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Circadian Abnormalities in Depression
   
CITATION:  Bunney, W. E. & Bunney, B. G. (2000).  Molecular clock genes in man and lower animals:  possible implications for circadian abnormalities in depression.  Neuropsychopharmacology, 22 (4), 335-345. 

ABSTRACT:  The authors of this article discuss the association of circadian rhythm abnormalities and certain types of depression, including seasonal affective disorder (SAD).  Their hypothesis is based on findings that suggest the presence of a clock gene in all organisms, which responds to environmental changes (e.g. light, noise level, temperature) by adjusting physiological mechanisms and behaviors accordingly.  In humans, the most important circadian regulator is the suprochiasmatic nucleus (SCN) found above the optic chiasm in the anterior hypothalamus.  The cells of this nucleus are interconnected and create a rhythmic, autonomic pattern of neural stimulation resulting from the shutting down of protein production once certain levels have been exceeded and turning it back on once levels have fallen sufficiently.   Changes in light activate retinal photoreceptors, which stimulate the SCN directly via the retinohypothalmic tract, or indirectly via the geniculohypothalmic pathway.  Neural interactions between the SCN and pineal gland, then, result in behavioral changes relative to sleep, night-time body temperature, cortisol, as well as the synthesis of melatonin and neuropeptides. 

Current evidence suggest that mutations of the clock gene interfere with protein production and thereby alter the speed of the circadian rhythm and period lengths.  Consequently, the physiological mechanisms and behaviors depending on the clock genes present the symptoms typically associated with SAD,  such as sleep disturbances, increases in night-time temperature, as well as disturbances in the release of melatonin and cortisol.  Similarily, symptoms in certain clinically depressed patients that indicate circadian rhythm aberrations, include changes in temperature and melatonin secretion during sleep, shortened REM latency, and mood swings marked by depression in the morning and near euthymia by evening. 

Therefore, clients presenting with symptoms of depression should be assessed for circadian rhythm disruptions.  For instance, clients with SAD might complain about depressed mood, carbohydrate cravings, overeating, and hypersomnia.  The use of a temperature strip or other non-disruptive means could be used to determine increases in nocturnal temperature.  Clinicians need to pay special attention to clients in high risk groups for SAD, such as women between the ages of 20 to 40 and those living in northern regions.  Clients presenting as clinically depressed should be questioned for symptoms of extreme daily mood swings from very depressed early in the morning to almost euthymic in the evenings.  If circadian rhythm abnormalities are suspected, a sleep clinic assessment might benefit to determine REM latency, early awakening, and elevations in nocturnal temperature.  Similar to SAD, blood tests and urinalysis would be helpful in assessing decreases in melatonin and cortisol release. 

Treatment for clients with SAD should include 2500 lux or higher for two hours per day for at least one week, preferably in the morning.  For clients with clinical depression phase advance treatment of 6 hours for two weeks or a combination treatment of one night of sleep deprivation followed by phase advance treatment might be helpful.  In addition, the SCU has a high density of serontonergic receptors, making SSRIs providing yet another treatment option. 

References

Abe, H., Honma, S., Namithira, M., Tanahashi, Y., Ikeda, M. and Honma, K., 1999. Circadian rhythm and light responsiveness of BMAL1 expression, a partner of mammalian clock gene, Clock, in the suprachiasmatic nucleus of rats. Neuroscience Letters 258, pp. 93¯96.

Albert, R., Merz, A., Schubert, J. and Ebert, D., 1998. Sleep deprivation followed by sleep phase advance therapy to stabilize the positive sleep-deprivation effect in depressive episodes. Der Nervenarzt 69, pp. 66¯69. 

Abstract-EMBASE | Abstract | Abstract-BIOSIS Previews  | Full-text via CrossRef
Albrecht, U., Sun, Z.S., Eichele, G. and Lee, C.C., 1997. A differential response of two putative mammalian circadian receptors, mper1 and mper2 to light. Cell 91, pp. 1055¯1067.

Atkinson, M., Kripke, D.F. and Wolf, S.R., 1975. Autorhythmometry in manic-depressives. Chronobiologia 2, pp. 325¯335. 

