Tryptophan depletion studies

Bell, C, Forshall, S, Adrover, M., et aI Does 5-HT restrain panic A tryptophan depletion study in panic disorder patients recovered on paroxetine. J. Psychopharmacol. 16(1), 5-14, 2002. 

Experimental tryptophan depletion studies in humans and in animals have been utilized to determine the effects of reduced serotonin levels in the brain. Since acute tryptophan depletion leads to diminished serotonin levels, it has been considered a desirable and specific way to study effects or influences of serotonin. In general, it appears that alterations in serotonin levels influence a variety of mood disorders and neuropsychiatric conditions. This raises the question of whether the administration of tryptophan may prove to be beneficial in treating some patients. This aspect is considered further in Chapter 8. 

Studies in which the availability of serotonin is manipulated in combination with a laboratory panic challenge has considerably increased insight into the relationship between serotonin and panic disorder. Tryptophan depletion caused an increased panic response to a 5% or 35% CO2 challenge in panic disorder patients (Miller et al. 2000 Schruers et al. 2000). Conversely, panic anxiety and symptoms, as well as the number of panic attacks following 35% CO2 inhalation, were significantly reduced by pretreatment with the serotonin precursor L-hydroxytryptophan, suggesting that under certain circumstances serotonin may act to inhibit panic (Schruers et al. 2002). 

Barr LC, Goodman WK, Price LH, et al The serotonin hypothesis of OCD implications of pharmacologic challenge studies. J Chn Psychiatry 4 17-28s, 1992 Barr LC, Goodman WK, Price LH The serotonin hypothesis of obsessive compulsive disorder. Int Clin Psychopharmacol 8 (suppl 2 79-82, 1993 Barr LC, Goodman WK, McDougle CJ, et al Tryptophan depletion in patients with OCD who respond to serotonin reuptake inhibitors. Arch Gen Psychiatry 51 309-17, 1994... 

Possibly the best evidence suggesting involvement of norepinephrine and serotonin in major depressive disorder devolved from depletion studies (Delgado et al., 1990). In these stndies, patients who have responded to treatment for depression are given procedures, which deplete brain levels of serotonin or norepinephrine. Serotonin levels are decreased by nse of a low monoamine diet, followed by a drink which inclndes all the amino acids except the serotonin precnrsor tryptophan. Norepinephrine levels are depleted by administration of alpha-methylparatyrosine. In patients who had responded to treatment with a serotonergic antidepressant, depletion of serotonin cansed a prompt and dramatic, but brief reoccurrence of the symptoms of major depression. In patients who had responded to treatment with a noradrenergic antidepressant, depletion of norepinephrine caused a relapse into depression. The converse was not true in other words, serotonin depletion did not canse relapse in patients who responded to noradrenergic antidepressants, and vice versa. 

It has been known for many years that diets deficient in tryptophan lead to depletion of brain serotonin and hence to disturbances in serotonin-mediated brain function.41 Subsequently, in the early 1970s, Fernstrom and Wurtman42-43 began a systematic investigation of the relationship between tryptophan supply and serotonin synthesis under a variety of circumstances. The role of tryptophan deficiency on neuropsychiatric conditions is reviewed in Chapter 7. In addition, studies of rapid tryptophan depletion have been conducted on a wide variety of neuropsychiatric conditions in humans and in experimental conditions in animals. This approach and the findings are also reviewed in detail in Chapter 7. 

Rapid Tryptophan Depletion Experiments — Studies with rapid tryptophan depletion, which causes diminished blood tryptophan levels, have been conducted with a variety of neuropsychiatric conditions in humans and also in experimental animal studies. These findings are reviewed in detail in Chapter 7. 

Experimental Studies with Acute Tryptophan Depletion.165... 

The effects of L-tryptophan on the central nervous system have been investigated mainly in studies with acute tryptophan depletion. This approach has been utilized on a wide variety of neuropsychiatric conditions in humans and also in experimental models in animals. The rationale is that the rapid decrease in L-tryptophan levels in the circulation leads to a decrease in brain serotonin levels. 

This section describes the rationale for the utilization of dietary tryptophan depletion. Also, it reviews a number of studies designed to determine the consequences of acute tryptophan depletion upon a variety of disorders in humans and conditions in animals. The literature contains a plethora of reports utilizing acute tryptophan depletion. Selected examples have been chosen to illustrate the effects or influences of L-tryptophan levels on a variety of behavioral and psychiatric states. 

