- Email: [email protected]
Circadian misalignment in major depressive disorder
Psychiatry Research 168 (2009) 259–261
Contents lists available at ScienceDirect
Psychiatry Research j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p s y c h r e s
Brief report
Circadian misalignment in major depressive disorder Jonathan Emens a,⁎, Alfred Lewy b, John Mark Kinzie a, Diana Arntz a, Jennifer Rough a a b
Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA Departments of Psychiatry, Ophthalmology and Physiology/Pharmacology, Oregon Health & Science University, Portland, OR, USA
a r t i c l e
i n f o
Article history: Received 12 September 2008 Received in revised form 24 March 2009 Accepted 15 April 2009
a b s t r a c t It has been hypothesized that the circadian pacemaker plays a role in major depressive disorder (MDD). We sought to determine if misalignment between the timing of sleep and the pacemaker correlated with symptom severity in MDD. Depression severity correlated with circadian misalignment: the more delayed, the more severe the symptoms. © 2009 Elsevier Ireland Ltd. All rights reserved.
Keywords: Melatonin Circadian rhythms Depression Dim light melatonin onset (DLMO) Phase angle difference (PAD) Sleep
1. Introduction Affective disorders have long been thought to be related to circadian rhythms (for reviews, see Van den Hoofdakker, 1994; Boivin, 2000). In addition to circadian rhythmicity in mood (Boivin, 2000), other indications of a relationship include symptoms of sleep disruption and polysomnographic changes (Peterson and Benca, 2006; Armitage, 2007), differences in the amplitude and timing (phase) of the biological clock (endogenous circadian pacemaker) (Boivin, 2000), therapeutic effects of sleep deprivation or advancement of sleep timing (Van den Hoofdakker, 1994; Wehr, 2000), and therapeutic effects of light therapy (Golden et al., 2005). One of the first circadian theories for major depressive disorder (MDD) posited that the endogenous circadian pacemaker is set abnormally early (misaligned) with respect to the timing of sleep (Kripke et al., 1978; Wehr et al., 1979). Accordingly, advancing the timing of sleep was found to be antidepressant in some patients (Wehr et al., 1979). However, subsequent studies have not consistently found that the endogenous circadian pacemaker is set either abnormally early (phase advanced) or late (phase delayed) in individuals with depression (Van den Hoofdakker, 1994). Nonetheless, misalignment between timing of the clock and the timing of sleep, in either direction, could be depressant within vulnerable individuals (Kripke, 1983; Lewy et al., 1985; Wehr, 2000; Lewy et al., 2006). Indeed, we have recently shown that such misalignment correlates with symptom severity in seasonal affective disorder (SAD) ⁎ Corresponding author. Sleep and Mood Disorders Laboratory, Department of Psychiatry, L-469, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97239 USA. Tel.: +1 503 494 4041; fax: +1 503 494 5329. E-mail address: [email protected] (J. Emens). 0165-1781/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2009.04.009
(Lewy et al., 2006). We conducted a small pilot study to determine if a similar finding could be demonstrated in MDD. 2. Methods Eighteen females, 19 to 60 years old, with persistent symptoms (including poor sleep), despite current treatment for depression, were recruited by advertisement and referral by providers. Subjects gave written informed consent and were screened using the Mini-International Neuropsychiatric Interview (Sheehan et al., 1998), a health questionnaire and routine laboratory tests. Inclusion criteria included a DSM-IV diagnosis of MDD (including partial remission), a scoreN 7 on the 21-Item Hamilton Depression Rating scale (HAM-D), current treatment for depression, and no changes in antidepressant medications for the past 6 weeks and for the week of study. Exclusion criteria included active suicidal ideation, SAD, clinically significant laboratory abnormalities, transmeridian travel or shift work for the prior 3 months and use of medications that would interfere with melatonin production. Subjects were asked to maintain a daily sleep/wake schedule of their choosing (8 h in bed, bedtimes and wake times within ±1/2 hour) at home for 1 week. They kept a sleep diary to document bedtimes, midsleep, wake times and time in bed, and a wrist actigraph (AW-64 Actiwatch ®, Mini-Mitter Co., Bend, OR) was used to document sleep start, sleep end, total sleep time, sleep efficiency