Sleep disturbance and cognitive impairment are frequent complaints of depressed patients under standard antidepressant medication. Therefore, additional therapies are required which specifically focus on the improvement of these deficits without exerting major side effects. Ginkgo biloba extract (EGb) has been shown to improve cognitive abilities in elderly subjects and in patients with disorders of the dementia spectrum. Animal studies surmise that EGb may reduce CRH activity, which is substantially related to depressive mood and behavior, predominantly cognition and sleep. An open non-randomized pilot study has been conducted to investigate the effects of ginkgo biloba extract (EGb Li 1370) on cognitive performance and sleep regulation in depressed inpatients. 16 patients were treated with a trimipramine (T)-monotherapy (200 mg) for six weeks. In eight of the 16 patients, an adjunct EGb therapy (240 mg/d) was applied for four weeks after a baseline week, the other eight patients remained on trimipramine monotherapy (200 mg) during the entire study. Polysomnography, cognitive psychomotor performance and psychopathology were assessed at baseline, after short-term and long-term adjunct EGb treatment, and after one week of ginkgo discontinuation (at the respective evaluation times in the eight patients on T-monotherapy). This report focuses on the results of EGb on sleep EEG pattern. EGb significantly improved sleep pattern by an increase of sleep efficiency and a reduction of awakenings. In addition, sleep stage 1 and REM-density were reduced, while stage 2 was increased. Non-REM sleep, predominantly slow wave sleep in the first sleep cycle, was significantly enhanced compared to trimipramine monotherapy. Discontinuation of EGb reversed most of these effects. Based on the animal data, these results suggest that EGb may improve sleep continuity and enhance Non-REM sleep due to a weakening of tonic CRH-activity. The compensation of the deficient Non-REM component in depression by the EGb application may provide a new additional treatment strategy, especially in the treatment of the depressive syndrome with sleep disturbance.
References
-
1 American Psychiatric Association (APA) .DSM-III-R: Diagnostic and statistical manual of mental disorders. 3rd ed., revised. Washington DC; APA 1987
-
2
Amri H, Ogwuegbu O, Boujard N, Drieu K, Papadopoulos V.
In vivo regulation of peripheral-type benzodiazepine receptor and glucocorticoid synthesis by ginkgo biloba extract EGb 761 and isolated ginkgolides.
Endocrinology.
1996;
137
5707-5718
-
3
Assalian P, Rosengarten M D, Philips R.
A comparative trial of the antidepressant, anxiolytic, and cardiovascular effects of trimipramine and doxepin in depressed hospitalized patients.
J Clin Psychiatry.
1985;
46
(3)
90-94
-
4
Borbély A A.
The S-deficiency hypothesis of depression and the two-process model of sleep regulation.
Pharmacopsychiatry.
1987;
20
23-29
-
5 Bortz J, Lienert G A, Boehnke K. Verteilungsfreie Methoden in der Biostatistik. Berlin, Heidelberg; Springer Verlag 1990
-
6 Beck A T. Depression. Clinical, experimental, and theoretical aspects. New York; Harper and Row 1967
-
7
Benca R M, Obermeyer W H, Thisted R A, Gillin C H.
Sleep and Psychiatric Disorders.
Arch Gen Psychiatry.
1992;
49
51-668
-
8 Branconnier R J, Cole J O, Ghazvinian S et a l. et al .Treating the depressed elderly patients: The comparative behavioral pharmacology of mianserin and amitriptyline. In: Costa E, Racagni G (eds) Typical and Atypical Antidepressants: Clinical Practice. New York; Raven Press 1982
-
9
Chen C N.
Sleep depression and antidepressants.
Br J Psychiatry.
1979;
135
395-402
-
10 Christen Y, Courtois Y, Droy-Lefaix M T. Effects of ginkgo biloba extract (EGb 761) on aging and age-related disorders. Paris; Elsevier 1995
-
11
Cole J O, Braconnier E, Salomon M, Dessain E.
Tricyclic use in the Cognitively Impaired Elderly.
Clin. Psychiatry.