Gessa et al.1 were the first to demonstrate that the acute administration of an amino acid mixture containing all of the essential amino acids, except tryptophan, caused a rapid fall in plasma free and total tryptophan in rats. Furthermore, this effect was associated with a parallel depletion in brain tryptophan, serotonin, and 5-hydroxyindole acetic acid in rats.2 These early studies opened the way for subsequent studies, using acute tryptophan depletion by feeding a tryptophan-free amino acid mixture, a simple, specific, and nontoxic method, to delete brain serotonin and thus provide a tool for clarifying the physiological role of serotonin in the central nervous system. 

Acute tryptophan depletion has been a research strategy that rapidly reduces the availability of tryptophan, especially as it relates to being the precursor to serotonin, and thus provides a useful tool for studying the behavioral consequences of low brain serotonin. 

The literature contains many studies relating to tryptophan depletion and various psychiatric diseases. Before beginning a discussion of human conditions in which decreased availability of L-tryptophan may play a role in the symptomatology of the disorder, one must mention pellagra, which is caused by a deficiency of niacin. Pellagra was described as being associated with poverty and diets that relied heavily on corn, which is low in both niacin and its precursor, tryptophan.29,30 Nonetheless, since it is not due per se to tryptophan deficiency itself, this condition is not included in the diseases reviewed in this chapter. 

Ellenbogen et al.31 studied the mood response to acute tryptophan depletion in healthy euthymic women devoid of any personal or familial history of psychiatric illness. Like the males, the women exhibited a significant lowering of mood. 

The involvement of the central nervous system serotonin function in the pathogenesis and treatment of affective disorders has been a subject of intensive research during the past 30 years.33 36 Studies using serotonin precursors and agonists as pharmacologic probes and measurements of cerebrospinal fluid monoamine metabolite levels indicated that alterations in central nervous system serotonin function may be involved in the pathophysiology of depression. Since the synthesis of serotonin depends on dietary intake of the precursor tryptophan, many studies have utilized tryptophan depletion techniques by which patients were fed a tryptophan-free diet for various time intervals. 

Delgado et al.20 studied the behavioral effects of rapid (24 h) tryptophan depletion in patients in antidepressant-induced remission. Patients receiving antidepressants leading to remission were then given a tryptophan-free amino acid drink, and they experienced a depressive relapse. Free plasma tryptophan level was negatively correlated with the depression score during acute tryptophan depletion. A number of other studies on the effects of tryptophan depletion on relapse of depression after treatment confirmed the previous findings.37 11... 

Sharma et al.69 utilized the acute tryptophan depletion paradigm to evaluate patients with schizophrenia under controlled conditions. They observed no clinical or statistically significant improvement in symptoms compared to baseline when tryptophan depletion was imposed. The authors considered that their findings with schizophrenic or schizoaffective patients (treated but still symptomatic) may differ from those in untreated symptomatic patients. Other studies with the effects of tryptophan depletion differ markedly in treated remitted vs. untreated symptomatic depressed patients.20 70... 

Huwig-Poppe etal.73 studied the effects of tryptophan depletion in 12 patients with obsessive-compulsive disorder and in 12 healthy subjects. They reported that tryptophan depletion led to more pronounced disturbances of sleep continuity in the patients than in healthy subjects, in terms of an increase of wake time and a decrease of total sleep time. 

Panic Disorder — Goddard etal.83 conducted studies in which the effects of tryptophan depletion were evaluated in panic disorder patients. In this study, tryptophan depletion was not found to be anxiogenic in unmedicated panic disorder patients. They concluded that tryptophan depletion alone is not particularly panicogenic. 

B. F., and Mathe, A. A., Serotonergic vulnerability in affective disorder A study of the tryptophan depletion test and relationships between peripheral and central serotonin indexes in citalopram-responders, Acta Psychiatr. Scand., 97, 374, 1998. 

In general, the results of experimental studies in patients with PMS have given mixed results on whether there is lowered serotonin function in these patients. Menkes et al.84 reported that acute tryptophan depletion aggravated symptoms, particularly irritability, for women with PMS compared to controls. Ellenbogen et al.85 reported that tryptophan depletion caused a modest lowering of mood in healthy women without PMS and with no family history of depression. On the other hand, Benkelfat et al.86 reported no lowering of mood in healthy male subjects with no history of depression. 

It might be anticipated that Be deficiency would result in deficient pyridine nucleotide synthesis, since 3-hydroxykynureninase is sensitive to PLP depletion. Studies of nutritional B deficiency in man, however, indicate that, although tryptophan metabolism becomes abnormal, urinary output of quinolinic acid still increases after a tryptophan load (R15). Decreased formation of pyridine nucleotides from tryptophan may occur only when PLP depletion is severe (R15). 

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