Measurement of 5-hydroxyindole compounds during L-5-HTP treatment in depressed patients.

L-5-hydroxytryptophan (L-5-HTP), an immediate serotonin precursor, was given to the hospitalized depressed patients in an open clinical trial of the Phase 2 study for antidepressive effects of the agent. A relatively small dose, 150mg orally for seven days, was employed, and seven of 14 patients responded to the treatment with mild or moderate emelioration of their depressive symptoms. Urinary excretion levels and plasma concentrations of three 5-hydroxyindole compounds, 5-HTP, 5-HT and 5-HIAA, were measured during the drug treatment. Approximately 70% of the orally administered dose of L-5-HTP was recovered from the urine of depressed patients. Major part of urinary indoleamine metabolites was free and conjugate 5-HIAA. Excretion levels of these compounds in urine were not consistenly altered in the depressed patients as compared to those in normal subjects. Clinical response to L-5-HTP treatment appeared to have some correlation with the biochemical measures in the depressed patients, that is, non-responders exhibited significantly lower excretion levels of 5-HT and 5-HIAA in urine, and lower plasma levels of 5-HT than responders. Administered L-5-HTP may not be fully utilized in the depressed patients who did not react to the agent.     

L-5HTP treatment and serum 5-HT level after L-5-HTP loading on depressed patients.

Based on 5-HT hypothesis, L-5-HTP (150 or 300 mg/day) was given orally to 18 depressed patients. The global estimates were 2 very much improved; 8 much improved; 3 minimally improved, and 5 unchanged. The action of L-5-HTP was usually rapid. The elevation of the serum 5-HT level 1 week after L-5-HTP administration was relatively lower in the 5-HTP nonresponder group, compared with the responders. The chronological change of the serum 5-HT level in depressed patients after an oral loading dose of 3 mg/kg of L-5-HTP showed a gradual and slight elevation, compared with manic and normal groups. It seemed that the therapeutic effect of L-5-HTP on responders was related to lower 5-HT level in the brain for their pathogenesis, and that there was a metabolic disturbance of L-5-HTP into 5-HT in some depressed patients.     

THE LEVEL AND DIURNAL RHYTHM OF SERUM SEROTONIN IN MANIC-DEPPESSIVE PATIENTS

The serum levels and diurnal rhythm of serotonin before and during treatment were investigated in 65 manic-depressive patients, comparing with those in 34 normal controls and 13 schizophrenics. 1. The serum serotonin level in 40 newly admitted depressive patients who had not been medicated (127±58 ng/ml) was significantly lower than that in normal controls (221±96ng/ml). 2. The serum serotonin level in 24 recovering patients with depression had the tendency to return to normal while under treatment with imipramine type antidepressants (281±189 ng/ml). 3. The serum serotonin level in 10 manic patients (365±85 ng/ml) was significantly higher than that in normal controls. 4. After the injection of imipramine to depressive patients, serum serotonin level tended to increase (1.5 times). 5. Electroconvulsive shock did not appear to alter the serum serotonin level in depressive patients and normal dogs. 6. As for the diurnal rhythm of serum serotonin of depressive patients, the serotonin level in the morning was the lowest, which seemed to be related to the worst depressed mood in the morning. In the manic patients, the serotonin level at 20.00 hours was the highest. This pattern of rhythm resembled that of normal controls. 7. The significance of serum serotonin levels in manic-depressive patients was discussed.     

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

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.     