Avery, D.H., Wildschiodtz, G. and Rafaelsen, O.J., 1982. Nocturnal temperature in affective disorder. Acta Psychiatrica Scand 74, pp. 269¯280.

Avery, D.H., Dahl, K., Savage, M.V., Brengelman, G.L., Larsen, L.H., Kenny, M.A., Eder, D.N., Vitiello, M.V. and Prinz, 1997. Circadian temperature and cortisol rhythms during a constant routine are phase-delayed in hypersomnic winter depression. Biol Psychiatry 41, pp. 1109¯1123. 

Bargiello, T.A., Jackson, F.R. and Young, M.W., 1984. Restoration of circadian behavioural rhythms by gene transfer in Drosophila. Nature 312, pp. 652¯754.

Benca, R.M., Obermeyer, W.H., Thisted, R.A. and Gillin, J.C., 1992. Sleep and psychiatric disorders. A meta-analysis. Arch Gen Psychiatry 49, pp. 651¯668.

Berger, M., Vollmann, J., Hohagen, F., Konig, A., Lohner, H., Volderholzer, U. and Riemann, D., 1997. Sleep deprivation combined with consecutive sleep-phase advance as a fast-acting therapy in depression: an open pilot trial in medicated and unmedicated patients. Am J Psychiatry 154, pp. 870¯872 a. 

Berger, M., Konig, A., Hohagen, F., Kjemen, A., Homyak, Steffes P., Voderholzer, U. and Riemann, D., 1997. Total sleep deprivation and consecutive sleep-phase-advance therapy as fast acting antidepressant strategy. Biol Psychiatry 42, p. 77S b. 

Branchey, L., Weinberg, U., Branchey, M., Linkowski, P. and Mendlewicz, J., 1982. Simultaneous study of 24-hour patterns of melatonin and cortisol secretion in depressed patients. Neuropsychobiology 8, pp. 225¯232. 

Breakthroughs of the Year: The Runners-Up (1998): Science 282:2157¯2161.

Bunney WE, Akil HA (1998): Molecular clocks in man and in lower animals: Possible implications for circadian abnormalities in depression. American College of Neuropsychopharmacology Annual Meeting Abstract, December 13¯17.

Buysse, D.J., Monk, T.H., Kupfer, D.J., Frank, E. and Stapf, D., 1995. Circadian patterns of unintended sleep episodes during a constant routine in remitted depressed patients. J Psychiatric Research 29, pp. 407¯416. 

Carpenter Jr, W.T. and Bunney Jr, W.E., 1971. Adrenal cortical activity in depressive illness. Am J Psychiatry 128, pp. 63¯72.

Crosthwaite, S.K., Dunlap, J.C. and Loros, J.J., 1997. Neurospora wc-1 and wc-2: transcription, photoresponses and the origins of circadian rhythmicity. Science 276, pp. 763¯769. 

Dahl, K., Avery, D.H., Lewy, A.J., Savage, M.V., Brengelmann, G.L., Larsen, L.H., Vitiello, M.V. and Prinz, P.N., 1993. Dim light melatonin onset and circadian tepmperature during a constant routine in hypersomnic winter depression. Acta Psychiatrica Scandinavica 88, pp. 60¯66. 

Darlington, T.K., Wager-Smith, K., Ceriani, M.F., Staknis, D., Gekakis, N., Steeves, T.D.L., Weitz, C.J., Takahashi, J.S. and Kay, S.A., 1998. Closing the circadian loop: CLOCK-induced transcription of its own inhibitors per and tim. Science 280, pp. 1599¯1603. 

Abstract-EMBASE | Abstract-Elsevier BIOBASE  | Full-text via CrossRef Dietzel, M., Saletu, B., Lesch, O.M., Sieghart, W. and Schjerve, M., 1986. Light treatment in depressive illness: polysomnographic, psychometric and neuroendocrinological findings. Eur Neurol 25 suppl 2, pp. 93¯103. 

Duncan Jr., W.C., 1996. Circadian rhythms and the pharmacology of affective illness. Pharmacol Ther 71, pp. 253¯312. Abstract | Journal Format-PDF (5190 K)  

Dunlap, J.C., 1999. Molecular bases for circadian clocks. Cell 96, pp. 271¯290. 

