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Table of Contents

image Tranylcypromine in depression resistant to cyclic antidepressions.
image L-5-hydroxytryptophan alone and in combination with a peripheral decarboxylase inhibitor in the treatment of depression.
image The relationship of serotonin to depression in Parkinson's disease.
image Fibromyalgia and the serotonin pathway.
image 5-Hydroxytryptophan: a clinically-effective serotonin precursor.
image Neuroendocrine response to 5-hydroxy-L-tryptophan in prepubertal children at high risk of major depressive disorder.
image Low brain uptake of L-[11C]5-hydroxytryptophan in major depression: a positron emission tomography study on patients and healthy volunteers.
image Double-blind study of 5-hydroxytryptophan versus placebo in the treatment of primary fibromyalgia syndrome.
image Neuroendocrine perturbations in fibromyalgia and chronic fatigue syndrome.


Tranylcypromine in depression resistant to cyclic antidepressions.

Nolen WA Department of Biological Psychiatry, Psychiatric Centre Bloemendaal, The Hague, The Netherlands.

Prog Neuropsychopharmacol Biol Psychiatry 1989;13(1-2):155-8
Non-responders to cyclic antidepressants were treated with the MAO-inhibitor tranylcypromine in two studies: the first study in an open comparison with L-5-hydroxytryptophan (L-5HTP), the second study in a double blind comparison with nomifensine. 2. While both L-5HTP and nomifensine appeared to be ineffective, tranylcypromine was effective in 26 out of 45 patients. 3.It is concluded that besides ECT also MAO-inhibitors such as tranylcypromine are an effective alternative for depressed patients not responding to cyclic antidepressants.

L-5-hydroxytryptophan alone and in combination with a peripheral decarboxylase inhibitor in the treatment of depression.

Zmilacher K, Battegay R, Gastpar M Psychiatric University Outpatient Department, Basel, Switzerland.

Neuropsychobiology 1988;20(1):28-35
In an open study 25 depressed patients were treated with L-5-hydroxytryptophan (L-5-HTP) either alone or in combination with a peripheral decarboxylase inhibitor. The therapeutic efficacy of L-5-HTP was considered as equal to that of traditional antidepressants. There was no difference in efficacy between the two treatments. Best results were obtained in patients with an anxious-agitated depressive syndrome and in patients with an endogenous depression if the illness had been acute. The onset of action was rapid (within 3 or 5 days). Gastrointestinal side effects proved to be dose-dependent and occurred more frequently in patients receiving L-5-HTP alone, whereas psychopathological side effects (especially acute anxiety states) have mainly been reported in patients receiving L-5-HTP in combination with a peripheral decarboxylase inhibitor.

The relationship of serotonin to depression in Parkinson's disease.

Mayeux R, Stern Y, Sano M, Williams JB, Cote LJ Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York 10032.

Mov Disord 1988;3(3):237-44
We have previously reported a correlation between depression in patients with idiopathic Parkinson's disease and decreased concentrations of the cerebrospinal fluid content of the serotonin metabolite, 5-HIAA. To further examine this relationship, we repeated the study in a new cohort of patients while they remained on dopaminergic medications, conducted follow-up interviews and examinations in our original cohort, and conducted an open trial of the serotonin precursor, 5-hydroxytryptophan in a group of new patients with depression. We were again able to demonstrate a significant reduction in cerebrospinal 5-HIAA in depressed patients in comparison to controls and patients without depression. Demented patients with Parkinson's disease, particularly those with concurrent depression, had the lowest values of 5-HIAA. No new cases of depression occurred in our original cohort after 2 1/2 years of follow-up, and depression remitted following conventional or experimental treatment in four patients. Depression improved in six of the seven new patients following oral 5-hydroxytryptophan. Three of these patients allowed a repeat lumbar puncture, and the concentration of 5-HIAA increased following 5-hydroxytryptophan. These three studies support our hypothesis that depression in idiopathic Parkinson's disease is associated with a reduction in brain serotonin. However, it also suggests that other factors, biological or environmental, may be causal factors.

Fibromyalgia and the serotonin pathway.