and average activity. One subject failed to complete a sleep diary (subject 7), and reliable actiwatch data were not obtained in another (subject 6). After the ambulatory week, subjects were admitted to the Clinical and Translational Research Center in the late afternoon. Following clinical assessments that included ratings on the Hamilton Rating Scale for Depression (HAM-D), an intravenous catheter was inserted and blood samples were drawn in dim light (b10 lux) every 30 min for 6 h (approximately 18:00 to midnight). Plasma samples were assayed for melatonin by RIA (ALPCO Ltd., Windham, NH). The lower limit of sensitivity is 0.2 pg/ml. Circadian phase was determined using the dim light melatonin onset (DLMO) defined as the interpolated time when plasma melatonin concentrations crossed the threshold of 10 pg/ml (Lewy et al., 1999). Circadian misalignment was measured using the time interval or phase angle difference (PAD) between the DLMO and the average midpoint of sleep of the prior week (Lewy et al., 2006). Spearman correlations (rs) were calculated with SPSS 12.0 (SPSS Inc.). Subjects were studied while taking a variety of psychiatric medications at different times of year. Subject 1 (□) was studied in October while taking citalopram. Subject 2
260
J. Emens et al. / Psychiatry Research 168 (2009) 259–261
Fig. 1. Correlation of Phase Angle Difference (PAD) with depression severity measured using the HAM-D. The PAD is the time interval in hours between the 10 pg/ml dim light melatonin onset (DLMO) and diary midsleep during the prior week.
(▲) was studied in November while taking duloxetine and quetiapine. Subject 3 (■) was studied in February while taking escitalopram. Subject 4 ( ) was unmedicated and studied in June; Subject 5 (●) was studied in June while taking extended release venlafaxine and alprazolam. Subject 6 (⋄) was unmedicated and studied in July. Subject 7 was studied in August while taking nortriptyline, sertraline and gabapentin. Subject 8 (○) was studied in September while taking citalopram; Subject 9(Δ) was studied in November while taking venlafaxine, buproprion and lorazepam; Subject 10 (✕) was studied in November while taking escitalopram; Subject 11(♦)was studied in September while taking buprorion, citalopram, and trazodone; Subject 12 ( ) was studied in March and was unmedicated; Subject 13 (✱) was studied in July while taking citalopram; Subject 14 ( ) was studied in August while taking duloxetine, buproprion, ) was studied in December clonazepam, quetiapine, and zolpidem; Subject 15 ( while taking fluoxetine, venlafaxine, and buproprion; Subject 16 ( ) was studied in February while taking venlafaxine, trazodone, and lamotrigine; Subject 17 ( ) was studied in April while taking duloxetine and buproprion; Subject 18 ( ) was studied in April and was unmedicated.
3. Results Subjects had an average HAM-D score (±SD) of 15.9 ± 4.6 (range: 7–19) indicating mild to moderate symptoms of depression. There was no difference between the screening and study HAM-D score (16.1 vs. 15.9, respectively, P = 0.89). Average bedtimes and wake times were 23:17 ± 1:20 and 7:39 ± 1:08, respectively, the average time of the DLMO was 21:13 ± 2:03 and subjects had an average PAD of 6:10 ± 1:37 h [consistent with normal historical controls, 6:04 ± 0:55 h (Lewy et al., 1998)]. There was a negative correlation (rs = −0.61, P = 0.01) between HAM-D scores and the PAD calculated using sleep diaries (excluding subject 7): shorter PADs were associated with worse symptoms of depression (Fig. 1 shorter PADs indicate a delay of the endogenous circadian pacemaker relative to the timing of sleep). This correlation remained significant when the sleep items were removed from the HAM-D (rs = − 0.53, P = 0.03). The correlation of HAM-D score and PAD calculated using actigraphy data (excluding subject 6) was similar (rs = − 0.57, P = 0.02). There were consistent correlations between HAM-D scores and the DLMO-bedtime (rs = − 0.62, P = 0.01) and wake time-DLMO (rs = 0.57, P = 0.02) intervals. No significant correlations were found between HAM-D scores and any sleep diary or actigraphy measures. 4. Discussion We found a correlation between symptoms of depression and circadian misalignment in a small number of heterogeneously treated subjects with persistent mild to moderate depression and complaints of poor sleep. This correlation is in the phase-delay direction, as opposed to the phase-advance direction previously hypothesized (Wehr et al., 1979; Kripke, 1983; Wehr, 2000). The present results are to some extent consistent with those in SAD (Lewy et al., 2006), in which symptom severity in the prototypical phase-delayed group (pre-treatment baseline PAD b6) correlated with the degree of phase