Eastman, C.L., Young, M.A., Fogg, L.F., Liu, L. and Meaden, P.M., 1998. Bright light treatment of winter depression: a placebo-controlled trial. Archives of General Psychiatry 55 10, pp. 883¯889 [see comments]. 

Gekakis, N., Staknis, D., Nguyen, H.B., Davis, F.C., Wilsbacher, L.D., King, D.P., Takahashi, J.S. and Weitz, C.J., 1998. Role of the CLOCK protein in the mammalian circadian mechanism. Science 280, pp. 1564¯1569. 

Gillin, J.C., Duncan, W., Pettigrew, B.L., Frankel, F. and Snyder, F., 1979. Successful separation of depressed, normal and insomniac subjects by sleep EEG data. Arch Gen Psychiatry 36, pp. 85¯90. 

Goetze, U. and Tölle, R., 1987. Circadian rhythm of free urinary cortisol, temperature and heart rate in endogenous depressives and under antidepressant therapy. Neuropsychobiology 18, pp. 175¯184. 

Goldman BD, Elliot JA (1988): Photoperiodism and seasonality in hamsters: Role of the pineal gland. In Stetson MH (ed), Processing of Environmental Information in Vertebrates. New York: pp. 203¯218.

Gordijn, M.C., Beersma, D.G., Korte, H.J. and van den Hoofdakker, R.H., 1998. Testing the hypothesis of a circadian phase disturbance underlying depressive mood in nonseasonal depression. J Biol Rhythms 13, pp. 132¯147. 

Griffin EA Jr, Staknis D, Weitz CJ (1999) Light-independent role of CRY1 and CRY2 in the mammalian circadian clock. Science 286:768¯771. 

Halbreich, U., Asnis, G.M., Shindledecker, R., Zumoff, B. and Nathan, S., 1985. Cortisol secretion in endogenous depression. II. Time related functions. Arch Gen Psychiatry 42, pp. 909¯914. 

Hamblen, M.J., White, N.E., Emery, P.T., Kaiser, K. and Hall, J.C., 1998. Molecular and behavioral analysis of four period mutants in Drosophila melanogaster encompassing extreme short, novel long, and unorthodox arrhythmic types. Genetics 149, pp. 165¯178. 

Honma, S., Ikeda, M., Abe, H., Tanahashi, Y., Namihira, M., Honma, K. and Nomura, M., 1998. Circadian oscillation of BMAL1, a partner of a mammalian clock gene Clock, in rat suprachiasmatic nucleus. Biochem Biophysical Res Comm 250, pp. 83¯87. 

Ikeda, M. and Nomura, M., 1997. cDNA cloning and tissue-specific expression of a novel basic-loop-helix/pas protein (BMAL1) and identification of alternatively spliced variants with alternative translation initiation site usage. Biochem Biophys Res Commun 233, pp. 258¯264. 

Jacobsen, F.M., Wehr, T.A., Skwerer, R.A., Sack, D.A. and Rosenthal, N.E., 1987. Morning versus midday phototherapy of seasonal affective disorder. Am J Psychiatry 144, pp. 1301¯1305. 

Jarrett, D.B., Coble, P.A. and Kupfer, D.J., 1983. Reduced cortisol latency in depressive illness. Arch Gen Psychiatry 40, pp. 506¯511.

Jin, X., Shearman, L.P., Weaver, D.R., Zylka, M.J., deVries, G.J. and Reppert, S.M., 1999. A molecular mechanism in regulating rhythmic output from the suprachiasmatic circadian clock. Cell 96, pp. 57¯68. 

Jones, C.R., Campbell, S.S., Zone, S.E., Cooper, F., Desano, A., Murphy, P.J., Jones, B., Czajowski, L. and Ptcek, L.J., 1999. Familial advanced sleep-phase syndrome: A short period circadian rhythm variant in humans. Nature Medicine 5, pp. 1062¯1065.

Katzenberg, D., Young, T., Finn, L., Lin, L., King, D.P., Takahashi, J.S. and Mignot, E., 1998. A CLOCK polymorphism associated with human diurnal preference. Sleep 21, pp. 569¯576. 

