Patients With Seasonal Affective Disorder Have Lower Odor Detection Thresholds Than Control Subjects FREE

MANY SPECIES exhibit seasonal changes in behavior and physiology, such as those associated with breeding, hibernation, and migration. Humans also exhibit seasonal changes, but in humans the changes are now of a more modest degree,^1- 2 as humans have increasingly isolated themselves from the natural environment.³ However, certain individuals experience marked seasonal changes in mood and behavior. Some, for example, have significant recurrent episodes of fall-winter depression with spontaneous remission in spring and summer (seasonal affective disorder winter type [SAD]).⁴ Certain season-specific physiologic⁵ and behavioral⁴ changes that occur in patients with SAD, such as sleepiness, weight gain, loss of interest in sex, and decreased activity and social interactions, resemble some season-specific behavioral changes that occur in other mammals.³

Many organisms use changes in natural light to detect change of season and to regulate seasonal behavior. Light also is likely to be one of the most important factors in the regulation of seasonal changes that occur in SAD, inasmuch as winter symptoms improve after patients are exposed to bright artificial light.^4,6- 7

Olfactory bulbectomy disrupts seasonal responses to light in a variety of mammalian species.^8- 10 Conversely, in laboratory rats¹¹ and house mice,¹² olfactory deafferentation releases seasonal responsiveness to light. With these examples in mind, we hypothesized that the olfactory acuity of patients with SAD would differ from healthy control subjects. We compared olfactory detection thresholds in patients and healthy controls once in the winter and again in the subsequent summer.

Sixteen patients with SAD were enrolled in the study; 14 (7 men and7 women) completed the protocol. The patients' ages ranged from 27 to 66 years, with a mean (SD) age of 42.3 (11.5) years. Patients were diagnosed according to the criteria of Rosenthal et al.⁴ In addition, patients had to meet the DSM-IV criteria for past major depressive episode and be free of any comorbid lifelong Axis I psychiatric disorders.

Twenty-one healthy controls were initially selected to participate;16 (7 men and 9 women) completed the study. The controls' ages ranged from23 to 61 years, with a mean (SD) of 39.0 (10.8) years. Healthy controls were required to have had no personal or family history of Axis I psychiatric disorders.

Patients and controls had to be medically healthy, as determined by medical history, physical examination, and routine laboratory test results. We excluded subjects who reported smoking tobacco within 1 year prior to or during the study, or who used psychotropic medications in the 3 months prior to or during the study. Subjects gave written informed consent after receiving a full explanation of the study, which was approved by the institutional review board of the intramural National Institute of Mental Health, Bethesda, Md.

Subjects were studied during the winter (December, January, or February), when patients were depressed, and during the following summer (June, July, or August), when patients were in remission. The criteria for depressed and remitted conditions were based on scores on the Structured Clinical Interview Guide for the Hamilton Depression Rating Scale, SAD version (SIGH-SAD)¹³ as described in detail elsewhere.¹⁴ After the olfactory test in the winter, patients received light treatment, which was gradually tapered in spring. At least 3 months elapsed between discontinuation of light treatment and summer olfactory testing.

The detection thresholds were measured using a single staircase paradigm.^15- 17 Phenyl ethyl alcohol dissolved in US Pharmacopeia–grade light mineral oil, served as the olfactory stimulus. The odor presentation procedure is described in detail elsewhere.^17- 19 Threshold testing was performed twice, once for each side of the nose, in random order. The naris opposite to the side being tested was occluded with an extensible closed cell foam tape coated with an acrylic adhesive (Microfoam tape; 3M Corp, St Paul, Minn).¹⁷ No feedback was provided.

Patients were asked not to eat or drink for at least 2 hours before testing, and not to use cosmetics on the day of testing. All tests were scheduled between 2 and 5 PM. If an upper respiratory tract infection was present at the time of testing, the test was postponed until the subject had recovered for at least 2 weeks. The tester was blind to whether the subject was a patient or a control. These data were subjected to a 4-way repeated measures analysis of covariance, with group and gender as between-subjects factors, season and side-of-the-nose as within-subjects factors, and age as a covariate.

Patients with SAD had lower detection thresholds (mean = −7.84 log₁₀ vol/vol concentration) than those of controls (mean = −6.23 log₁₀ vol/vol concentration) (F_1,25 = 9.2; P = .006). Detection thresholds were not significantly related to age, gender, side-of-the-nose, season, or their interactions.

As listed in Table 1, there was a nonsignificant trend (group × season interaction; F_1,26 =3.25; P = .08) for a larger difference between patients and controls in the summer (2.2 log₁₀ vol/vol concentration) than in the winter (1.0 log₁₀ vol/vol concentration). A post hoc sample size analysis indicated that at least 35 subjects would be needed in each of the groups for the current group-season interaction to be statistically significant at an α level of .05 with statistical power at 80%.