delay in PAD, whereas a smaller phase-advanced group (PADN6) was also found. As in SAD, no trait difference was found: PAD average and range were similar to that of historical controls (Lewy et al., 1998). This was a small pilot study and a larger data set could confirm the linear relationship between circadian misalignment and depression symptoms, favor a parabolic relationship as we found in SAD, or fail to confirm either (Lewy et al., 2006). In any event, we think it less likely that a larger sample will reveal a correlation in the opposite direction (i.e., greater symptom severity the more the DLMO is advanced relative to mid-sleep), which is what would be predicted based on the phase-advance hypothesis of depression (Kripke et al., 1978; Wehr et al., 1979). Various potential confounders limit our conclusions. Sleep duration has been shown to correlate with symptom severity in MDD (Hubain et al., 2006), and this in turn might affect PAD. However, we think it unlikely that such an association explains our findings: HAM-D score did not significantly correlate with sleep duration; furthermore when the sleep items were removed from the HAM-D, the correlation with PAD was essentially unchanged. The correlation we found may be due to an association between symptom severity and differences in the timing or intensity of time cues that reset the circadian pacemaker (e.g., light). In particular, antidepressant medications have been shown to reset the pacemaker (Morin, 1999), and differences in dose and medication type could account for our findings. However, even if circadian misalignment is not causal in MDD, as it appears to be in SAD, these data remain important because circadian misalignment might explain why sleep complaints persist in treated depressed patients (Peterson and Benca, 2006; Sack et al., 2007). Despite the limitations inherent in such a small study, the correlation of a biological marker with depressive symptoms in MDD is worthy of follow-up, controlling for confounders and in a more numerous and broader patient population (e.g., males, patients with minimal sleep complaints, and patients with more severe symptoms). Further studies are also warranted to investigate whether correcting circadian misalignment by using circadian resetting agents, such as light or melatonin, to advance the pacemaker (Lewy et al., 2006), or by delaying the timing of sleep, improves symptoms in depression. Also of interest would be studies investigating whether treatment responses to conventional antidepressants correlate with circadian realignment. Acknowledgements This study was supported by NARSAD (Young Investigator Award to J.S.E.) and Public Health Service Grants K23 RR017636 (to J.S.E.); R01 EY018312, R01 HD42125, and R01 AG21826 to AJL; and UL1 RR024140 (to the Oregon Clinical and Translational Research Institute).
References Armitage, R., 2007. Sleep and circadian rhythms in mood disorders. Acta Psychiatrica Scandinavica 115, 104–115. Boivin, D.B., 2000. Influence of sleep-wake and circadian rhythm disturbances in psychiatric disorders. Journal of Psychiatry and Neuroscience 25, 446–458. Golden, R.N., Gaynes, B.N., Ekstrom, R.D., Hamer, R.M., Jacobsen, F.M., Suppes, T., Wisner, K.L., Nemeroff, C., 2005. The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of the evidence. American Journal of Psychiatry 162, 656–662. Hubain, P., Le Bon, O., Vandenhande, F., Van Wijnendaele, R., Linkowski, P., 2006. Major depression in males: effects of age, severity and adaptation on sleep variables. Psychiatry Research 145, 169–177. Kripke, D.F., 1983. Phase-advance theories for affective illness. In: Wehr, T.A., Goodwin, F.K. (Eds.), Circadian Rhythms in Psychiatry. Boxwood Press, Pacific Grove, CA, pp. 41–69. Kripke, D.F., Mullaney, D.J., Atkinson, M., Wolf, S., 1978. Circadian rhythm disorders in manic-depressives. Biological Psychiatry 13, 335–351. Lewy, A.J., Bauer, V.K., Cutler, N.L., Sack, R.L., Ahmed, S., Thomas, K.H., Blood, M.L., Latham Jackson, J.M., 1998. Morning versus evening light treatment of patients with winter depression. Archives of General Psychiatry 55, 890–896. Lewy, A.J., Cutler, N.L., Sack, R.L., 1999. The endogenous melatonin profile as a marker for circadian phase position. Journal of Biological Rhythms 14, 227–236.