Kloss, B., Price, J.L., Saez, L., Blau, J., Rothenfluh, A., Wesley, C.S. and Young, M.W., 1998. The Drosophila clock gene double-time encodes a protein closely related to human casein kinase Iepsilon. Cell 94, pp. 97¯107. 

Koike, N., Hida, A., Numano, R., Hirose, M., Sakaki, Y. and Tei, H., 1998. Identification of the mammalian homologues of the Drosophila timeless gene, Timeless1. Febs Letters 441, pp. 427¯431. 

Kripke, D.F., 1998. Light treatment for nonseasonal depression: speed, efficacy and combined treatment. J Affect Dis 49, pp. 109¯117. SummaryPlus | Article | Journal Format-PDF (291 K) 

Kripke, D.F., Mullaney, D.J., Atkinson, M. and Wolf, S., 1978. Circadian rhythm disorders in manic-depressives. Biol Psychiatry 13, pp. 335¯351. 

Kume K, Zylka MJ, Sriram S, Shearman LP, Weaver DR, Jin X, Maywood ES, Hastings MH, Reppert SM (1999) mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 98:193¯205.

Lewy, A.J., Bauer, V.K., Cutler, N.L., Sack, R.L., Ahmed, S., Thoman, K.H., Blood, M.L. and Jackson, J.M., 1998. Morning versus evening light treatment of patients with winter depression. Arch Gen Psychiatry 55, pp. 890¯896. 

Lewy, A.J., Sack, R.L., Miller, L.S. and Hoban, T.M., 1987. Antidepressant and circadian phase-shifting effects of light. Science 235, pp. 352¯354. 

Linkowski, P., Mendlewicz, J., Leclercq, R., Brasseur, M., Hubain, P., Golstein, J., Copinshi, G. and van Cauter, E.M., 1985. The 24-hour profile of adrenocorticotropin and cortisol in major depressive illness. J Clin Endocrin Metab 61, pp. 429¯438. 

Lisansky, J., Fava, G.A., Zielezny, M.A., Morphy, M.A. and Kellner, R., 1987. Nocturnal prolactin and cortisol secretion and recovery from melancholia. Psychoneuroendocrinology 12, pp. 303¯312.

Lucas, R.J., Stirland, J.A., Darrow, J.M., Menaker, M. and Loudon, A.S., 1999. Free running circadian rhythms of melatonin, leutinizing hormone, and cortisol in Syrian hamsters bearing the circadian tau mutation. Endocrinology 140, pp. 758¯764.

Moore, R.Y., 1999. Circadian rhythms: A clock for the ages. Science 284, p. 2102. 

Morin, L.P., 1999. Serotonin and the regulation of mammalian circadian rhythmicity. Annals of Medicine 31, pp. 12¯33. 

Nambu, J.R., Lewis, J.O., Wharton, K.A.J. and Crews, S.T., 1991. The Drosophila single-mined gene encodes a helix-loop-helix protein that acts as a master regulator of CNS midline development. Cell 67, pp. 1157¯1167.  Abstract-MEDLINE | Abstract-BIOTECHNOBASE | Abstract-EMBASE  

Neumeister, A., Goessler, R., Lucht, M., Kaptiany, T., Bamas, C. and Kasper, S., 1996. Bright light therapy stabilizes the antidepressant effect of partial sleep deprivation. Biol Psychiatry 39, pp. 16¯21. 

Oishi, K., Sakamoto, K., Okada, T., Nagase, T. and Ishida, N., 1998. Antiphase circadian expression between BMAL1 and period homologue mRNA in the suprachiasmatic nucleus and peripheral tissues of rats. Biochem Biophys Res Commun 253, pp. 199¯203. 

Papousek, M., 1975. Chronobiologische Aspekte der Zyklothymie. Forstchr Neuro Psychiat 43, pp. 381¯440. 

Parry, B.L., Mendelson, W.B., Duncan, W.C., Sack, D.A. and Wehr, T.A., 1989. Longitudinal sleep EEG, temperature, and activity measurements across the menstrual cycle in patients with premenstrual depression and in age-matched controls. Psychiatry Res 30, pp. 285¯303. 