L-5-Hydroxytryptophan-(L-5-HTP) Therapie*

Our experience on 107 cases of endogenous depression shows that L-5-hydroxy-tryptophan is clinically effective. If we disregard the cases who showed improvement only after 4 weeks, more than half of the cases improved within a few weeks by L-5-HTP. We propose that endogenous depression is a disease in which biosynthesis of serotonin is periodically decreased, and this decrease is shown clinically as depression, and L-5-HTP, which penetrates into brain through blood brain barrier and is decar-boxylated to form serotonin, may well be supplying serotonin the brain of depression needs. The dose used by us is rather low comparing to L-DOPA dose on parkinsonism, and changes of serotonin or 5-hydroxyindole acetic acid level in blood or cerebrospinal fluid may be very small, although still to be determined. As far as we have experienced, the administration of L-5-HTP for several weeks caused no severe side effects. The administration of L-5-HTP, we believe, opened a new approach to treat and analyse endogenous depression. Clinically, it is effective for the treatment and prevention of the depressive phase of endogenous depression. An important problem is why the biosynthesis of serotonin is decreased in endogenous depression, and this problem is to be solved to understand the basic disorder of the disease.     

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

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.     

The treatment of depression with L-5-Hydroxytryptophan versus imipramine

Summary In the last few years several open studies supported the hypothesis that L-5-HTP may be an effective antidepressant. Because of the lack of a controlled double-blind trial we started our own investigations to confirm this hypothesis in L-5-HTP. In 1972 we performed two open dose finding trials with L-5-HTP in combination with Benzerazide. These open studies were followed by a double-blind trial comparing L-5-HTP in combination with Benzerazide to Imipramine in 30 patients. Assessments were carried out on day 0, 5, 10, 15 and 20.For data collection we used the Hamilton Rating Scale for Depression, the AMP-system, a Global Rating Scale of Severity of Depression and a Brief Rating Scale for the Behaviour on the ward. In this article we report only a part of the results, mainly on the findings with the AMP-system and the Hamilton Rating Scale for Depression.During our double-blind trial we could not find any significant difference in efficacy of L-5-HTP and Imipramine. The same was found in an open trial. Furthermore the L-5-HTP results showed no difference compared with the results of an Imipramine treatment in 40 patients in earlier double-blind studies.L-5-HTP and Imipramine caused different patterns of side effects. L-5-HTP caused mainly gastrointestinal side effects and Imipramine caused mainly dryness of the mouth and tremor. The gastrointestinal side effects caused by L-5-HTP seemed to be dose dependent.     

Sex-linked differences in cortisol, ACTH and prolactin responses to 5-hydroxy-tryptophan in healthy controls and minor and major depressed patients

Some researchers have found that the administration of 5-hydroxytryptophan (5-HTP) results in increased cortisol secretion in major depressives but not in healthy controls. Other authors observed gender-related differences in cortisol responses to 5-HTP in major depressives. In order to investigate the pituitary/adrenal responsivity to 5-HTP, the authors measured cortisol, adrenocorticotropic hormone (ACTH) and prolactin (PRL) in 30 healthy controls and in 90 depressed patients; the hormone levels were determined in baseline conditions and 60, 90 and 120 min after 125 mg L-5-HTP (orally, non-enteric coated). We found that healthy men had significantly higher cortisol responses to L-5-HTP than healthy women. In the major depressives with melancholia and/or psychotic features these differences were reversed: women exhibited significantly higher cortisol and PRL responses than men. In the female group the most severely depressed patients had increased cortisol and PRL responses to L-5-HTP. The amplitudes of the cortisol, ACTH and PRL responses to L-5-HTP were significantly and positively correlated. It was concluded that the central serotonergic regulation of ACTH and PRL is significantly different between the sexes and between healthy controls, minor depressives and severely depressed patients.     