J. Emens et al. / Psychiatry Research 168 (2009) 259–261 Lewy, A.J., Lefler, B.J., Emens, J.S., Bauer, V.K., 2006. The circadian basis of winter depression. Proceedings of the National Academy of Sciences of the United States of America 103, 7414–7419. Lewy, A.J., Sack, R.L., Singer, C.M., 1985. Treating phase typed chronobiologic sleep and mood disorders using appropriately timed bright artificial light. Psychopharmacology Bulletin 21, 368–372. Morin, L.P., 1999. Serotonin and the regulation of mammalian circadian rhythmicity. Annals of Medicine 31, 12–33. Peterson, M.J., Benca, R.M., 2006. Sleep in mood disorders. Psychiatr. Clin. North Am. 29, 1009–1032. Sack, R.L., Auckley, D., Auger, R.R., Carskadon, M.A., Wright, K.P., Vitiello, M.V., Zhdanova, I., 2007. Circadian rhythm sleep disorders: Part I, basic principles, shift work and jet lag disorders. Sleep 30, 1460–1483.
261
Sheehan, D.V., Lecrubier, Y., Sheehan, K.H., Amorim, P., Janavs, J., Weiller, E., Hergueta, T., Baker, R., Dunbar, G.C., 1998. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. Journal of Clinical Psychiatry 59 (Suppl 20), 22–57. Van den Hoofdakker, R.H., 1994. Chronobiological theories of nonseasonal affective disorders and their implications for treatment. Journal of Biological Rhythms 9, 157–183. Wehr, T.A., 2000. Chronobiology. In: Sadock, B.J., Sadock, V.A. (Eds.), Comprehensive Textbook of Psychiatry. Lippincott Williams & Wilkins, Philadelphia, PA, pp. 133–142. Wehr, T.A., Wirz-Justice, A., Goodwin, F.K., Duncan, W., Gillin, J.C., 1979. Phase advance of the circadian sleep-wake cycle as an antidepressant. Science 206, 710–713.
Contents lists available at ScienceDirect
Psychiatry Research j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p s y c h r e s
Brief report
Circadian misalignment in major depressive disorder Jonathan Emens a,⁎, Alfred Lewy b, John Mark Kinzie a, Diana Arntz a, Jennifer Rough a a b
Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA Departments of Psychiatry, Ophthalmology and Physiology/Pharmacology, Oregon Health & Science University, Portland, OR, USA
a r t i c l e
i n f o
Article history: Received 12 September 2008 Received in revised form 24 March 2009 Accepted 15 April 2009
a b s t r a c t It has been hypothesized that the circadian pacemaker plays a role in major depressive disorder (MDD). We sought to determine if misalignment between the timing of sleep and the pacemaker correlated with symptom severity in MDD. Depression severity correlated with circadian misalignment: the more delayed, the more severe the symptoms. © 2009 Elsevier Ireland Ltd. All rights reserved.
