Brief Communication
Nightmares and Serum Cholesterol Level: A Preliminary Report Mehmet Yucel Agargun, MD1, Mustafa Gulec, MD2, Ali Savas Cilli, MD3, Hayrettin Kara, MD4, Ramazan Sekeroglu, PhD5, Haluk Dulger, PhD6, Lutfullah Besiroglu, MD7, Rifat Inci, MD8 Objective: To examine whether there is a relation between nightmares and serum lipid levels. Methods: Fifteen subjects who met DSM-IV criteria for the diagnosis of nightmare disorder and 15 healthy control subjects participated in the study. We used an enzymatic colorimetric method for cholesterol and triglyceride determination. We measured high-density lipoprotien (HDL) cholesterol using the direct HDL-cholesterol method. Low-density lipoprotein (LDL) was calculated according to the Friedewald formula. Results: Patients with nightmare disorder had lower serum triglyceride, lower total cholesterol, and lower LDL levels than healthy control subjects. Conclusion: These findings suggest that nightmares are associated with low serum lipid levels. (Can J Psychiatry 2005;50:361–364) Information on author affiliations appears at the end of the article.
Clinical Implications · Nightmare sufferers have lower serum lipid concentrations than do healthy control subjects. · Low cholesterol may be related to serotonergic inhibition in the brain during nightmares. · A relation between nightmares and depression should be examined in terms of serum lipid concentrations. Limitations · The findings are based on a relatively small group of patients. · The exact mechanisms of this association are not clear. · We did not match the groups for body mass index.
Key words: nightmares, serum cholesterol, serotonin here is a burgeoning focus on the relation between serum cholesterol levels and psychiatric disorders, including depression and other anxiety disorders (1,2). Information about the relation between serum lipid levels and sleep disorders is relatively limited in the psychiatric literature. In a previous study, we found that serum cholesterol level was higher in patients with recurrent panic attacks, compared with panic disorder patients without sleep panic and with healthy subjects (3). In a recent study, we also examined the relation between serum lipid concentrations in subjects with sleep-
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related violent behaviours (4). Low serum cholesterol level was associated with violent behaviour during sleep.
Nightmares are long, frightening dreams that wake the sleeper. They typically occur later in the night during REM sleep and produce vivid dream imagery, complete awakenings, autonomic arousal, and detailed recall of the event; they may cause psychological distress and social or occupational dysfunction (5). In this study, we aimed to examine the relation between recurrent nightmares and serum lipid levels. 361
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Table 1 Serum lipid levels of patients with ND and healthy control subjects Patients with ND (n = 15)
Normal control subjects (n = 15)
t
P
Triglyceride
122.8 (71.7)
162.4 (8.8)
2.91
0.007
Total cholesterol
162.5 (10.8)
194.3 (28.8)
2.57
0.017
HDL
49.1 (15.1)
40.4 (9.8)
1.06
0.30
LDL
88.8 (15.2)
121.4 (25.1)
3.10
0.006
VLDL
24.4 (14.3)
32.4 (13.7)
2.17
0.04
Lipids
Methods The study subjects were 15 patients with ND (2 men and 13 women) and 15 healthy control subjects (2 men and 13 women). Subjects were aged between 18 and 65 years and had to meet the DSM-IV criteria for ND (for patients only), have good physical health as determined by physical and laboratory examination, and have no history of psychotic disorders, other sleep disorders, or current substance abuse. We interviewed all the patients with the SCID-I:CV (6), and none of them met the criteria for other psychiatric disorders that might impact sleep and sleep architecture (for example, major depressive disorder or posttraumatic stress disorder). Two psychiatrists interviewed all patients to confirm the diagnosis of ND. To provide interrater reliability between 2 clinicians, we used the kappa statistic (kappa value was 0.77). We controlled for age in selecting our control group. The mean (SD) ages in the patient and control group were 31.5 (6.2) years and 29.6 (3.5) years, respectively. No patient was treated with antidepressants or benzodiazepines during the study. Before blood collection, there was a washout period of at least 2 weeks for psychotropic drugs. Abbreviations used in this article 5-HT
serotonin
CNS
central nervous system
GABA
gamma-aminobutryic acid
HDL
high-density lipoprotein
LDL
low-density lipoprotein
ND
nightmare disorder
REM
rapid eye movement
SCID-I:CV
Structured Clinical Interview for DSM-IV Axis I Disorders: Clinician Version
SSRI
selective serotonin reuptake inhibitor
VLDL
very low density lipoprotein
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All subjects gave informed consent to participate in this study. They were requested to avoid medication affecting lipid levels (for example, beta blockers, diuretics, androgens, estrogens, disulfiram, corticosteroids, levodopa, and aminosalycylic acid) and to abstain from a cholesterol-lowering diet for at least 2 weeks. Blood was centrifuged at 940 g for 1 minute in a refrigerated centrifuge and the serum samples were separated from blood cells. Serum cholesterol, triglyceride, and HDL-cholesterol levels were determined with commercially available kits (Roche Diagnostic GmbH, Mannheim, Germany) on a Hitachi 747 autoanalyzer (Hitachi Ltd, Tokyo, Japan). An enzymatic colorimetric method was used for cholesterol and triglyceride determination. HDL cholesterol was measured according to the direct HDLcholesterol method. LDL was calculated according to the Friedewald formula (7). We report all data as mean (SD). We used Student’s t test to analyze group data. All significant levels were 2-tailed and set at the 0.02 level, and all analyses were performed with the Statistical Package for the Social Sciences (SPSS) for windows, Version 9.01 (8).
