Central catecholamine metabolism in vivo and the cognitive and motor deficits in Parkinson''s disease.

Cerebrospinal fluid levels of homovanillic acid (HVA) in unmedicated patients with Parkinson's disease were 45% of levels in control subjects. Levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) and platelet monoamine oxidase activity (MAO) did not differ. Within the Parkinson's disease group platelet MAO B activity correlated with HVA (an MAO B substrate) but not MHPG (an MAO A substrate). A mild global dementia was found that did not correlate with the more severe motor deficit. There was a negative correlation between the motor deficit and HVA levels but not with MHPG. Cognitive functioning correlated positively with platelet MAO, and the ratio of HVA to MHPG levels and negatively with MHPG alone. It is postulated that dopaminergic and noradrenergic activity or the functional balance between these systems may contribute to the observed cognitive dysfunction.     

TRH stimulation test and depression

A thyrotropin-releasing hormone (TRH) stimulation test was performed in 52 male inpatients with major depressive disorder. Twenty-nine percent of the 52 subjects had a delta thyroid-stimulating hormone (delta TSH) less than 5 microU/ml. The cerebrospinal fluid (CSF) amine metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5HIAA), were measured in 29 subjects, and a dexamethasone suppression test (DST) was performed in 48 subjects. Of the three CSF amine metabolites, only MHPG correlated significantly with baseline TSH and none correlated with delta TSH. The baseline TSH correlated positively with the TSH response at 30 minutes. Neither baseline TSH nor delta TSH correlated with cortisol levels before or after dexamethasone. The correlation between CSF MHPG and serum TSH suggests a relationship between central norepinephrine and baseline TSH.     

Heterogeneity of major affective disorders. Biological and clinical evidence

In this paper we summarize the results of our recent and present research focused on analyzing the correlations between neurochemical, pharmacological and clinical parameters in patients with Major Depression. There is evidence that: a) pretreatment urinary MHPG is a useful predictor for clinical response to tricyclic antidepressants and to long-term lithium treatment; b) urinary MHPG is positively correlated to the age at onset of the disease; c) previous responses to tricyclics and age at onset of affective illness are supplementary tools for predicting the effectiveness of lithium and antidepressant drugs; d) platelet alpha-2-adrenoceptor density is inversely correlated with both urinary MHPG and age at onset; e) cerebral ventricular size is positively correlated with urinary MHPG and age at onset and may discriminate between patients with different outcomes on lithium prophylaxis; f) low MHPG excretors are more likely to have suffered from stressful life events in early childhood than normal-to-high excretors. Taken together, these results lend strong support to the hypothesis that Major Affective Disorder is a heterogeneous illness and that inherently different subgroups of affective patients can be recognized.     

Beta-phenylethylamine and noradrenergic function in depression.

1. The relationship between plasma levels of beta-phenylethylamine (PEA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) was investigated in depressive patients. 2. The mean PEA level in plasma in healthy subjects was 1.19 ng/ml (N = 32). No clearly age-related difference was found. The plasma levels of PEA were measured in major depression, but no significant difference was found between healthy and depressive subjects. 3. Plasma levels of MHPG correlated positively with age in healthy subjects (N = 22, R = 0.71, p less than 0.01). There was no significant difference in MHPG levels between healthy subjects and depressive patients. 4. There was no significant correlation between PEA and MHPG levels in healthy subjects; however, in depressive patients, there was a significant negative correlation between plasma PEA levels and plasma MHPG levels (N = 14, R = -0.73, p less than 0.05). These results suggested that PEA may regulate noradrenergic function in depression.     

Monoamine metabolites in cerebrospinal fluid and behavioral ratings in patients with early and late onset of Alzheimer dementia

Patients with Alzheimer disease (AD, onset less than 65 years of age, n = 13) and senile dementia of the Alzheimer type (SDAT, onset greater than or equal to 65 years of age, n = 28) were investigated for cerebrospinal fluid (CSF) content of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxy-phenylglycol (MHPG) and compared with a group of controls (n = 26). A geriatric rating scale, the Gottfries-Br?ne-Steen scale, was used to assess impairment of motor performance, intellectual and emotional functioning, and symptoms common in dementia disorders. The HVA levels in CSF were significantly lower in the AD group than in the SDAT group and controls. MHPG was slightly but significantly increased in the SDAT group when compared with the controls. The HVA and 5-HIAA concentrations were correlated negatively with impairment of motor performance in the SDAT group; 5-HIAA correlated positively with impaired performance in the AD group; and 5-HIAA/HVA ratios were correlated positively with the performance variables. HVA correlated significantly and negatively with "impaired wakefulness" and "inability to increase tempo" in the SDAT group. 5-HIAA and the ratio 5-HIAA/HVA correlated significantly and positively with some items measuring intellectual and emotional impairment. In the AD group, "anxiety" and "fear-panic" correlated positively with 5-HIAA and "restlessness" with MHPG. The data indicate qualitative differences in the CSF monoamine pattern between AD and SDAT.     