Neuropharmacology of Progressive Myoclonus Epilepsy: Response to 5-Hydroxy-L-Tryptophan

Summary: Low concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) of patients with progressive myoclonus epilepsy (PME) suggest hypofunctional serotonergic neurotransmission. To study this hypothesis, we enrolled 6 patients with PME [Unverricht-Lundborg disease (U-L), mitochondria1 encephalomyopathy, or Lafora disease] in a controlled, double-blinded, dose-ranging, cross-over add-on pilot clinical trial of 5-hydroxy-L-tryptophan (L- 5-HTP) plus carbidopa after 2 other patients had received open-label L-5-HTP for compassionate use. Prestudy CSF 5-HIAA concentrations were low (<20 ng/ml) in 6 patients regardless of the etiology of PME. One patient with U-L disease showed clinical improvement and a fivefold increase in CSF 5-HIAA, and 1 with Lafora disease showed a twofold increase in CSF 5-HIAA without improvement. A patient with Lafora disease reported enough improvement in myoclonus-evoked convulsions to continue chronic use of the drug. One patient with mitochondria1 encephalomyopathy developed status epilepticus during treatment with L-5-HTP.As a group, patients had no statistically significant changes in myoclonus evaluation scale scores, subjective and objective measures of ataxia, seizure frequency, antiepileptic drug (AED) levels, or routine blood tests. These data suggest a serotonergic abnormality regardless of the underlying etiology of PME, but one that seldom responds to acute treatment with L-5-HTP.     

L-5-hydroxytryptophan stimulated cortisol escape from dexamethasone suppression in melancholic patients

The dexamethasone suppression test (DST) was carried out in 62 depressed patients. At 0800 the postdexamethasone cortisol values were determined and 125 mg L-5-hydroxytryptophan (L-5-HTP) was administered. The second cortisol sample at 0930 revealed a significant enhancing effect for L-5-HTP on the postdexamethasone cortisol values in melancholic patients, whereas no effects were detected in minor depressives. Our results show that L-5-HTP converts some DST suppressors into nonsuppressors, whereas the escape from dexamethasone in some nonsuppressors is markedly stimulated. The L-5-HTP-stimulated 0930 postdexamethasone cortisol values performed markedly better than the 0800 DST results: at a cut-off value of greater than or equal to 5 micrograms/dl the sensitivity for melancholia increased from 46% to 68%, and the specificity remained unchanged (96%).     

The relationships between the cortisol responses to dexamethasone and to L-5-HTP, and the availability of L-tryptophan in depressed females

In order to investigate the relationships between the hypothalamic-pituitary-adrenal (HPA)-axis activity, the central serotonergic neurotransmission, and the peripheral metabolism of l-tryptophan (L-TRP), the authors measured the following: the postdexamethasone cortisol values, the cortisol responses to 125 mg 5-hydroxy-L-tryptophan (L-5-HTP) orally, and the total L-TRP/competing amino acids (CAA) ratio in 64 depressed females. Severely depressed females showed significantly lower values for L-TRP/CAA, significantly higher postdexamethasone cortisol values, and cortisol responses to L-5-HTP as compared with minor depressives. Dexamethasone nonsuppressors showed significantly lower L-TRP/CAA values as compared with suppressors. The cortisol responses to dexamethasone were significantly and negatively correlated with the availability of L-TRP. The cortisol responses to L-5-HTP were not related to either the availability of L-TRP or to the postdexamethasone cortisol values.     

Distribution of growth hormone and thyroid-stimulating hormone in cerebrospinal fluid and pathological compartments of the central nervous system