Pflug, B., Erickson, R. and Johnson, A., 1976. Depression and daily temperature. Acta Psychiatr Scand 54, pp. 254¯266. Abstract-MEDLINE | Abstract-EMBASE 
Pickard, G.E. and Rea, M.A., 1998. Serotonergic innervation of the hypothalamic suprachiasmatic nucleus and photic regulation of circadian rhythms. Biology of the Cell 89, pp. 513¯523.

Price, J.L., Blau, J., Rosenfluh, A., Abdodeely, M., Kloss, B. and Young, M.W., 1998. Double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation. Cell 94, pp. 83¯95. 

Riemann, D., Volmann, J., Hohagen, F., Lohner, H., Konig, A., Faler, C., Edali, N. and Berger, M., 1995. Treatment of depression with sleep deprivation and sleep phase advance. Fortschr der Neuro-Psych 63, pp. 27¯276.

Riemann, D., Hohagen, F., Konig, A., Schwarz, B., Gomille, J. and Voderholzer, U., 1996. Advanced vs normal sleep timing: Effects of depressed mood after response to sleep deprivation in patients with major depressive disorder. J Affective Dis 37, pp. 121¯128. 

Riemann, D, Konig A, Hohagen F., Kiemen A, Voderholzer U, Backhaus J, Bunz J, Weslack B, Hermle L, Berger M (in press): How to preserve the antidepressant effect of sleep deprivation: A comparison of sleep phase advance and sleep phase delay. Eur Archives Clin Psychiatry.

Rosenthal, N.E., Sack, D.A., Gillin, J.C., Lewy, A.J., Goodwin, F.K., Davenport, Y., Mueller, P.S., Newsome, D.A. and Wehr, T.A., 1984. Seasonal affective disorder. A description of the symptoms and preliminary findings with light therapy. Arch Gen Psychiatry 41, pp. 72¯80. 

Rosenthal, N.E., 1993. . In: Winter Blues: Seasonal Affective Disorder Guilford Press, New York, pp. 1¯318.

Rosenthal, N.E., Mazzanti, C.M., Barnett, R.L., Hardin, T.A., Turner, E.H., Lam, G.K., Ozaki, N. and Goldman, D., 1998. Role of serotonin transporter promoter repeat length polymorphism (5-HTTLPR) in seasonality and seasonal affective disorder. Mol Psychiatry 3, pp. 175¯177. 

Rutila, J.E., Suri, V., Le, M., So, W.V., Rosbash, M. and Hall, J.C., 1998. CYCLE is a second bHLH clock protein essential for circadian rhythmicity and transcription of Drosophila period and timeless. Cell 93, pp. 805¯814 a. 

Rutila, J.E., Maltseva, O. and Rosbash, M., 1998. The timSL mutant affects a restricted portion of the Drosophila melanogaster circadian cycle. J Biol Rhythms 13, pp. 380¯392 b.

Sack, D.A., Nurnberger, J., Rosenthal, N.E., Ashburn, E. and Wehr, T.A., 1985. Potentiation of antidepressant medications by phase advance of the sleep-wake cycle. Am J Psychiatry 142, pp. 606¯608. 

Sangoram, A.M., Saez, L., Antoch, M.P., Gekakis, N., Staknis, D., Whiteley, A., Fruechte, E.M., Vitaterna, M.H., Shimomura, K., King, D.P., Young, M.W., Weitz, C.J. and Takahashi, J.S., 1998. Mammalian autoregulatory loop: a timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcription. Neuron 21, pp. 1101¯1113. 

Sassone-Corsi, P., 1998. Molecular clocks: mastering time by gene regulation. Nature 392, pp. 871¯874. 

Schwartz, P.J., Rosenthal, N.E., Turner, E.H., Drake, C.L., Liberty, V. and Wehr, T.A., 1997. Seasonal variation in core temperature regulation during sleep in patients with winter seasonal affective disorder. Biol Psychiatry 42, pp. 122¯131 a. 

Schwartz, P.J., Murphy, D.L., Wehr, T.A., Garcia-Borreguero, D., Oren, D.A., Moul, D.E., Ozaki, N., Snelbaker, A.J. and Rosenthal, N.E., 1997. Effects of meta-chlorophenylpiperazine infusions in patients with seasonal affective disorder and healthy control subjects. Diurnal responses and nocturnal regulatory mechanisms. Arch Gen Psychiatry 54, pp. 375¯385 b. 