Juhl JH

Altern Med Rev 1998 Oct;3(5):367-75
Fibromyalgia syndrome is a musculoskeletal pain and fatigue disorder manifested by diffuse myalgia, localized areas of tenderness, fatigue, lowered pain thresholds, and nonrestorative sleep. Evidence from multiple sources support the concept of decreased flux through the serotonin pathway in fibromyalgia patients. Serotonin substrate supplementation, via L-tryptophan or 5-hydroxytryptophan (5-HTP), has been shown to improve symptoms of depression, anxiety, insomnia and somatic pains in a variety of patient cohorts. Identification of low serum tryptophan and serotonin levels may be a simple way to identify persons who will respond well to this approach.

5-Hydroxytryptophan: a clinically-effective serotonin precursor.

Birdsall TC

Altern Med Rev 1998 Aug;3(4):271-80
5-Hydroxytryptophan (5-HTP) is the intermediate metabolite of the essential amino acid L-tryptophan (LT) in the biosynthesis of serotonin. Intestinal absorption of 5-HTP does not require the presence of a transport molecule, and is not affected by the presence of other amino acids; therefore it may be taken with meals without reducing its effectiveness. Unlike LT, 5-HTP cannot be shunted into niacin or protein production. Therapeutic use of 5-HTP bypasses the conversion of LT into 5-HTP by the enzyme tryptophan hydroxylase, which is the rate-limiting step in the synthesis of serotonin. 5-HTP is well absorbed from an oral dose, with about 70 percent ending up in the bloodstream. It easily crosses the blood-brain barrier and effectively increases central nervous system (CNS) synthesis of serotonin. In the CNS, serotonin levels have been implicated in the regulation of sleep, depression, anxiety, aggression, appetite, temperature, sexual behaviour, and pain sensation. Therapeutic administration of 5-HTP has been shown to be effective in treating a wide variety of conditions, including depression, fibromyalgia, binge eating associated with obesity, chronic headaches, and insomnia.

Neuroendocrine response to 5-hydroxy-L-tryptophan in prepubertal children at high risk of major depressive disorder.

Birmaher B, Kaufman J, Brent DA, Dahl RE, Perel JM, al-Shabbout M, Nelson B, Stull S, Rao U, Waterman GS, Williamson DE, Ryan ND University of Pittsburgh Medical Center, Western Psychiatric Institute and Clinic, Pa., USA.

Arch Gen Psychiatry 1997 Dec;54(12):1113-9
BACKGROUND: Altered serotonergic function has been observed in prepubertal children and adults with an acute episode of major depressive disorder (MDD). However, it is not known whether these alterations are present prior to the onset of MDD. METHODS: A serotonergic precursor, 5-hydroxy-L-tryptophan (L-5HTP) (oxitriptan) (0.8 mg/kg), was administered through an indwelling catheter to 36 children at high risk of MDD (with high family loading for MDD), 31 children with MDD, and 23 low-risk normal controls (with low family loading for mood disorders and no history of psychopathology). Blood samples for cortisol, prolactin (PRL), and growth hormone were obtained every 15 minutes for 180 minutes, beginning 30 minutes before L-5HTP infusion. RESULTS: Children at high risk of MDD and children with MDD had similar hormonal responses following L-5HTP infusion. After controlling for baseline values, both groups secreted significantly less cortisol and more PRL than did the low-risk normal controls, with the PRL finding being limited to girls. There were no between-group differences in baseline cortisol, PRL, or growth hormone secretion measures. CONCLUSIONS: Before the onset of affective illness, high-risk children had the same pattern of neuroendocrine response to the L-5HTP challenge as did children with MDD. These results extend earlier findings of altered serotonergic regulation in association with early-onset depression and indicate that these alterations may represent a trait marker for depression in children.

Low brain uptake of L-[11C]5-hydroxytryptophan in major depression: a positron emission tomography study on patients and healthy volunteers.

Agren H, Reibring L, Hartvig P, Tedroff J, Bjurling P, Hornfeldt K, Andersson Y, Lundqvist H, Langstrom B Department of Psychiatry, University Hospital, Uppsala, Sweden.

