Effect of 5-hydroxytryptophan on serum cortisol levels in major affective disorders. I. Enhanced response in depression and mania

The serum cortisol concentration following administration of 5-hydroxytryptophan (5-HTP), 200 mg orally, a precursor of serotonin (5-HT), was significantly greater in unmedicated depressed and manic patients than in normal controls. Increases in serum cortisol levels greater than 5 micrograms/dL were significantly more frequent in both unmedicated depressed and manic patients than in the normal controls. There was significant test-retest reliability. Baseline serum cortisol concentration correlated negatively with the cortisol response to 5-HTP in normal controls. These results suggest increased 5-HT receptor sensitivity may be present, possibly in the hypothalamus or pituitary, in some patients with affective disorders. These results are consistent with the hypothesis that decreased serotonergic activity, which would be expected to produce increased 5-HT receptor sensitivity, may be present in both depression and mania.     

Effect of 5-hydroxytryptophan on serum cortisol levels in major affective disorders. II. Relation to suicide, psychosis, and depressive symptoms

Serum cortisol levels were significantly higher after administration of 5-hydroxytryptophan (5-HTP), 200 mg orally, in unmedicated patients with affective disorders than in controls. The magnitude of the serum cortisol increase correlated positively with the Schedule for Affective Disorders and Schizophrenia-Change (SADS-C) depression syndrome ratings and correlated negatively with psychotic symptoms in 26 patients with major depression. The serum cortisol response was greater in four depressed and three manic patients who made suicide attempts than in 33 patients who were not suicidal or only had suicidal thoughts. The cortisol response was also greater in patients with bipolar depression than in those with unipolar depression and those with a first-degree relative with an affective disorder. Absence of psychotic symptoms and commission of suicidal acts were associated with an increased cortisol response to 5-HTP in the depressed patients. The cortisol response to 5-HTP in the manic patients also tended to correlate with the SADS-C manic syndrome score.     

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.     

Pituitary thyrotropin response to thyrotropin-releasing hormone in affective illness: relationship to spinal fluid amine metabolites.

The authors studied pituitary thyrotropin, i.e., thyroid-stimulating hormone (TSH), response to thyrotropin-releasing hormone (TRH) in patients with primary affective disorder. There were no overall differences between either depressed or manic patients and normal controls; however, the TSH response was significantly lower in the unipolar depressed patients than in either bipolar depressed patients or normal subjects. Bipolar patients in the manic phase tended to have a lower response than bipolar depressed patients. In the unipolar group, the TSH response showed a significant negative correlation with the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the CSF. These neuroendocrine responses may constitute markers of specific monoamine dysfunction in subgroups of patients with affective illness.     

Effect of 5-hydroxytryptophan on serum cortisol levels in major affective disorders. III. Effect of antidepressants and lithium carbonate

Serum cortisol levels were significantly increased following administration of 5-hydroxytryptophan (5-HTP), 200 mg orally, to patients with affective disorders. A three- to five-week period of treatment with lithium carbonate or monoamine oxidase (MAO) inhibitor augmented the mean 5-HTP-induced increase in serum cortisol concentration in manic or depressed patients, respectively: tricyclic antidepressant (TCA) and second-generation antidepressant treatment diminished the mean serum cortisol response in patients with major depression. These results are consistent with the hypothesis that lithium carbonate may enhance serotonin (5-HT) receptor sensitivity, whereas TCA and second-generation antidepressants diminish 5-HT receptor sensitivity. The enhancement of the cortisol response to 5-HTP by MAO inhibitors may be due to decreased metabolism of 5-HT. It is important to assess the effect of thymoleptic drug treatment on various responses to biogenic amine precursors or agonists in patients rather than laboratory animals.     

5-Hydroxytryptophan-induced cortisol response and CSF 5-HIAA in depressed patients

To determine if the enhanced cortisol response to oral administration of the serotonin (5-HT) precursor 5-hydroxytryptophan (5-HTP) that has been reported in unmedicated depressed and manic patients might be related to brain monoaminergic metabolism, the authors assessed correlations between 5-HTP-induced cortisol response and CSF in nine depressed patients. They found a significant negative correlation with CSF levels of 5-hydroxyindoleacetic acid, a 5-HT metabolite, but not with CSF levels of other monoamine metabolites. This finding is consistent with the hypothesis that low presynaptic brain serotonergic activity may be related to enhanced cortisol response to 5-HTP in depressed patients.     

Biogenic amine metabolites in cerebrospinal fluid of patients with affective disorders

Concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured in lumbar CSF from 33 patients with affective illnes and from 23 neurological controls. The group of patients with affective illness comprised 29 depressed and four manic patients. During illness, the concentration of HVA was higher in the depressed patients (P >0.001) than in the controls. Both unipolar and bipolar depressed patients had increased HVA levels (P >0.001 and P >0.05, respectively). The concentration of MHPG was greater than control values in the unipolar (P < 0.001) and bipolar (P < 0.002) subgroups but did not differ from control values in the depressed group as a whole. The concentration of 5-HIAA in the depressed patients as a whole and in the unipolar and bipolar subgroups did not differ from control concentrations. During illness the manic patients had increased levels of HVA (P >0.01) and normal levels of 5-HIAA and MHPG. Sixteen of the 29 depressed patients had a second lumbar puncture after they had recovered. Compared with the pre-recovery values, the concentration of HVA was reduced in the unipolar depressives (P < 0.01) and the concentration of 5-HIAA lowered in the depressed group as a whole (P >0.02). The present findings suggest involvement of catecholamines in affective disorders.     