Results Table 1 shows serum triglyceride, total cholesterol, HDL, LDL, and VLDL levels of the groups. As shown in Table 1, t test revealed a significant difference in serum triglyceride (P = 0.007), total cholesterol (P = 0.017), and LDL (P = 0.006) levels between the groups. Patients with ND had lower serum triglyceride, lower total cholesterol, and lower LDL levels than did healthy control subjects. There was no significant between-group difference in serum HDL and VLDL levels.
Discussion In this study, we found that patients with ND had lower serum triglyceride, lower total cholesterol, and lower LDL levels than did healthy control subjects. This is the first study in the literature to examine the relation between serum lipid levels and nightmares. The underlying neurobiological mechanisms of the relation between low serum lipid concentrations and recurrent nightmares are not clear. Various neurotransmitters W Can J Psychiatry, Vol 50, No 6, May 2005
Nightmares and Serum Cholesterol Level: A Preliminary Report
(for example, serotonin, histamine, GABA and acetylcholine) and hormones (that is, peptides and steroids) participate in sleep regulation. All of them are related in complex ways through reciprocal influences and feedback and may contribute to the pathophysiology of nightmares. The serotonergic system is involved in the regulation of sleep and wakefulness, its activity being maximum during wakefulness and minimum during sleep. In particular, the production of REM sleep depends on the decrease of serotonergic tone in brain stem structures (9). Dorsal raphe nucleus neurons are most active during waking; the activity is considerably lower during slow wave sleep and lowest during REM sleep (10). Recently, decreased dream frequency during SSRI treatment was reported (11). This implicates serotonergic REM suppression as well. Conversely, the authors suggested an augmentation of report length and bizarreness during acute SSRI discontinuation. This augmentation may be related to cholinergic rebound from serotonergic suppression. SSRIs may induce nightmares (12), although controversial results have also been reported in the literature (13). A recent study investigated the effect of pyridoxine (vitamin B6) on dreaming in a double-blind, placebo-controlled study (14). Vitamin B6 was found to increase dream vividness and the ability to recall dreams. This result may suggest that vitamin B6, an enzyme that catalyzes the rate-limiting step in 5-HT synthesis, acts by increasing cortical arousal during periods of REM sleep. Membrane cholesterol modulates the functional properties of the 5-HT transporter by specific molecular interactions (15). Low cholesterol may affect serotonergic neuronal activity and some types of 5-HT receptors and thus may be related to nightmares. Some neuroactive steroids are potent modulators of an array of ligand-gated ion channels and distinct G protein–coupled receptors, and they can influence sleep and memory (16). This ability of this class of compounds may affect both the primary excitatory and the inhibitory systems of the CNS. For example, allopregnanolone displays anxiolytic and hypnotic activities enhancing GABA-medicated chloride (17,18). A possible association between nightmares and lipid levels may be established through these compounds because they are synthesized de novo from cholesterol by astrocytes and oligodendrocites. As a conclusion, during nightmares in which REM sleep is predominant, serotonin release is clearly silent, whereas dopamine level increases. Thus low cholesterol may be related to serotonergic inhibition in the brain during nightmares. A relation between nightmares and depression should be examined in terms of serum lipid concentrations because nightmares are relatively common in depression patients. Further studies that take into consideration the effect of
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neuroactive steroids on sleep, in particular REM sleep and dream affect, are needed to replicate our findings in larger samples.