Acta Psychiatr Scand 1991 Jun;83(6):449-55
The precursor of serotonin, L-5-hydroxytryptophan (L-5-HTP), was radiolabelled with 11C in the beta-position, yielding [beta-11C]serotonin after decarboxylation, allowing positron emission tomography studies of L-5-HTP uptake across the blood-brain barrier. We studied 8 healthy volunteers and 6 patients with histories of DSM-III major depression, 2 with repeated examinations after clinically successful treatment. We report a significantly lower uptake of [11C]5-HTP across the blood-brain barrier in depressed patients, irrespective of phase of illness. The findings emphasize that serotonin is involved in depressive pathophysiology and support earlier suggestions that the transport of 5-HTP across the blood-brain barrier is compromised in major depression.

Double-blind study of 5-hydroxytryptophan versus placebo in the treatment of primary fibromyalgia syndrome.

Caruso I, Sarzi Puttini P, Cazzola M, Azzolini V Rheumatology Unit, L. Sacco Hospital, Milan, Italy.

J Int Med Res 1990 May-Jun;18(3):201-9
A double-blind, placebo-controlled study of the efficacy and tolerability of 5-hydroxytryptophan (5-HTP) was conducted in 50 patients with primary fibromyalgia syndrome. All the clinical parameters studied were significantly improved by treatment with 5-HTP and only mild and transient side-effects were reported. Further controlled studies are required to define properly the value of 5-HTP in patients with primary fibromyalgia syndrome.

Neuroendocrine perturbations in fibromyalgia and chronic fatigue syndrome.

Neeck G, Crofford LJ Department of Rheumatology, University of Giessen, Bad Nauheim, Germany.

Rheum Dis Clin North Am 2000 Nov;26(4):989-1002
A large body of data from a number of different laboratories worldwide has demonstrated a general tendency for reduced adrenocortical responsiveness in CFS. It is still not clear if this is secondary to CNS abnormalities leading to decreased activity of CRH- or AVP-producing hypothalamic neurons. Primary hypofunction of the CRH neurons has been described on the basis of genetic and environmental influences. Other pathways could secondarily influence HPA axis activity, however. For example, serotonergic and noradrenergic input acts to stimulate HPA axis activity. Deficient serotonergic activity in CFS has been suggested by some of the studies as reviewed here. In addition, hypofunction of sympathetic nervous system function has been described and could contribute to abnormalities of central components of the HPA axis. One could interpret the clinical trial of glucocorticoid replacement in patients with CFS as confirmation of adrenal insufficiency if one were convinced of a positive therapeutic effect. If patient symptoms were related to impaired activation of central components of the axis, replacing glucocorticoids would merely exacerbate symptoms caused by enhanced negative feedback. Further study of specific components of the HPA axis should ultimately clarify the reproducible abnormalities associated with a clinical picture of CFS. In contrast to CFS, the results of the different hormonal axes in FMS support the assumption that the distortion of the hormonal pattern observed can be attributed to hyperactivity of CRH neurons. This hyperactivity may be driven and sustained by stress exerted by chronic pain originating in the musculoskeletal system or by an alteration of the CNS mechanism of nociception. The elevated activity of CRH neurons also seems to cause alteration of the set point of other hormonal axes. In addition to its control of the adrenal hormones, CRH stimulates somatostatin secretion at the hypothalamic level, which, in turn, causes inhibition of growth hormone and thyroid-stimulating hormone at the pituitary level. The suppression of gonadal function may also be attributed to elevated CRH because of its ability to inhibit hypothalamic luteinizing hormone-releasing hormone release; however, a remote effect on the ovary by the inhibition of follicle-stimulating hormone-stimulated estrogen production must also be considered. Serotonin (5-HT) precursors such as tryptophan (5-HTP), drugs that release 5-HT, or drugs that act directly on 5-HT receptors stimulate the HPA axis, indicating a stimulatory effect of serotonergic input on HPA axis function. Hyperfunction of the HPA axis could also reflect an elevated serotonergic tonus in the CNS of FMS patients. The authors conclude that the observed pattern of hormonal deviations in patients with FMS is a CNS adjustment to chronic pain and stress, constitutes a specific entity of FMS, and is primarily evoked by activated CRH neurons.