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.     

双相情感障碍混合发作血清细胞因子水平研究

目的：比较双相情感障碍混合发作与躁狂发作及抑郁发作患者之间血清细胞因子的水平。方法：采用酶联免疫吸附法测定38例双相情感障碍混合发作患者（混合组）、54例躁狂发作患者（躁狂组）、47例抑郁发作患者（抑郁组）及38名正常人（对照组）血清白介素-1（IL-1β）、白介素-2（IL-2）及白介素-6（IL-6）的浓度;混合组患者于治疗前和治疗8周进行Hamilton抑郁量表（HAMD-24）和Young躁狂量表（YMRS）评定。结果：混合组IL-1β浓度显著高于躁狂组及抑郁组（P〈0.01）,但与对照组差异无统计学意义（P〉0.05）。混合组IL-2浓度与躁狂组、抑郁组及对照组之间差异均无统计学意义（P〉0.05）。混合组IL-6浓度显著高于躁狂组、抑郁组及对照组（P〈0.001）。混合组IL-6浓度治疗8周后较治疗前显著下降（t=3.372,P〈0.01）,与对照组比较差异无统计学意义（t=1.823,P〉0.05）。混合组治疗前后IL-6浓度差值与HAMD-24、YMRS减分率之间均无显著相关（r分别=-0.211、-0.100,P均〉0.05）。结论：双相情感障碍混合发作可能存在IL-6诱导的免疫功能异常,有不同于双相情感障碍躁狂发作及抑郁发作的生物学特征。     

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.     

Trait and state dependent functional impairments in bipolar disorder

Bipolar disorder (BD) is characterized by abnormalities in emotion processing. Specifically, the processing of affective faces appears to be impaired. This study explored functional abnormalities in the neural network underlying the processing of facial affect in three different mood states (euthymic, depressed, and manic) associated with BD. Functional magnetic resonance imaging (fMRI) data were acquired from 18 healthy controls and 18 euthymic, 12 depressed, and 12 manic BD patients while viewing affective or neutral faces. Compared with controls, BD patients in all mood states showed reduced activation in the bilateral orbitofrontal cortex (OFC), indicating that activation in this region is independent of mood state. Activation in the amygdala, dorsolateral prefrontal cortex (DLPFC), and right temporal pole depended on mood state. Whereas activation levels of depressed patients were not significantly different from those of controls, activation levels in both euthymic and manic patients were significantly reduced compared with activation levels of both controls and depressed patients. However in the right DLPFC euthymic patients showed an increased level of activation compared with manic patients. These results add to the evidence for functional deficits in the affective network in BD patients, of which reduced bilateral OFC activation was found to be the most pronounced deficit across all mood states.     

Motor activity and affective illness. The relationship of amplitude and temporal distribution to changes in affective state

We measured motor activity with a self-contained monitoring device worn on the wrists of affectively ill patients and volunteer normal control subjects. Decreases in the daytime motor activity level were observed in depressed patients, compared with their improved (euthymic) or manic mood states. Moreover, affectively ill patients, even during euthymic periods, showed lower daytime motor activity levels than the control group housed in the same ward. These data provide objective evidence for decreases in motor activity that occur concomitantly with the depressive phase of illness in patients with affective disorder, and fluctuate in patients in euthymic or manic phases.     

Age effects on trail making test during acute depressive and manic episode

Impairment of executive functions and attention has been found in patients with acute depressive episodes but has rarely been investigated in manic patients to date. At the same time, executive functions decline with age. Thus, it is currently a matter of debate how to best measure decreased executive performance in elderly patients with affective disorders. In our study, we examined 30 depressed patients, 28 manic patients, and 30 healthy subjects of all age groups, using the Trail Making Test (TMT). Both depressed and manic patients needed twice as long as healthy subjects to perform the TMT Part A. In addition to this reduced performance due to affective disorders, we were also able to detect a decline in performance due to age. One could thus postulate that age and affective disorders each influence a different neuropsychological function, age affecting executive performance and affective disorders affecting attention, as measured in both cases by the TMT.     

Affective syndromes, psychotic features, and prognosis. II. Mania

Fifty-six patients with mania and psychotic features and 14 with schizoaffective disorder, manic type, were followed up with biannual assessments during a 5-year period. Results were treated as they were in an analogous follow-up of patients with psychotic major depression or schizoaffective disorder, depressed type. Patients with schizoaffective mania experienced more morbidity during follow-up than did patients with psychotic mania. Among patients with schizoaffective mania, those with a chronic subtype did far worse than did the others, while the mainly schizophrenic--mainly affective distinction was not predictive. When depressed and manic groups were combined (n = 173), the following baseline variables were significant independent predictors of a sustained delusional outcome: longer duration of the index episode, temporal dissociation between psychotic features and affective symptoms, and impaired adolescent friendship pattern.     