Shearman, L.P. and Weaver, D.R., 1999. Photic induction of Period gene expression is reduced in Clock mutant mice. Neuroreport 10, pp. 613¯618. Abstract-MEDLINE | Abstract-BIOSIS Previews 

Sher, L., Hardin, T.A., Greenberg, B.D., Murphy, D.L., Li, Q. and Rosenthal, N.E., 1999. Seasonality associated with the serotonin transporter promoter repeat length polymorphism. Am J Psychiatry 156, p. 1837. 

Sollars, P.J. and Pickard, G.E., 1998. Restoration of circadian behavior by anterior hypothalamic grafts containing the suprachiasmatic nucleus: graft/host interconnections. Chronobiology International 15, pp. 513¯533. 

Souétre, E., Salvati, E., Wehr, T.A., Sack, D.A., Krebs, B. and Darcourt, G., 1988. Twenty-four-hour profiles of body temperature and plasma TSH in bipolar patients during depression and during remission and in normal control subjects. Am J Psychiatry 145, pp. 1133¯1137. 

Souétre, E., Salvati, E., Belugou, J.-L., Pringuey, D., Candidito, M., Krebs, B., Ardisson, J.-L. and Darcourt, 1989. Circadian rhythms in depression and recovery: Evidence for blunted amplitude as the main chronobiological abnormality. Psychiatry Res 28, pp. 263¯278. 

Stanewsky, R., Kaneko, M., Emery, P., Beretta, B., Wager-Smith, K., Kay, S.A., Rosbash, M. and Hall, J.C., 1998. The cryb mutation identifies cryptochrome as a circadian photoreceptor in Drosophila. Cell 95, pp. 681¯692.

Steeves, D.L., King, D.P., Zhaio, Y., Sangoram, A.M., Du, F., Bowcock, A., Moore, R. and Takahashi, J., 1999. Molecular cloning and characterization of the human CLOCK gene: Expression in the suprachiasmatic nucleus. Genomics 57, pp. 189¯200.

Steiger, A., von Bardeleben, U., Herth, T. and Holsboer, F., 1989. Sleep EEG and nocturnal secretion of growth hormone in male patients with endogenous depression before treatment and after recovery. J Affect Dis 16, pp. 189¯195. 

Szuba, M.P., Guze, B.H. and Baxter Jr., L.R., 1997. Electroconvulsive therapy increases circadian amplitude and lowers core body tempearture in depressed subjects. Biol Psychiatry 42, pp. 1130¯1137. Abstract | Journal Format-PDF (611 K) 

Takumi, T., Matsubara, C., Shigeyoshi, Y., Taguchi, K., Yagita, K., Maebayashi, Y., Sakakida, Y., Okumura, K., Takashima, N. and Okamura, H., 1998. A new mammalian period gene predominantly expressed in the suprachiasmatic nucleus. Genes to Cells 3, pp. 167¯176. 

Takumi, T., Taguchi, K., Miyake, S., Sakakida, Y., Takashima, N., Matsubara, C., Maebayashi, Y., Okumura, K., Takekida, S., Yamamoto, S., Yagita, K., Yan, L., Young, M.W. and Okamura, H., 1999. A light-independent oscillatory gene mPer3 in mouse SCN and OVLT. Embo Journal 17, pp. 4753¯4759.

Thalaen, B.E., Merkrid, L., Kjellman, B.F. and Wetterberg, L., 1997. Cortisol in light treatment of seasonal and non-seasonal depression: relationship between melatonin and cortisol. Acta Psychiatrica Scandinavica 96, pp. 385¯394.

Thresher, R.J., Vitaterna, M.H., Miyamoto, Y., Kazantsev, A., Hsu, D.S., Petit, C., Selby, C.P., Dawut, L., Smithies, O., Takahashi, J.S. and Sancar, A., 1998. Role of mouse cryptochrome blue-light photoreceptor in circadian photoresponses. Science 282, pp. 1490-1494.