Plasma MHPG and age in detoxified alcoholics

Plasma levels of 3 methoxy, 4-hydroxy phenylethyl glycol (MHPG) of detoxified alcoholics were found to be positively correlated with age as previously found with normal subjects. The slope of the regression line of plasma MHPG and age of the alcoholics in remission was significantly steeper than that of normal controls, indicating a faster age-related increase of MHPG in alcoholics.     

DBH, MHPG, and MAO in children with depressive, anxiety, and conduct disorders: relationship to diagnosis and symptom ratings

Plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), plasma dopamine-beta-hydroxylase (DBH) activity, and platelet monoamine oxidase (MAO) were obtained in 42 boys (7-14 years old) consecutively evaluated at a community mental health clinic. The boys were diagnosed according to DSM-III criteria by a child psychiatrist using a semistructured interview with the parent and child. The Revised Behavior Problem Checklist (RBPC) and the Revised Children's Manifest Anxiety Scale (RCMAS) were consecutively obtained on the last 24 subjects. No relationship of any of the plasma measures was found with respect to the DSM-III diagnoses. Plasma MHPG was positively correlated with the parent's rating of the child's anxiety on the Anxiety-Withdrawal factor of the RBPC. Plasma MHPG as well as platelet MAO activity, correlated positively with the child's self-rating of anxiety on the RCMAS. Children classified by the RBPC as having high conduct symptoms and low anxiety symptoms had significantly lower plasma MHPG than those subjects with low conduct problems and high anxiety. Platelet MAO activity was found to be negatively correlated to the child's score on the Lie Scale of the RCMAS.     

CSF neurochemistry of women with anorexia nervosa and normal women

CSF tyrosine, tryptophan, 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), gamma-aminobutyric acid, choline, and calcium were compared in 33 anorexic and 14 normal women. The only significant difference between groups was a lower tyrosine level in the anorexic patients; their MHPG level was nonsignificantly higher. No significant group differences in body weight or depressive subgroup were found. HVA levels were positively related to body weight, and choline was negatively correlated with anorexia severity. The role of tyrosine requires further research, but these findings do suggest that HVA and choline increase with some recovery measures and MHPG is increased with this illness.     

Serotonin and monoamine metabolites in cerebrospinal fluid in children: interrelationships and the influence of age, sex and precursor]

Cerebrospinal fluid and blood were taken from 15 non-neurologic children. Tryptophan(Trp), 5-HTP, 5-HT, 5-HIAA, HVA, MHPG in CSF, and 5-HT, free and total Trp(F-Trp and T-Trp) in serum were determined by HPLC method. Results showed that Trp, 5-HTP, 5-HT, 5-HIAA in CSF were positively correlated significantly. Good correlations were also found between F-Trp in serum and Trp in CSF (C-Trp), 5-HIAA and HVA, 5-HTP and MHPG. C-Trp, 5-HTP, 5-HT, 5-HIAA and HVA declined significantly with increasing age. MHPG was higher in male than in female children.     

CSF monoamine metabolites and MRI brain volumes in alcohol dependence

Correlations between cerebrospinal fluid (CSF) concentrations of monoamine metabolites (MAM) and brain structure have been described in schizophrenia, but not in alcoholism. To investigate the relationship between monoaminergic transmission and brain structure in alcoholism, the metabolites of dopamine (homovanillic acid, HVA), norepinephrenine (3-methoxy-4-hydroxyphenylethyleneglycol, MHPG) and serotonin (5-hydroxyindoleacetic acid, 5-HIAA) were measured in lumbar CSF in 54 alcohol-dependent patients and 20 healthy subjects. The volumes of the cerebrum, total grey and white matter, total and ventricular CSF, left and right hippocampus, and corpus callosum area were measured with MRI. MHPG and age were positively correlated in alcoholic women. The MAM concentrations were not significantly correlated with the MRI volumes in the subject categories. There were no differences in MAM across subjects defined by diagnosis and gender, age of onset of alcoholism or comorbidity of psychiatric disorders. Total CSF, cerebrum, and white and grey matter tissue volumes differed between patients and healthy subjects. The greatest difference was the white matter reduction in alcoholic women. In alcoholic women and men, monoaminergic neurotransmission measured by the CSF MAM HVA, MHPG, and 5-HIAA is not significantly correlated with the size of different brain structures.     