Human growth hormone (HGH) radio-immunoassay (RIA) was adapted for an accurate measurement of immunoreactive HGH concentrations in the CSF in different cases of hypothalamic-somatotropin dysfunctions.In control subjects (n = 43) mean HGH levels were 0.35 ± 0.03 ng/ml in CSF and 1.95 ± 0.2 ng/ml in plasma with a $\text{CSF}\text{plasma}$ ratio of 17%. The thyroid-stimulating hormone (TSH) RIA gave in controls mean basal levels of 2.65 ± 0.2 μU/ml in CSF and 5.95 ± 0.3 μU/ml in plasma with a $\text{CSF}\text{plasma}$ ratio of 44%. HGH and TSH concentrations in CSF and plasma show a very good correlation; but the regression curves for both hormones are distinctly different and appear specific for each polypeptide hormone.Hypothalamic-somatotropin hyperreactivity was reported in diabetic retinopathy (DR). CSF and plasma HGH concentrations in a group of diabetic patients with progressing retinopathy (n = 27) were not different from those in normal subjects (respectively 0.35 ± 0.05 in CSF and 2.10 ± 0.25 ng/ml in plasma with a $\text{CSF}\text{plasma}$ ratio of 16%). The HGH regression curve obtained in diabetics is similar to that of controls. These data do not substantiate the hypothesis of an HGH hyperreactivity in diabetic retinopathy.In somatotropin hypersecretion (acromegaly) without adenoma suprasellar extension, higher HGH concentrations recorded in CSF than in plasma cannot be attributed to an anatomical break-down of the CSF blood-brain barrier and suggest an active transport process of pituitary hormones to the CNS.HGH and TSH concentrations were measured in the cystic fluid of CNS tumors. In 1 case of a cystic dysembryoma, the HGH and TSH of CF were considerably increased. In gliomas (n = 8) the HGH and TSH cystic fluid concentrations were more elevated (respectively 0.72 ± 0.2 ng/ml and 3.6 ± 0.7 μU/ml) than in the CSF of controls.     

Effects of L-5-Hydroxytryptophan in autistic children

Behavioral effects of L-5-Hydroxytryptophan (L-5-HTP), administered in combination with carbidopa, were evaluated in three autistic children using direct behavioral observation and parent ratings. Children were assessed under each of four experimental conditions: Baseline, Placebo I, L-5-HTP plus carbidopa, and Placebo II. During the 20-week study two children showed behavioral change that appeared to be unrelated to drug treatment. The findings did not support the hypothesis that a functional deficit in brain 5-HT underlies the autistic syndrome.The authors wish to thank Gerald Angert, of the Downstate Medical Center Pharmacy, for his assistance in preparing the L-5-HTP dosages. We must particularly acknowledge the parents of the children in our study, who showed a good deal of restraint, patience, and optimism with yet another experimental procedure.     

Suppressive effects of L-5-hydroxytryptophan in a feline model of photosensitive epilepsy

We recently demonstrated that long-lasting photosensitivity is acquired as a result of kindling of the lateral geniculate nucleus (LGN), and that the LGN-kindled cat pretreated with D, L-allylglycine represents a useful model of epilepsy for drug studies. The present experiments studied anticonvulsant effects of a serotonin precursor, L-5-hydroxytryptophan (5-HTP), on photosensitivity in the LGN-kindled cat under D,L-allylglycine and on LGN-kindled seizures. 5-HTP suppressed both myoclonic responses and paroxysmal EEG discharges induced by photic stimulation in a dose-related manner. Photically-induced seizures were completely blocked 1.5-2 h after injection of 20 mg/kg 5-HTP. 5-HTP was also effective in reducing the afterdischarge duration and behavioral seizure stage in LGN-kindled seizures; following 40 mg/kg administration, no electroclinical seizures were elicited in the LGN-kindled cats. Serotonergic mechanisms may play an important role in epileptic photosensitivity; the 5-HTP suppressive effect on photosensitivity is at least partly due to reduced neuronal activity at the level of the LGN via serotonergic inhibition.     

Endocrinological function in schizophrenic patients under haloperidol treatment: plasma PRL, HGH and 5HT levels after L-5HTP loading