The adjusted phenyl ethyl alcohol detection threshold mean of the controls(−6.23) falls within the 95% confidence interval of scores from healthy subjects used in recently published birhinal normative data for this test(−6.72 to −6.00).¹⁷ However, the adjusted mean threshold value for patients with SAD (−7.84) falls outside of this range implying that patients with SAD are more sensitive to this odor than age-matched historic controls.¹⁷

Increased olfactory acuity in patients with SAD is consistent with a recent finding that patients with SAD report more discomfort than healthy controls when smelling certain odors.²⁰ As has been previously described in rodents, neuroanatomical connections exist between olfactory pathways and the suprachiasmatic nucleus of the hypothalamus,²¹ a central structure that mediates behavioral responses to change of season that are induced by change in the length of daylight.²² Furthermore, olfactory stimulation coadministered with light augments light-induced phase shifts in circadian rhythms generated by the suprachiasmatic nucleus and fos expression in its neurons.²³ Thus, it is possible that a lower detection threshold results in increased olfactory stimulation and, subsequently, via olfactory projections to the suprachiasmatic nucleus neurons, altering their response to changes in natural daylight. This could either contribute to, or compensate for, previously described vestigial photoperiodic responses in patients with SAD.⁵

In light of the evidence that depression and seasonality may be 2 distinct factors that coexist in patients with SAD,^24- 25 our results might also reflect a relationship between olfaction and depression, rather than seasonality. Given a partial colocalization between olfactory and emotional processing, researchers had hypothesized an impaired olfactory performance in patients with recurrent depression. However, testing olfactory abilities (such as odor identification^14,26- 30 and odor detection thresholds^{14,26,31- 32})in patients with depressive disorders, produced inconsistent results. This lack of consistency could be a result of diagnostic heterogeneity, variable depression severity, variable testing methods, and small samples. Consistent with our current results, Gross-Isseroff et al³² found a greater rather than weaker odor detection ability in patients with major depression than in healthy controls. Specifically, the authors reported that patients with major depression in remission after 6 weeks of antidepressant treatment exhibit higher olfactory acuity than healthy controls. Our results are similar to those Gross-Isseroff et al³² in that the difference in odor detection thresholds between patients and controls was most apparent when patients were in remission.

What is the mechanism of increased olfactory acuity in patients with depression? Functional neuroimaging data suggest that the orbitofrontal cortex and the amygdala, neuroanatomical areas of partial overlap between olfactory and emotional processing, are overly activated in patients with major depression.^33- 34 It is thus possible that increased activity in the orbitofrontal cortex or amygdala, persisting even when depression is in remission,³³ may be associated with increased olfactory acuity. During an episode of major depression, cognitive impairment related to the severity of depression may weaken patients' odor detection performance.

Although light treatment in winter is effective,^4,6- 7 it does not make patients with SAD feel as well as they do in summer.³⁵ Since olfactory stimulation augments phase shifting effects of light and increases light-induced fos expression in the suprachiasmatic nucleus in rodents,²³ it seems worth investigating whether olfactory stimulation can augment the efficacy of light treatment.

Limitations of the study include a small sample size and an order effect(summer following winter) that might have contributed to the lack of statistical significance of the group-season interaction, but seem unlikely to have contributed to our main finding. Another limitation is not measuring nasal airflow. One cannot rule out that an ultradian rhythm in airflow (alternation in higher and lower airflow on each side of the nose),^36- 38 might be related to an ultradian rhythm in monorhinal detection thresholds. Nevertheless, data based on actual measurement of odor detection thresholds, argue against a relationship between airflow and olfactory acuity.^39- 40

Patients with SAD had lower odor detection thresholds than healthy controls. One or more coexisting physiologic and clinical features of SAD (eg, vestigial responses to seasonal changes in natural light, marked seasonal behavioral rhythms, or recurrent depression) may be associated with a more acute sense of smell.

Submitted for publication September 5, 2001; final revision received February 8, 2002; accepted February 20, 2002.

This study was supported by the National Institute of Mental Health(Intramural Research Program) and by grant PO1 00161 from the the National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Md.

The preliminary results of this study were presented at the International Congress on Chronobiology, Washington, DC, August 28, 1999.

We thank John Stiller, MD, and Daniel Aeschbach, PhD, for comments on the manuscript; Poupak Afshar for logistical support; Mulon Luo and Charles No for olfactory testing; Agatha O. Ndika for data management; Ronald Barnett, PhD, Frances Myers, Holly Lowe, and Todd Hardin for screening and rating patients; and Holly Giesen for editorial assistance.

Corresponding author and reprints: Teodor T. Postolache, MD, Section on Biological Rhythms, National Institute of Mental Health, National Institutes of Health, 10 Center Dr, Room 3S-231, Bethesda, MD 20892 (e-mail: postolache@nih.gov).