References 1. Agargun MY. Serum cholesterol concentration, depression, and anxiety [editorial]. Acta Psychiatr Scand 2002;105:81–3. 2. Agargun MY, Algun E, Sekeroglu R, Kara H, Tarakcioglu M. Low cholesterol level in patients with panic disorder: the association with major depression. J Affect Disord 1998;50:29–32. 3. Agargun MY, Kara H, Algün E, Sekeroglu R, Tarakçioglu M. High cholesterol level in patients with sleep panic. Biol Psychiatr 1996;40:1064 –5. 4. Agargun MY, Sekeroglu MR, Kara H, Özer ÖA, Tombul T, Kýran Ü, Selvi Y. Sleep-related violence and low serum cholesterol: a preliminary study. Psychiatr Clin Neurosci 2002;56:195– 8. 5. Nielsen T, Zadra A. Dreaming disorders. In: Principles and practice of sleep medicine. Kryger MH, Roth T, Dement W, editors. Philedelphia (PA): WB Saunders Company; 2000. p 753–72. 6. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for DSM-IV clinical version (SCID-I-CV). Washington (DC): American Psychiatric Press; 1997. 7. Friedewald WT, Levy RI, Fredricskon DS. Estimation of the concentration of the low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499–502. 8. SPSS Inc. Statistical Package for the Social Sciences (SPSS) for windows, Version 9.01. Chicago (IL): SPSS Inc; 1999. 9. Adrien J. Neurobiological bases for the relation between sleep and depression. Sleep Med Rev 2002; 6:341–51. 10. Portas CM, Bjorvatn B, Ursin R. Serotonin and the sleep/wake cycle: special emphasis on microdialysis studies. Prog Neurobiol 2000;60:13–35. 11. Pace-Schott EF, Gersh T, Silvestri R, Stickgold R, Salzman C, Hobson JA. SSRI treatment suppresses dream recall frequency but increases subjective dream intensity in normal subjects. J Sleep Res 2001;10:129–42. 12. Lepkifker E, Dannon PN, Iancu I, Ziv R, Kotler M. Nightmares related to fluoxetine treatment. Clin Neuropharmacol 1995;18:90–4. 13. De Boer M, Op den Velde W, Falger PJ, Hovens JE, De Groen JH, Van Duijn H. Fluvoxamine treatment for chronic PTSD: a pilot study. Psychother Psychosom 1992;57:158–63. 14. Ebben M, Lequerica A, Spielman A. Effects of pyridoxine on dreaming: a preliminary study. Percept Mot Skills 2002;94:135–40. 15. Scanlon SM, Williams DC, Schloss P. Membrane cholesterol modulates serotonin transporter activity. Biochemistry 2001;40:10507–13. 16. Darnaudery M, Pallares M, Bouyer JJ, Le Moal M, Mayo W. Infusion of neurosteroids into the rat nucleus basalis affects paradoxical sleep in accordance with their memory modulating properties. Neuroscience 1999;92:583–8. 17. Rupprecht R, Hauser CA, Trapp T, Holsboer F. Neurosteroids: molecular mechanisms of action and psychopharmacological significance. J Steroid Biochem Mol Biol 1996;5:163–8. 18. Engel SR, Grant KA. Neurosteroids and behavior. Int Rev Neurobiol 2001;46:321–48.
Manuscript received November 2003, revised, and accepted September 2004. 1 Professor of Psychiatry, School of Medicine, Department of Psychiatry and Neuroscience Research Unit, Yüzüncü Y2l University, Van, Turkey. 2 Research Fellow, School of Medicine, Department of Psychiatry, Yüzüncü Y2l University, Van, Turkey. 3 Assistant Professor of Psychiatry, Meram Faculty of Medicine, Department of Psychiatry, Selcuk University, Konya, Turkey. 4 Professor of Psychiatry, School of Medicine, Department of Psychiatry, Yüzüncü Y2l University, Van, Turkey. 5 Professor of Biochemistry, School of Medicine, Department of Biochemistry, Yüzüncü Y2l University, Van, Turkey. 6 Assistant Professor of Biochemistry, School of Medicine, Department of Biochemistry, Yüzüncü Y2l University, Van, Turkey. 7 Assistant Professor of Psychiatry, School of Medicine, Department of Psychiatry, Yüzüncü Y2l University, Van, Turkey. 8 Research Fellow, School of Medicine, Department of Psychiatry, Yüzüncü Y2l University, Van, Turkey. Address for correspondence: Dr MY Agargun, School of Medicine, Department of Psychiatry, Yüzüncü Y2l University, Van 65200 Turkey e-mail:
[email protected]
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Résumé : Les cauchemars et le taux de cholestérol sérique : un rapport préliminaire Objectif : Examiner s'il y a une relation entre les cauchemars et les taux de lipides sériques. Méthodes : Quinze sujets qui satisfaisaient aux critères diagnostiques du trouble des cauchemars du DSM-IV et 15 sujets témoins normaux ont participé à l'étude. Nous avons utilisé une méthode enzymatique colorimétrique pour déterminer le cholestérol et les triglycérides. Nous avons mesuré le cholestérol à lipoprotéines de haute densité (HDL) à l'aide de la méthode directe du cholestérol HDL. Le cholestérol à lipoprotéines de basse densité (LDL) a été calculé d'après la formule de Friedewald. Résultats : Les patients souffrant du trouble des cauchemars avaient un taux sérique de triglycérides plus faible, un cholestérol total plus faible, et des taux de LDL moins élevés que les sujets témoins. Conclusion : Ces résultats indiquent que les cauchemars sont associés à des taux de lipides sériques faibles.
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