In order to examine 5HT metabolism in the hypothalamo-pituitary (HP) system of chronic schizophrenic patients taking haloperidol for a short or long period, chronological changes of blood 5HT, PRL and HGH were measured after an oral loading dose of L-5hydroxytryptophan (L-5HTP), a precursor of 5HT. The subjects consisted of 8 male patients with chronic schizophrenia, who were divided into the following two groups. The 1st group--4 patients taking haloperidol (5.6 mg/day) for 8 months on an average (short-term treatment). The 2nd group--4 patients taking haloperidol (4.8 mg/day) for 7.5 years on an average (long-term treatment). The control group was made up of 9 healthy male volunteers. As a result, the basal level of blood 5HT in the 1st group was significantly higher than that in the control group. The blood 5HT levels in the 1st and 2nd groups showed an equally remarkable increase as compared with the control group. The basal level of plasma PRL in the 2nd group was significantly lowe than that in the control group. Moreover, in the 2nd group, an increase in the plasma PRL level after the loading was suppressed, but it showed less suppression in the 1st group. There was no significant difference in the basal HGH levels among the control, 1st and 2nd groups. After the loading, an increase in the plasma HGH was suppressed in the 2nd group, but the suppression was less in the 1st group.(ABSTRACT TRUNCATED AT 250 WORDS)     

The treatment of depression with L-5-hydroxytryptophan versus imipramine. Results of two open and one double-blind study.

In the last few years several open studies supported the hypothesis that L-5-HTP may be an effective antidepressant. Because of the lack of a controlled double-blind trial we started our own investigations to confirm this hypothesis in L-5-HTP. In 1972 we performed two open dose finding trials with L-5-HTP in combination with Benzerazide. These open studies were followed by a double-blind trial comparing L-5-HTP in combination with Benzerazide to Imipramine in 30 patients. Assessments were carried out on day 0, 5, 10, 15 and 20. For data collection we used the Hamilton Rating Scale for Depression, the AMP-system, a Global Rating Scale of Severity of Depression and a Brief Rating Scale for the Behaviour on the ward. In this article we report only a part of the results, mainly on the findings with the AMP-system and the Hamilton Rating Scale for Depression. During our double-blind trial we could not find any significant difference in efficacy of L-5-HTP and Imipramine. The same was found in an open trial. Furthermore the L-5-HTP results showed no difference compared with the results of an Imipramine treatment in 40 patients in earlier double-blind studies. L-5-HTP and Imipramine caused different patterns of side effects. L-5-HTP caused mainly gastrointestinal side effects and Imipramine caused mainly dryness of the mouth and tremor. The gastrointestinal side effects caused by L-5-HTP seemed to be dose dependent.     

Endocrinological Function in Schizophrenic Patients under Haloperidol Treatment: Plasma PRL, HGH and 5HT Levels after L-5HTP Loading

Abstract: In order to examine 5HT metabolism in the hypothalamopituitary (HP) system of chronic schizophrenic patients taking haloperidol for a short or long period, chronological changes of blood 5HT, PRL and HGH were measured after an oral loading dose of L-5hydroxytryptophan (L-5HTP), a precursor of 5HT.
The subjects consisted of 8 male patients with chronic schizophrenia, who were divided into the following two groups. The 1st group—4 patients taking haloperidol (5.6 mg/day) for 8 months on an average (short-term treatment). The 2nd group—4 patients taking haloperidol (4.8 mg/day) for 7.5 years on an average (long-term treatment). The control group was made up of 9 healthy male volunteers.

• 1) 

  As a result, the basal level of blood 5HT in the 1st group was significantly higher than that in the control group. The blood 5HT levels in the 1st and 2nd groups showed an equally remarkable increase as compared with the control group.
• 2) 

  The basal level of plasma PRL in the 2nd group was significantly lower than that in the control group. Moreover, in the 2nd group, an increase in the plasma PRL level after the loading was suppressed, but it showed less suppression in the 1st group.
• 3) 

  There was no significant difference in the basal HGH levels among the control, 1st and 2nd groups. After the loading, an increase in the plasma HGH was suppressed in the 2nd group, but the suppression was less in the 1st group.

These results suggest that there might be a hyposensitivity of the 5HT neuron or a disorder in the 5HT-catecholamine interaction of the HP axis in schizophrenic patients undergoing a long-term haloperidol treatment.     

Clinical response and plasma levels: effect of dose, dosage schedules, and drug interactions on plasma chlorpromazine levels.