Age Effects on Trail Making Test During Acute Depressive and Manic Episode

Impairment of executive functions and attention has been found in patients with acute depressive episodes but has rarely been investigated in manic patients to date. At the same time, executive functions decline with age. Thus, it is currently a matter of debate how to best measure decreased executive performance in elderly patients with affective disorders. In our study, we examined 30 depressed patients, 28 manic patients, and 30 healthy subjects of all age groups, using the Trail Making Test (TMT). Both depressed and manic patients needed twice as long as healthy subjects to perform the TMT Part A. In addition to this reduced performance due to affective disorders, we were also able to detect a decline in performance due to age. One could thus postulate that age and affective disorders each influence a different neuropsychological function, age affecting executive performance and affective disorders affecting attention, as measured in both cases by the TMT.     

Calcium function in affective disorders and healthy controls

Calcium metabolism has been reported to be disturbed in some forms of affective disorder. We studied concurrently a battery of calcium measures in 29 unipolar, 14 bipolar depressed, 11 manic, and 10 healthy control subjects. In addition to measures of extracellular calcium, we studied intracellular calcium concentration in platelets and measures that reflect cellular capability to maintain a low intracellular Ca++ concentration in red blood cells (RBCs) and platelets. Plasma calcium was lower in unipolar and manic patients than in control subjects. Platelet calcium concentration was lower in unipolar than bipolar depressed patients. RBC Ca++ adenosine triphosphatase (ATPase) was lower in unipolar and control subjects than in bipolar depressed and manic patients. Platelet Ca++ ATPase and Ca++ uptake were inversely correlated with severity of illness in unipolar patients. In bipolar depressed patients, RBC Ca++ ATPase and platelet Ca++ uptake were inversely correlated with severity. In addition to indicating abnormalities in calcium activity in affective disorders, the data suggest that unipolar and bipolar patients differ in several measures and may have different pathophysiological disturbances in calcium metabolism.     

High reverse T3 levels in manic and unipolar depressed women

A relatively high percentage of patients with affective disorders have abnormalities of thyroid function, and over 60% of endogenously depressed and most manic patients show a blunted thyroid-stimulating hormone (TSH) response to thyroid-releasing hormone (TRH) injections. We now replicate earlier findings concerning relatively high 3,3',5'-triiodothyronine (reverse T₃) levels in unipolar depressives and find similarly high levels in manic women. The significance of the present finding is unknown, but measurement of reverse T₃ levels as a potential tool in differential diagnosis of affective disorders and in psychobiological research should be exploded further.     

Monoamine Oxidase Activity in Blood Platelets From Manic and Depressed Patients

To evaluate the possible abnormality in MAO activity in affective disorders, blood platelet samples were obtained from 80 patients with mania and depression. Blood-platelet MAO activity was measured by a newly developed assay procedures using serotonin as substrate. MAO activities in 121 normal adult subjects were in a range of 2.49-12.05 nM/mg protein/hour, with the mean values of 4.91 ±1.72 (±S.D.) for men and 6.88±1.99 for women. (p<0.001) MAO activities in the manic and depressed patients were in a range of 0.65–13.40 nM/mg protein/hour, and both manic and depressed patients showed the mean value very similar to that in the normal subjects. Bipolar depressed patients did not exhibited lower MAO activity in the blood platelets than other clinical subtypes of depressive illness, including unipolar, involutional, neurotic and chronic characterological, and first-episode depressions. No significant differences were established between these five subcategories of depression, while significant higher values were evident in female than male patients (p<0.001). No correlation was found between the MAO activity and serotonin levels in the blood platelets either in the normal subjects or in the depressed patients.     

Changes in lymphocyte beta-adrenergic receptors in depression and mania.

The beta-adrenergic receptors were studied in vitro in lymphocytes obtained from patients with major affective disorders and controls. Specific L-[3H]-dihydroalprenolol binding was decreased in both depressed and manic patients compared to controls and euthymic patients. Isoproterenol-stimulated, but not prostaglandin El-stimulated, cyclic adenosine-3',5'-monophosphate production was decreased in manic and depressed patients. These results suggest decreased lymphocyte beta-receptor functioning in depression and mania. This decrease may be an index of changes in brain beta-receptors in mania and depression, or may simply reflect homeostatic regulation of peripheral beta-receptors in response to stress-induced increases in circulating catecholamines.     

11C-glucose metabolism in manic and depressed patients

The authors used positron emission tomography (PET) and 11C-labeled glucose to study 15 unmedicated patients with affective disorders and 7 control subjects. Diagnoses of affective disorders were based on DSM-III criteria, and symptomatology was evaluated by the Hamilton Rating Scale for Depression. Blood counts of 11C in both unipolar and bipolar patients did not differ from those in controls after oral administration of 11C-glucose. By contrast, brain counts of 11C in unipolar depressed patients were significantly lower, whereas those in bipolar manic patients were significantly higher, than in normal controls.