Tischkau SA, Barnes JA, Lin F-J, Myers EM, Soucy JW, Meyer-Bernstein EL, Hurst WJ, Burgoon PW, Chen D, Sehgal A, MU Gillette (1999): Oscillation and light induction of TIMELESS mRNA in the mammalian circadian clock. Neuroscience Abstracts, Soc Neuroscience, 29th Annual Meeting, Miami Beach, Florida, October 23¯28, #459.9, p 1132.

Van der Horst, GTJ, Muijtjens M, Kobayashi K, Takano R, Kanno S-I, Takao M, de Wit, J, Verkerk A, Eker APM, van Leenen D, Buijs R, Bootsma D, Hoejimakers JHJ, Yasui A (1999) Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398:627¯630.

Van Dongen, H.P., Kerkhof, G.A. and Souverijn, J.H., 1998. Absence of seasonal variation in the phase of endogenous circadian rhythm in humans. Chronobiology International 15, pp. 623¯632. Abstract-MEDLINE | Abstract-BIOSIS Previews | 

Vollmann, J. and Berger, M., 1993. Sleep deprivation with consecutive sleep-phase advance therapy in patients with major depression: a pilot study. Biol Psychiatry 33, pp. 54¯57. 

von Zerssen, D., Doerr, P., Emrich, H.M., Lund, R. and Pirke, K.M., 1987. Diurnal variation of mood and the cortisol rhythm in depression and normal states of mind. Eur J Arch Neurol Sci 237, pp. 36¯45. 

von Zerssen, D., Barthelmes, H., Dirlich, G., Doerr, P., Emrich, H.M., von Lindern, L., Lund, R. and Pirke, K.M., 1985. Circadian rhythms in endogenous depression. Psychiatry Res 16, pp. 51¯63.

Wehr, T.A., Wirz-Justice, A., Goodwin, F.K., Duncan, W. and Gillin, J.C., 1979. Phase advance in the circadian sleep-wake cycle as an antidepressant. Science 206, pp. 710¯713. 

Wehr TA, Sack DA, Duncan WC Jr, Rosenthal, NE, Mendelson WB, Gillin JC, Goodwin FK (1985) Sleep and circadian rhythms in affective patients isolated from external time cues. Psychiatry Res 15:327¯339.

Wehr TA, Wirz-Justice A (1982). Circadian rhythm mechanisms in affective illness and in antidepressant drug action. Pharmacopsychiatry 15: 31¯39.

Wehr, T.A., Muscettola, G. and Goodwin, F.K., 1980. Urinary 3-methoxy-4-hydroxyphenylglycol circadian rhythm. Early timing (phase advance) in manic-depressives compared with normal subjects. Arch Gen Psychiatry 37, pp. 257¯263. 

Wehr, T.A., 1996. `A clock for all seasons' in the human brain. Prog Brain Res 111, pp. 321¯342. 

Welsh DK, Logothetis DE, Meister MM, Reppert SM (1995) Individual neurons dissociated from rat suprachiasmatic nucleus express independently phase circadian firing rhythms. Neuron 14:697¯705.

Wirz-Justice A (1998) Biological rhythms of mood disorders in Psychopharmacology, The Fourth Generation of Progress on CD ROM, Chapter 97, Lippincott, Williams and Wilkins.

Wu, J. and Bunney Jr., W.E., 1990. The biological basis of an antidepressant response to sleep deprivation and relapse: review and hypothesis. Am J Psychiatry 147, pp. 14¯21. 

Yamada, N., Martin-Iverson, M.T., Daimon, K., Tsujimoto, T. and Takahashi, S., 1995. Clinical and chronobiological effects of light therapy on nonseasonal affective disorders. Biol Psychiatry 37, pp. 866¯873. 

Young, M.W., 1998. The molecular control of circadian behavioral rhythms and their entrainment in Drosophila. Annual Rev Biochemistry 67, pp. 135¯152. 

Zylka, M.J., Shearman, L.P., Levine, J.D., Jin, X., Weaver, D.R. and Reppert, S.M., 1998. Molecular analysis of mammalian timeless. Neuron 21, pp. 1115¯1122 a. 

Zylka, M.J., Shearman, L.P., Weaver, D.R. and Reppert, S.M., 1998. Three period homologs in mammals: differential light responses in the suprachiasmatic circadian clock and oscillating transcripts outside of brain. Neuron 20, pp. 1103¯1110 b.