1983;
44
(9)
14-19
-
12 DeFeudis F V. Ginkgo biloba extract (EGb 761): Pharmacological activities and clinical applications. Paris; Elsevier 1991
-
13
Ehlers C L, Reed T K, Heriksen S J.
The effects of corticotropine releasing factor and growth hormone releasing factor on sleep and activity in rats.
Neuroendocrinology.
1986;
42
467-474
-
14
Ehlers C L, Kupfer D J.
Hypothalamic peptide modulation of EEG-sleep in depression: A further application of the S-process hypothesis.
Biol Psychiatry.
1987;
22
513-517
-
15
Hamilton M.
Development of a rating scale for primary depressive illness.
Br J Soc Clin Psychol.
1967 ;
6
278-296
-
16
Hemmeter U, Brüderlin U, Gerhard U, Hatzinger M, Hobi V, Seifritz E, Holsboer-Trachsler E.
REM density: a dual indicator of mood and cognition in major depression.
J of Sleep Res.
1998;
7
116
-
17
Hemmeter U, Bischof R, Hatzinger M, Seifritz E, Holsboer-Trachsler E.
Microsleep during partial sleep deprivation in depression.
Biol Psychiatry,.
1998;
43
829-839
-
18
Hindmarch I.
The behavioral toxicity of the selective serotonin reuptake inhibitors.
Int Clin Psychopharmacol.
1995;
9
(Suppl 4)
13-17
-
19
Hofferberth B.
The efficacy of EGb 761 in patients with senile dementia of the Alzheimer type: a double-blind, placebo-controlled study on different levels of investigation.
Hum Psychopharmacol.
1994;
9
215-222
-
20
Holsboer F, von Bardeleben U, Steiger A.
Effects of intravenous corticotropin-releasing hormone upon sleep-related growth hormone surge and sleep EEG in man.
Neuroendocrinology.
1988;
48
2-38
-
21
Holsboer F.
Antidepressants and hypothalamic-pituitary-adrenocortical regulation.
Endocrine Rev.
1996;
17
87-205
-
22
Holsboer-Trachsler E, Hemmeter U, Hatzinger M, Seifritz E, Gerhard U, Hobi V.
Sleep Deprivation and Bright Light as Potential Augmenters of Antidepressant Drug Treatment - Neurobiological and Psychometric Assessment of Course.
J Psychiat Res.
1994;
28
(4)
381-399
-
23
Judd L L, Rapaport M H, Paulus M P, Brown J L.
Subsyndromal symptomatic depression: a new mood disorder?.
J Clin Psychiatry.
1994;
55
(Suppl)
18-28
-
24
Judd L L, Akiskal H S, Maser J D, Zeller P J, Endicott J, Coryell W, Paulus M P, Kunovac J L, Leon A C, Mueller T I, Rice J A, Keller M B.
Major depressive disorder: a prospective study of residual subthreshold depressive symptoms as predictor of rapid relapse.
Journal of Affective disorders.
1998;
50
(2-3)
97-108
-
25
Kavanau J L.
Memory, sleep and the evolution of mechanisms of synaptic efficacy maintenance.
Neurosience.
1997;
79
7-44
-
26
Kanowski S, Herrmann W M, Stephan K, Wierich W, Hérr R.
Proof of efficacy of the ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia.
Pharmacopsychiatry.
1996;
29
47-56
-
27
Karni A, Tanne D, Rubenstein B S, Askenasy J JM, Sagi D.
Dependence on REM sleep of overnight improvement of a perceptual skill.
Science.
1994;
265
679-682
-
28
Kleijnen J, Knipschild P.
Ginkgo biloba.
The Lancet, .
1992;
7
1136-1139
-
29
Kupfer D J, Frank E, McEachran A B, Grochocinski V J.
A biological correlate of early recurrence in unipolar affective disorder.
Arch Gen Psychiat.
1990;
47
1100-1105
-
30
Lauer C, Riemann D, Wiegand M, Berger M.
From early to late adulthood changes in EEG sleep of depressed patients and healthy volunteers.
