TRYPTAN ICN L-Tryptophan Adjunct in the Management of Affective Disorders
Action and Clinical
The rationale for the use of L-tryptophan in affective disorders is based on clinical findings more than 20 years ago, that L-tryptophan increases 5-HT (serotonin) synthesis in the CNS of humans. It has been demonstrated in clinical trials that oral ingestion of L-tryptophan in humans caused a significant increase in the level of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in the lumbar cerebrospinal fluid, indicating an increased turnover of serotonin in the CNS.
L-tryptophan is 1 of the 8 essential amino acids. The minimum daily requirements are said to be 0.25 g for males and 0.15 g for females. It is present in the hydrolysates of most proteins, the average western diet containing between 1 and 3 g/day. There are 2 major metabolic pathways for L-tryptophan, the first to serotonin, the second to nicotinic acid. Approximately 98% of dietary L-tryptophan is metabolized into nicotinic acid and only a very small amount is being metabolized to serotonin via the intermediary stage of 5-hydroxy-tryptophan (5-HTP). Tryptophan hydroxylase, the enzyme responsible for this step, is the rate-limiting enzyme for serotonin production and is normally only about half- saturated. CNS serotonin is metabolized by monoamine oxidase to 5-HIAA.
Indications And Clinical Uses:
As a valuable adjunct to antidepressant drug treatment in the management of patients suffering from depressive disorders (bipolar affective disorders). An adjunctive effect has been observed in some cases when L-tryptophan is given in combination with lithium in bipolar patients with mania or depression for whom lithium alone or in combination with neuroleptics or tricyclics has shown little or no effect. Clinical observations suggest the possibility that the combination of lithium and L-tryptophan may reduce the need for the higher, more toxic doses of lithium necessary in control acute mania.
In patients with known sensitivity to L-tryptophan or any other compound in the formulation.
Warnings in Clinical States:
L-tryptophan should not be given to patients suffering from the following conditions or should be prescribed only under close supervison.
Bladder Cancer: To minimize the risk of bladder cancer, it may be recommended to give vitamin B 6 supplements if the L-tryptophan doses are many times in excess of those consumed normally in dietary protein. An increased incidence rate of bladder cancer has been observed in experimental animals after implantation of pellets containing any of the 7 tryptophan metabolites formed by tryptophan pyrrolase. Active metabolites included kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranillic acid, and xanthurenic acid, but not tryptophan itself. Vitamin B 6 has been reported to correct the metabolism of L-tryptophan and to reduce the metabolites to normal levels. A large study carried out by the National Cancer Institute did not find L-tryptophan to produce cancer in either rats or mice. Elevated levels of L-tryptophan metabolites in the urine have been reported both in bladder cancer patients relative to controls, in patients who had a recurrence of cancer relative to those who did not, and in patients taking oral contraceptives or hormones.
Diabetes Mellitus: Xanthurenic acid, which is increased on L-tryptophan loading, has a diabetogenic action in animals, possibly due to its ability to bind insulin, suggesting caution in the use of tryptophan in patients with a family history of diabetes.
Achlorhydria/Malabsorption: In ruminants, oral L-tryptophan caused pulmonary edema and emphysema, mediated by bacterial conversion of L-tryptophan to skatole (3-methylindole). This is not normally of concern in humans except where bacteria exist high in the gastrointestinal tract due to conditions such as achlorhydria, or where L-tryptophan reaches the bacterial populations lower in the gastrointestinal tract due to malabsorption.
Cataract Formation: Animal data suggest that photooxidation of L-tryptophan and some of its metabolites, such as kynurenine, may be involved in cataract formation. Although there is no evidence that this occurs in humans, L-tryptophan administration is likely to raise lenticular tryptophan and kynurenine concentrations, and this might make subjects more susceptible to cataract formation, particularly if exposed to ultraviolet light.
Drug Interactions: Drug interactions between tryptophan and other CNS affecting drugs have been reported. A higher occurrence of side effects was reported when tryptophan was given in combination with MAO inhibitors. The most common side effects caused by this drug combination were dizziness, nausea and headache. At a dosage of 20 to 50 mg/kg tryptophan in addition to MAO inhibitors, the following side effects have been reported: ethanol-like intoxication, drowsiness, hyperreflexia and clonus. Single case reports of adverse reactions to the drug combination include hypomanic behavior, ocular oscillation, ataxia, and myoclonus. Some of these reactions resemble the “serotonin syndrome” seen in experimental animals, which consists of tremor, hypertonus, myoclonus, and hyperreactivity. These symptoms disappear soon after cessation of tryptophan, and no detrimental long-term effects have been reported.
When tryptophan was given in combination with fluoxetine, the following side effects have been reported, but disappeared as soon as the medication was discontinued. Neither drug alone caused similar side effects: agitation, restlessness, poor concentration, nausea, diarrhea, and worsening of obsessive-compulsive disorder.