Keywords: Melatonin Circadian rhythms Depression Dim light melatonin onset (DLMO) Phase angle difference (PAD) Sleep
1. Introduction Affective disorders have long been thought to be related to circadian rhythms (for reviews, see Van den Hoofdakker, 1994; Boivin, 2000). In addition to circadian rhythmicity in mood (Boivin, 2000), other indications of a relationship include symptoms of sleep disruption and polysomnographic changes (Peterson and Benca, 2006; Armitage, 2007), differences in the amplitude and timing (phase) of the biological clock (endogenous circadian pacemaker) (Boivin, 2000), therapeutic effects of sleep deprivation or advancement of sleep timing (Van den Hoofdakker, 1994; Wehr, 2000), and therapeutic effects of light therapy (Golden et al., 2005). One of the first circadian theories for major depressive disorder (MDD) posited that the endogenous circadian pacemaker is set abnormally early (misaligned) with respect to the timing of sleep (Kripke et al., 1978; Wehr et al., 1979). Accordingly, advancing the timing of sleep was found to be antidepressant in some patients (Wehr et al., 1979). However, subsequent studies have not consistently found that the endogenous circadian pacemaker is set either abnormally early (phase advanced) or late (phase delayed) in individuals with depression (Van den Hoofdakker, 1994). Nonetheless, misalignment between timing of the clock and the timing of sleep, in either direction, could be depressant within vulnerable individuals (Kripke, 1983; Lewy et al., 1985; Wehr, 2000; Lewy et al., 2006). Indeed, we have recently shown that such misalignment correlates with symptom severity in seasonal affective disorder (SAD) ⁎ Corresponding author. Sleep and Mood Disorders Laboratory, Department of Psychiatry, L-469, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97239 USA. Tel.: +1 503 494 4041; fax: +1 503 494 5329. E-mail address: [email protected] (J. Emens). 0165-1781/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2009.04.009
(Lewy et al., 2006). We conducted a small pilot study to determine if a similar finding could be demonstrated in MDD. 2. Methods Eighteen females, 19 to 60 years old, with persistent symptoms (including poor sleep), despite current treatment for depression, were recruited by advertisement and referral by providers. Subjects gave written informed consent and were screened using the Mini-International Neuropsychiatric Interview (Sheehan et al., 1998), a health questionnaire and routine laboratory tests. Inclusion criteria included a DSM-IV diagnosis of MDD (including partial remission), a scoreN 7 on the 21-Item Hamilton Depression Rating scale (HAM-D), current treatment for depression, and no changes in antidepressant medications for the past 6 weeks and for the week of study. Exclusion criteria included active suicidal ideation, SAD, clinically significant laboratory abnormalities, transmeridian travel or shift work for the prior 3 months and use of medications that would interfere with melatonin production. Subjects were asked to maintain a daily sleep/wake schedule of their choosing (8 h in bed, bedtimes and wake times within ±1/2 hour) at home for 1 week. They kept a sleep diary to document bedtimes, midsleep, wake times and time in bed, and a wrist actigraph (AW-64 Actiwatch ®, Mini-Mitter Co., Bend, OR) was used to document sleep start, sleep end, total sleep time, sleep efficiency and average activity. One subject failed to complete a sleep diary (subject 7), and reliable actiwatch data were not obtained in another (subject 6). After the ambulatory week, subjects were admitted to the Clinical and Translational Research Center in the late afternoon. Following clinical assessments that included ratings on the Hamilton Rating Scale for Depression (HAM-D), an intravenous catheter was inserted and blood samples were drawn in dim light (b10 lux) every 30 min for 6 h (approximately 18:00 to midnight). Plasma samples were assayed for melatonin by RIA (ALPCO Ltd., Windham, NH). The lower limit of sensitivity is 0.2 pg/ml. Circadian phase was determined using the dim light melatonin onset (DLMO) defined as the interpolated time when plasma melatonin concentrations crossed the threshold of 10 pg/ml (Lewy et al., 1999). Circadian misalignment was measured using the time interval or phase angle difference (PAD) between the DLMO and the average midpoint of sleep of the prior week (Lewy et al., 2006). Spearman correlations (rs) were calculated with SPSS 12.0 (SPSS Inc.). Subjects were studied while taking a variety of psychiatric medications at different times of year. Subject 1 (□) was studied in October while taking citalopram. Subject 2
260
J. Emens et al. / Psychiatry Research 168 (2009) 259–261
Fig. 1. Correlation of Phase Angle Difference (PAD) with depression severity measured using the HAM-D. The PAD is the time interval in hours between the 10 pg/ml dim light melatonin onset (DLMO) and diary midsleep during the prior week.
(▲) was studied in November while taking duloxetine and quetiapine. Subject 3 (■) was studied in February while taking escitalopram. Subject 4 ( ) was unmedicated and studied in June; Subject 5 (●) was studied in June while taking extended release venlafaxine and alprazolam. Subject 6 (⋄) was unmedicated and studied in July. Subject 7 was studied in August while taking nortriptyline, sertraline and gabapentin. Subject 8 (○) was studied in September while taking citalopram; Subject 9(Δ) was studied in November while taking venlafaxine, buproprion and lorazepam; Subject 10 (✕) was studied in November while taking escitalopram; Subject 11(♦)was studied in September while taking buprorion, citalopram, and trazodone; Subject 12 ( ) was studied in March and was unmedicated; Subject 13 (✱) was studied in July while taking citalopram; Subject 14 ( ) was studied in August while taking duloxetine, buproprion, ) was studied in December clonazepam, quetiapine, and zolpidem; Subject 15 ( while taking fluoxetine, venlafaxine, and buproprion; Subject 16 ( ) was studied in February while taking venlafaxine, trazodone, and lamotrigine; Subject 17 ( ) was studied in April while taking duloxetine and buproprion; Subject 18 ( ) was studied in April and was unmedicated.