Biol Psychiatry.
1991;
29
979-993
-
31
Lauer C J, Schreiber W, Modell S, Holsboer F, Krieg J C.
The Munich vulnerability study on affective disorders: overview of the cross-sectional observation at index investigation.
J Psychiat Res.
1998;
32(6)
393-401
-
32
Le Bars P L, Katz M M, Berman N, Itil T M, Freedman A M, Schatzberg A F.
A placebo-controlled, double-blind, randomized trial of an extract of ginkgo biloba for dementia.
JAMA.
1997;
278
1327-1332
-
33
Lee S L, Wang W W, Lanzillo J, Gillis C N, Fanburg B L.
Superoxide scavenging effect of ginkgo biloba extract on serotonin-induced mitogenesis.
Biochem Pharmacol.
1998;
56
527-533
-
34
Marcilhac A, Dakine N, Bourhim N, Guillaume V, Grino M, Drieu K, Oliver C.
Effect of chronic administration of ginkgo biloba extract or ginkgolide on the hypothalamic-pituitary-adrenal axis in the rat.
Life Sci.
1998;
62
2329-2340
-
35
Matthews J NS, Altman D G, Campbell M J, Royston P.
Analysis of serial measurements in medical research.
BMJ.
1990;
300
230-235
-
36
Maurer K, Ihl R, Dierks T, Frölich L.
Clinical efficacy of ginkgo biloba special extract EGb 761 in dementia of the Alzheimer type.
J Psychiat Res.
1997 ;
31
654-655
-
37
Mendelson W B, Martin J V, Perlis M, Wagner R, Majewska M D, Paul S M.
Sleep induction by an adrenal steroid in the rat.
Psychopharmacol.
1987;
93
226-229
-
38
Montgomery S A.
Rapid onset of action of venlafaxine.
Int Clin Psychopharmacol.
1995;
10
(Suppl 2)
21-27
-
39 Nikita C, Patel N. StatXact Version 4.01. Cambridge; Cytel software corporation 1999
-
40
Oken B S, Storzbach D M, Kaye J A.
The Efficacy of ginkgo biloba on cognitive Function in Alzheimer Disease.
Arch Neruol.
1998;
55
1409-1415
-
41 Packer L, Haramaki N, Kawabata T. et al .Effect of ginkgo biloba extract (EGb 761) on Aging and Age-Related Disorders. Paris, France; Editions Scientifiques Elsevier Paris 1995: 23-47
-
42
Porsolt R D, Martin P, Lenegere A, Fromage S, Drieu K.
Effects of an extract of ginkgo biloba (EGb 761) on ”learned helplessness¿ and other models of stress in rodents.
Pharmacol Biochem Behav.
1990;
36
963-971
-
43
Rai G S, Shovlin C, Wesnes K A.
A double-blind, placebo controlled study of ginkgo biloba extract (‘Tanakan’) in elderly out-patients with mild to moderate memory impairment.
Curr Med Res Opin.
1991;
12
350-355
-
44
Rapin J R, Lamproglou I, Drieu K, DeFeudis F V.
Demonstration of the “anti-stress”¿ activity of an extract of ginkgo biloba (EGb 761) using a discrimination learning task.
Gen Pharmacol.
1994;
25
1009-1016
-
45 Rechtschaffen A, Kales A (eds.) A manual of standardized terminology techniques and scoring system for sleep stages of human subjects. Washington DC; Public Health Service, US Government Printing Office 1968
-
46
Reynolds C F, Kupfer D J.
Sleep research in affective illness: State of the art circa 1987.
Sleep.
1987;
10
199-215
-
47
Riemann D, Schnitzler M, Hohagen F, Berger M.
Depression und Schlaf - der gegenwärtige Forschungsstand.
Fortschr Neurol Psychiat.
1994;
62
458-478
-
48
Rifkin A, Reardon G, Siris S, Karagij B, Kin Y S, Hackstaff M SW, Endicott N.
Trimipramine in physical illness with depression.
J Clin Psychiatry.