Plasma chlorpromazine (CPZ) levels of 50 psychotic inpatients were measured by gas liquid chromatography; the clinical progress of 29 of these patients with acute psychoses was also assessed. CPZ levels of 50-300 ng/ml were usually associated with clinical improvement; there was also a relationship between CPZ levels and increases in certain symptoms. The 50-300 ng/ml level was best attained by doses of 400-800 mg/day. Trihexyphenidyl decreased plasma CPZ by a mean of 44.7% in 12 of 15 patients. A single 400-800-mg dose of CPZ at bedtime produced steady states equal to or better than those achieved with multiple doses. Those patients who failed to attain CPZ levels of more than 70 ng/ml despite doses of 400-1000 mg/day were receiving lithium throughout the study and had discharge diagnoses of manic-depressive psychosis, manic type, and schizo-affective schizophrenia--a finding with implications for future research.     

Basal plasma HGH and cortisol levels and the effect of clonidine administration in female migrainous patients

Clonidine, a central alpha-adrenergic agent and prophylactic antimigraine drug is known to stimulate human growth hormone (HGH) release and to suppress cortisol secretion. A possible association between basal hormonal levels and response to either acute clonidine test or chronic treatment in female migrainous patients was investigated. 15 females, aged 18-43 years, suffering from migraine, underwent an acute clonidine test by administration of a single oral dose of 0.15 mg. High basal HGH levels (greater than or equal to 9 ng/ml) were observed in 6 patients, while the other 9 patients demonstrated normal low basal HGH levels. Acute clonidine administration induced a marked rise of HGH in 8 of the 9 patients with low basal HGH. In 4 of the 8 responders HGH levels exceeded 20 ng/ml and 3 subjects reached the acromegalic range (greater than 90 ng/ml). The mean response in this group was higher than in a reference group consisting of children and adolescents. It is suggested that the basal hypersecretion and the hyperresponsiveness of HGH to clonidine provocation test in some migrainous patients results from a hypersensitivity of the central alpha-adrenergic receptors. 12 of the 15 females were treated for 10 weeks with clonidine at gradually increased doses of 0.05 mg/day up to a maximal dose of 0.15 mg/day. A marked suppressive effect on cortisol secretion was observed in the migrainous patients after acute and chronic administration of clonidine. No correlation was observed between HGH and cortisol response to acute or chronic clonidine administration and the prophylactic effect of clonidine on migraine.     

Reduction of blood platelet serotonin levels in manic and depressed patients.

Blood platelet serotonin levels were measured in unmedicated 12 manic and 74 depressive patients with 118 normal control subjects employed. Blood platelets were separated by multiple centrifugation in the medium of Na2-EDTA solution, and the loss of serotonin during collecting procedures was about 11%. The mean value of blood platelet serotonin levels in depressed patients was 594 +/- 288 ng/mg platelet protein (+/- S.D.), which was significantly lower than that for normal controls, 780 +/- 253 ng/mg protein (p less than 0.001). Age does not account for the reduction of serotonin levels both in depressed and in normal population. Unipolar and involutional depressed patients exhibited to have the most pronounced reduced levels of serotonin of various subtypes of depression, while bipolar depressed patients, neurotic and chronic characterological depressed patients as well as patients with first-episode depression had the values which were comparable with those in normal controls. Manic patients did not show enhancement but did reduction of serotonin levels, the mean being 580 +/- 152 ng/mg protein, which made a contrast with their clinical manifestations of exhilaration and hyperactivity. Changes in blood platelet serotonin levels were determined before, during and after administration of L-5-HTP with a maintenance dose of 300 mg daily in nine depressed patients. Serotonin levels in all subjects were lifted to normal levels during the L-5-HTP treatment, while clinical symptoms were not improved with the treatment. Reduction of blood platelet serotonin levels in depressed patients may be due to their psychobiological distinction, which involves abnormal biogenic amine metabolism in the brain.