3. Results Subjects had an average HAM-D score (±SD) of 15.9 ± 4.6 (range: 7–19) indicating mild to moderate symptoms of depression. There was no difference between the screening and study HAM-D score (16.1 vs. 15.9, respectively, P = 0.89). Average bedtimes and wake times were 23:17 ± 1:20 and 7:39 ± 1:08, respectively, the average time of the DLMO was 21:13 ± 2:03 and subjects had an average PAD of 6:10 ± 1:37 h [consistent with normal historical controls, 6:04 ± 0:55 h (Lewy et al., 1998)]. There was a negative correlation (rs = −0.61, P = 0.01) between HAM-D scores and the PAD calculated using sleep diaries (excluding subject 7): shorter PADs were associated with worse symptoms of depression (Fig. 1 shorter PADs indicate a delay of the endogenous circadian pacemaker relative to the timing of sleep). This correlation remained significant when the sleep items were removed from the HAM-D (rs = − 0.53, P = 0.03). The correlation of HAM-D score and PAD calculated using actigraphy data (excluding subject 6) was similar (rs = − 0.57, P = 0.02). There were consistent correlations between HAM-D scores and the DLMO-bedtime (rs = − 0.62, P = 0.01) and wake time-DLMO (rs = 0.57, P = 0.02) intervals. No significant correlations were found between HAM-D scores and any sleep diary or actigraphy measures. 4. Discussion We found a correlation between symptoms of depression and circadian misalignment in a small number of heterogeneously treated subjects with persistent mild to moderate depression and complaints of poor sleep. This correlation is in the phase-delay direction, as opposed to the phase-advance direction previously hypothesized (Wehr et al., 1979; Kripke, 1983; Wehr, 2000). The present results are to some extent consistent with those in SAD (Lewy et al., 2006), in which symptom severity in the prototypical phase-delayed group (pre-treatment baseline PAD b6) correlated with the degree of phase
delay in PAD, whereas a smaller phase-advanced group (PADN6) was also found. As in SAD, no trait difference was found: PAD average and range were similar to that of historical controls (Lewy et al., 1998). This was a small pilot study and a larger data set could confirm the linear relationship between circadian misalignment and depression symptoms, favor a parabolic relationship as we found in SAD, or fail to confirm either (Lewy et al., 2006). In any event, we think it less likely that a larger sample will reveal a correlation in the opposite direction (i.e., greater symptom severity the more the DLMO is advanced relative to mid-sleep), which is what would be predicted based on the phase-advance hypothesis of depression (Kripke et al., 1978; Wehr et al., 1979). Various potential confounders limit our conclusions. Sleep duration has been shown to correlate with symptom severity in MDD (Hubain et al., 2006), and this in turn might affect PAD. However, we think it unlikely that such an association explains our findings: HAM-D score did not significantly correlate with sleep duration; furthermore when the sleep items were removed from the HAM-D, the correlation with PAD was essentially unchanged. The correlation we found may be due to an association between symptom severity and differences in the timing or intensity of time cues that reset the circadian pacemaker (e.g., light). In particular, antidepressant medications have been shown to reset the pacemaker (Morin, 1999), and differences in dose and medication type could account for our findings. However, even if circadian misalignment is not causal in MDD, as it appears to be in SAD, these data remain important because circadian misalignment might explain why sleep complaints persist in treated depressed patients (Peterson and Benca, 2006; Sack et al., 2007). Despite the limitations inherent in such a small study, the correlation of a biological marker with depressive symptoms in MDD is worthy of follow-up, controlling for confounders and in a more numerous and broader patient population (e.g., males, patients with minimal sleep complaints, and patients with more severe symptoms). Further studies are also warranted to investigate whether correcting circadian misalignment by using circadian resetting agents, such as light or melatonin, to advance the pacemaker (Lewy et al., 2006), or by delaying the timing of sleep, improves symptoms in depression. Also of interest would be studies investigating whether treatment responses to conventional antidepressants correlate with circadian realignment. Acknowledgements This study was supported by NARSAD (Young Investigator Award to J.S.E.) and Public Health Service Grants K23 RR017636 (to J.S.E.); R01 EY018312, R01 HD42125, and R01 AG21826 to AJL; and UL1 RR024140 (to the Oregon Clinical and Translational Research Institute).