1985;
46
4-8
-
49
Rush A J, Armitage R, Gillin J C, Yonkers K A, Winokur A, Moldofsky H, Vogel G W, Kaplita S B, Fleming J B, Montplaisir J, Erman M K, Abala B J, McQuade R D.
Comparative Effects of Nefazodone and Fluoxetine on Sleep in Outpatients with Major Depressive Disorder.
Biol Psychiatry.
1998;
44
3-14
-
50
Saletu B, Frey R, Krupka M, Anderer P, Grunberger J, See W R.
Sleep laboratory studies on the single-dose effects of serotonin reuptake inhibitors paroxetine and fluoxetine on human sleep and awakening qualities.
Sleep.
1991;
14
(5)
439-447
-
51
Seifritz E, Müller M J, Trachsel L, Lauer C J, Hemmeter U, Hatzinger M, Moore P, Holsboer-Trachsler E.
Revisiting the Ehlers and Kupfer hypothesis: the growth-hormone cortisol secretion ratio during sleep is correlated with electroencephalographic slow wave activity in normal volunteers.
Biol Psychiatry.
1996;
39
39-142
-
52
Smith M J, Brèbion G, Banquet J P, Allilaire J F.
Experimental evidence for two dimensions of cognitive disorders in depressives.
J Psychiat Res.
1994;
4
401-411
-
53
Steiger A, von Bardeleben U, Herth T, Holsboer F.
Sleep EEG and nocturnal secretion of cortisol and growth hormone in male patients with endogenous depression before treatment and after recovery.
J of Affective Disorder.
1989;
16
189-195
-
54
Steiger A, von Bardeleben U, Wiedemann K, Holsboer F.
Sleep EEG and nocturnal secretion of testosterone and cortisol in patients with major endogenous depression during acute phase and after remission.
J Psychiatr Res.
1991;
25
(4)
169-177
-
55
Steiger A, von Bardeleben U, Guldner J, Lauer C, Rothe B, Holsboer F.
The sleep EEG and nocturnal hormonal secretion studies on changes during the course of depression and on effects of CNS-active drugs.
Prog Neuropsychopharmacol Biol Psychiatry.
1993;
17
(1)
125-137
-
56
Steiger A, Sonntag A, Guldner J, Rothe B, Holsboer F.
Changes in clinical symptoms, sleep EEG and nocturnal hormonal secretion during treatment with trimipramine or imipramine - a double-blind comparison in patients with major depression.
Eur Psychopharmacol.
1993;
3
339-340
-
57
Steiger A.
Schlafendokrinologie.
Nervenarzt.
1995;
66
15-27
-
58
Ware J C, Brown F W, Moorad J P, Pittard J T, Cobert B.
Comparison of trimipramine and imipramine in depressed insomnia patients.
Sleep Res.
1985;
14
65-66
-
59
Wiegand M, Berger M.
Action of trimipramine on sleep and pituitary hormone secretion.
Drugs.
1989;
38
(Suppl 1)
35-42
-
60
Wesnes K, Simmons D, Rook M, Simpson P.
A double-blind placebo-controlled trial of Tanakan in the treatment of idiopathic cognitive impairment in the elderly.
Hum Psychopharmacol.
1987;
2
159-169
-
61 Zerssen von D, Koeller D M. Klinische Selbstbeurteilungsskalen (KSb-S) aus dem Münchner Psychiatrischen Informationssystem (PSYCHIS, München). Weinheim; Beltz 1976
-
62 Zobel A, Yassouridis A, Frieboes R M, Holsboer F. Cortisol response to the combined dexamethasone-CRH test predicts medium-term outcome in patients with remitted depression. Am J of Psychiatry 1999 in press
1 This study was supported by Medichemie AG, Switzerland.
Dr. med. Dr. phil. Dipl.-Psych. Ulrich Hemmeter
Zentrum für Nervenheilkunde
Klinik für Psychiatrie und Psychotherapie
Philips Universität Marburg
Rudolph Bultmann Straße 8
30533 Marburg
Germany
Telefon: 0049-6421-28 68939
Fax: 0049-6421-28 66882
