young AH, Sahakian BJ, Robbins TW, Cowen PG. The effects of chronic administration of hydrocortisone on cognitive function in normal male volunteers. Pharmacology (Berl). 1999;145:260-266.
40. Lacoste V, Wirz-Justice A. Seasonal variation in normal subjects: an update of variables current in depression research. In: Rosenthal NE, Blehar MC, eds. Seasonal Affective Disorders and Phototherapy. New York: Guilford Press; 1989:167-229.
41. King JA, Rosal MC, Ma Y, et al. Sequence and seasonal effects of salivary cortisol. Behav Med. 2000;26: 67-73.
42. Walker BR, Best R, Noon JP, et al. Seasonal variation in glucocorticoid activity in healthy men. J Clin Endocrinol Metab. 1997;82:4015-4019.
43. Reinberg A, Lagoguey M, Cesselin F, et al. Circadian and circannual rhythms in plasma hormones and other variables of five healthy young human males. Acta Endocrinol (Copenh). 1978;88:417-427.
44. Kennaway DJ, Royles P. Circadian rhythms of 6-sulphatoxy melatonin, cortisol and electrolyte ex-cretion at the summer and winter solstices in normal men and women. Acta Endocrinol (Copenh). 1986;113: 450-456.
45. Griffiths PA, Folkard S, Bojkowski C, et al. Persistent 24-h variations of urinary 6-hydroxy melatonin sulphate and cortisol in Antarctica. Experientia. 1986;42: 430-432.
46. Joseph-Vanderpool JR, Rosenthal NE, Chrousos GP, et al. Abnormal pituitary-adrenal responses to corticotropin-releasing hormone in patients with seasonal affective disorder: clinical and pathophysiological implications. J Clin Endocrinol Metab. 1991;72:1382-1387.
47. Weitzman ED, Zimmerman JC, Czeisler CA, Ronda J. Cortisol secretion is inhibited during sleep in normal man. J Clin Endocrinol Metab. 1983;56:352-358.
48. Avery DH, Dahl K, Savage MV, et al. Circadian temperature and cortisol rhythms during a constant routine are phase-delayed in hypersomnic winter depression. Biol Psychiatry. 1997;41:1109-1123.
49. Sher L, Oquendo MA, Galfalvy HC, et al. Higher cortisol levels in spring and fall in patients with major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2005; 29:529-534.
50. Beck-Friis J, Ljunggren JG, Thoren M, et al. Melatonin, cortisol and ACTH in patients with major depressive disorder and healthy humans with special reference to the outcome of the dexamethasone suppression test. Psychoneuroendocrinology. 1985;10:173-186.
51. Maes M, Schotte C. Seasonal variation in postdexamethasone cortisol values in depressed inpatients. Results of least squares cosine spectral analysis. J Affect Disord. 1997;44:5-12.
52. Khait VD, Huang Y, Malone KM, et al. Is there circannual variation of human platelet 5-HT(2A) binding in depression? J Affect Disord. 2002;71:249-258.
53. Lam RW, Tam EM, Gorman CP, et al. Light treatment. In: Levitt AJ, Lam RW, eds. Canadian Consensus Guidelines for the Treatment of Seasonal Affective Disorder. Toronto: Clinical & Academic Publishing; 1999: 64-88.
54. Bauer M, Whybrow PC, Angst J, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: acute and continuation treatment of major depressive disorder. World J Biol Psychiatry. 2002;3: 5-43.
55. Terman M, Terman JS. Light therapy for seasonal and nonseasonal depression: efficacy, protocol, safety, and side effects. CNS Spectr. 2005;10:647-663.
56. Sher L. Light therapy for depressive disorders. Psychiatric Times. 2004;22:68, 70-71.
57. Lam RW, Levitt AJ, Levitan RD, et al. The Can-SAD study: a randomized controlled trial of the effectiveness of light therapy and fluoxetine in patients with winter seasonal affective disorder. Am J Psychiatry. 2006;163:805-812.
58. Modell JG, Rosenthal NE, Harriett AE, et al. Seasonal affective disorder and its prevention by anticipatory treatment with bupropion XL. Biol Psychiatry. 2005;58: 658-667.
59. DeBattista C, Belanoff J. The use of mifepristone in the treatment of neuropsychiatric disorders. Trends Endocrinol Metab. 2006;17:117-121.
60. Sher L. Daily hassles, cortisol, and the pathogenesis of depression. Med Hypotheses. 2004;62:198-202.