References Armitage, R., 2007. Sleep and circadian rhythms in mood disorders. Acta Psychiatrica Scandinavica 115, 104–115. Boivin, D.B., 2000. Influence of sleep-wake and circadian rhythm disturbances in psychiatric disorders. Journal of Psychiatry and Neuroscience 25, 446–458. Golden, R.N., Gaynes, B.N., Ekstrom, R.D., Hamer, R.M., Jacobsen, F.M., Suppes, T., Wisner, K.L., Nemeroff, C., 2005. The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of the evidence. American Journal of Psychiatry 162, 656–662. Hubain, P., Le Bon, O., Vandenhande, F., Van Wijnendaele, R., Linkowski, P., 2006. Major depression in males: effects of age, severity and adaptation on sleep variables. Psychiatry Research 145, 169–177. Kripke, D.F., 1983. Phase-advance theories for affective illness. In: Wehr, T.A., Goodwin, F.K. (Eds.), Circadian Rhythms in Psychiatry. Boxwood Press, Pacific Grove, CA, pp. 41–69. Kripke, D.F., Mullaney, D.J., Atkinson, M., Wolf, S., 1978. Circadian rhythm disorders in manic-depressives. Biological Psychiatry 13, 335–351. Lewy, A.J., Bauer, V.K., Cutler, N.L., Sack, R.L., Ahmed, S., Thomas, K.H., Blood, M.L., Latham Jackson, J.M., 1998. Morning versus evening light treatment of patients with winter depression. Archives of General Psychiatry 55, 890–896. Lewy, A.J., Cutler, N.L., Sack, R.L., 1999. The endogenous melatonin profile as a marker for circadian phase position. Journal of Biological Rhythms 14, 227–236.
J. Emens et al. / Psychiatry Research 168 (2009) 259–261 Lewy, A.J., Lefler, B.J., Emens, J.S., Bauer, V.K., 2006. The circadian basis of winter depression. Proceedings of the National Academy of Sciences of the United States of America 103, 7414–7419. Lewy, A.J., Sack, R.L., Singer, C.M., 1985. Treating phase typed chronobiologic sleep and mood disorders using appropriately timed bright artificial light. Psychopharmacology Bulletin 21, 368–372. Morin, L.P., 1999. Serotonin and the regulation of mammalian circadian rhythmicity. Annals of Medicine 31, 12–33. Peterson, M.J., Benca, R.M., 2006. Sleep in mood disorders. Psychiatr. Clin. North Am. 29, 1009–1032. Sack, R.L., Auckley, D., Auger, R.R., Carskadon, M.A., Wright, K.P., Vitiello, M.V., Zhdanova, I., 2007. Circadian rhythm sleep disorders: Part I, basic principles, shift work and jet lag disorders. Sleep 30, 1460–1483.
261
Sheehan, D.V., Lecrubier, Y., Sheehan, K.H., Amorim, P., Janavs, J., Weiller, E., Hergueta, T., Baker, R., Dunbar, G.C., 1998. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. Journal of Clinical Psychiatry 59 (Suppl 20), 22–57. Van den Hoofdakker, R.H., 1994. Chronobiological theories of nonseasonal affective disorders and their implications for treatment. Journal of Biological Rhythms 9, 157–183. Wehr, T.A., 2000. Chronobiology. In: Sadock, B.J., Sadock, V.A. (Eds.), Comprehensive Textbook of Psychiatry. Lippincott Williams & Wilkins, Philadelphia, PA, pp. 133–142. Wehr, T.A., Wirz-Justice, A., Goodwin, F.K., Duncan, W., Gillin, J.C., 1979. Phase advance of the circadian sleep-wake cycle as an antidepressant. Science 206, 710–713.