Patients taking high doses of L-tryptophan should not be protein deprived since an amino acid imbalance can ensue.
:L-tryptophan, in doses below 5 g/day may cause dry mouth and drowsiness. In higher doses (9 to 12 g/day) nausea, anorexia, dizziness and headache have been reported.
Side effects disappear when medication is continued and in most cases only a light dizziness may persist.
Sexual disinhibition has been reported in some patients with emotional disorders.
L-tryptophan, when given with lithium, might increase some side effects associated with lithium therapy by potentiating the lithium effect (nausea, vomiting, dermatological eruptions, psoriasis, alopecia).
Symptoms And Treatment Of Overdose:
OverdoseAccording to the toxicity described, symptoms of overdosage would include vomiting and might include serotonin syndrome symptoms. Treatment of overdosage would be symptomatic with close monitoring and support of vital systems as necessary.
Dosage And Administration:
Clinical reports on the use of L-tryptophan as an adjunct in the management of affective disorders have indicated the dose of 8 to 12 g/day to be the most effective one. Lower doses have been reported to be effective in combination with other antidepressants. Some patients may not tolerate 12 g/day but might still benefit from doses reduced to 8 g/day.
The treatment might be initiated with 12 g/day of L-tryptophan, given in 3 to 4 equally divided doses. Administration with meals or snacks is recommended to reduce the incidence of nausea. The dose and frequency of administration may have to be adjusted to the patient’s need and tolerance.
A small number of bipolar patients are particularly sensitive to L-tryptophan and will not tolerate higher doses than 1 or 2 g/day. Patients on concomitant medication should be monitored for possible reduction of the concomitant medication since L-tryptophan may enhance their efficacy.
If L-tryptophan is used in the acute treatment of mania in conjunction with lithium it will potentiate some of the side effects associated with lithium such as nausea and vomiting. Thus, often it will be necessary to decrease the lithium dosage especially when it is given in doses above 900 to 1 200 mg/day. In manic-depressive illness chronically treated with lithium, the lithium dose may need to be decreased when L-tryptophan is added because of increased side effects. In these patients L-tryptophan tends to produce an increase in lithium concentrations, thus it is important to monitor the lithium concentration closely for at least 2 weeks after the addition of L-tryptophan.
With some of the more sedative neuroleptics and antidepressants, if L-tryptophan is added, an increased incidence of sedation may occur.
Information for the Patient: For better results, L-tryptophan should be taken with a protein-low, carbohydrate-rich snack or meal.
Availability And Storage:
Capsules: Each opaque white capsule, size No. 00, imprinted with ICN T17, contains: L-tryptophan, USP 500 mg. Nonmedicinal ingredients: magnesium stearate and talc. Bottles of 100 and 250.
Tablets: 250 mg: Each white, oval, film-coated tablet, embossed “TRYPTAN” on one side and “250 mg” on the other side, contains: L-tryptophan, USP 250 mg. Nonmedicinal ingredients: calcium phosphate, croscarmellose sodium, film coating base solution (includes: acetylated monoglyceride, hydroxypropylmethyl cellulose, povidone, titanium dioxide), magnesium stearate, methylcellulose, opaspray white and wax solution. Bottles of 100.
500 mg: Each white, oval, biconvex, film-coated tablet, embossed “TRYPTAN” on one side and “500 mg” on the other side, contains: L-tryptophan, USP 500 mg. Nonmedicinal ingredients: calcium phosphate, croscarmellose sodium, film coating base solution (includes: acetylated monoglyceride, hydroxypropylmethyl cellulose, povidone, titanium dioxide), magnesium stearate, methylcellulose, opaspray white and wax solution. Bottles of 100 and 250.
750 mg: Each white, oval, biconvex, film-coated tablet, embossed “TRYPTAN” on one side and “750 mg” on the other side, contains: L-tryptophan, USP 750 mg. Nonmedicinal ingredients: calcium phosphate, croscarmellose sodium, film coating base solution (includes: acetylated monoglyceride, hydroxypropylmethyl cellulose, povidone, titanium dioxide), magnesium stearate, methylcellulose, opaspray white and wax solution. Bottles of 100.
1 g: Each white, oval, film-coated tablet, embossed “TRYPTAN” 1 g on one side, contains: L-tryptophan, USP 1 g. Nonmedicinal ingredients: calcium phosphate, croscarmellose sodium, film coating base solution (includes: acetylated monoglyceride, hydroxypropylmethyl cellulose, povidone, titanium dioxide), magnesium stearate, methylcellulose, opaspray white and wax solution. Bottles of 100 and 250.
Store at controlled room temperature (15 to 30°C). Protect from heat and light.
TRYPTAN ICN L-Tryptophan Adjunct in the Management of Affective Disorders
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