Hormonal responses to clonidine and urinary MHPG in delusional and nondelusional melancholic patients: a placebo-controlled study

Summary The growth hormone (GH) and cortisol responses to intravenous clonidine (0.15mg) treatment of 25 melancholic patients, 12 with and 13 without delusions, were studied with placebo control. The baseline concentrations of the main noradrenaline metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG) were also estimated in urine. Cortisol plasma levels decreased significantly and equally after both placebo and clonidine. Baseline cortisol levels correlated positively with urinary MHPG. Clonidine did not increase GH levels significantly over time compared with placebo. Delusional melancholic patients tended to have smaller GH responses to clonidine than nondelusionals (F=2.18,P=0.06). There were no differences in GH response to clonidine between high and low MHPG excretors.     

Dexamethasone suppression test and urinary MHPG X SO4 determination in depressive disorders

The Dexamethasone Suppression Test (DST) was performed in 64 depressed inpatients, in 48 schizophrenics, and in 20 normal controls. Thirty-four percent of depressive inpatients were found to escape from dexamethasone suppression significantly higher than either schizophrenics (13%) or normal subjects (5%). Among subgroups, bipolar and unipolar endogenous depression patients had much higher abnormal rates for the DST (59% and 48%, respectively) than nonendogenous cases (8%). DST results were also found to be positively correlated with patients' Hamilton scores. These findings suggested that DST could be helpful in diagnosis, discrimination of subtypes, and in assessment of severity of symptoms. In 32 of the 64 depressed inpatients, urinary MHPG X SO4 excretion was determined and compared with 21 normal controls. Bipolar patients (n = 7) had less MHPG X SO4 excretion than unipolar endogenous patients (n = 16). Excretion was positively correlated with cortisol level at 17 hr after dexamethasone administration in 32 depressive inpatients, especially in the unipolar subgroup. A trend toward negative correlation, though not statistically significant, was found in bipolar depression between cortisol levels at 17 hr after dexamethasone administration and urinary MHPG X SO4 excretion. This may indicate that some differences in norepinephrine (NE) metabolism may exist between unipolar and bipolar depression, leading to differing correlations between deviation of central NE function and hypothalamus-pituitary-adrenal (HPA) axis in different subgroups of depression.     

Symptom patterns in unipolar and bipolar depression correlating with monoamine metabolites in the cerebrospinal fluid: II. Suicide

Suicidality scores from the Schedule for Affective Disorders and Schizophrenia on 21 unipolar and 12 bipolar depressives were correlated with monoamine metabolites in the cerebrospinal fluid using multiple regression analyses. The single item of Suicidal Tendencies Worst Week correlated highly significantly and negatively with 3-methoxy-4-hydroxyphenylglycol (MHPG) and only to a very slight degree with 5-hydroxyindoleacetic acid (5HIAA). Seriousness of Intent of Worst Suicide Attempt earlier in life correlated significantly and negatively with both MHPG and 5HIAA. Subjective Anger was positively and Overt Anger negatively associated with thoughts of suicide. The results support earlier reports that depressives with low 5HIAA are prone to violent suicides, but also point to the equal, if not even greater involvement of MHPG and noradrenergic neuronal systems in carrying out a wish for death.     

Clinical studies on norepinephrine metabolism: how to interpret the numbers

Metabolism, synthesis rates, and pharmacokinetics of major metabolites of endogenous norepinephrine were investigated in 38 drug-free depressed patients receiving a low monoamine diet on a closed ward. In a group of 21 patients, plasma and cerebrospinal fluid (CSF) concentrations of 3-methoxy-4-hydroxyphenyl-glycol (MHPG) correlated positively, but not significantly. In two groups of eight patients each, effects of desipramine and zimelidine on the central production rate of MHPG were examined using CSF and urine data. Both desipramine and zimelidine significantly reduced the central production rate of MHPG.     

Urinary MHPG and ward behavior in unmedicated psychiatric patients

The relationship between urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) and overt behaviors emitted in two hospital environments was examined in a group of 27 drug-free psychiatric patients. Depressed patients with high MHPG excretion ate less and engaged in less visual activity in the lunch environment. Schizophrenic patients but not depressive patients with high MHPG tended to have greater body activity during the gym environment. The implications of these findings for the identification of subtypes of depression and schizophrenia, and for an improved methodology in investigation of biobehavioral relations in clinical populations, are discussed.     

Purine and monoamine metabolites in cerebrospinal fluid: parallel purinergic and monoaminergic activation in depressive illness?

In the cerebrospinal fluid of 38 patients with major depressive disorders the purine metabolites hypoxanthine and xanthine were positively correlated to the monoamine metabolites HVA and 5HIAA (p less than 0.0001). Hypoxanthine was also positively linked to the noradrenaline metabolite MHPG (p less than 0.005). By the use of multiple regression analysis 70% of the variance in hypoxanthine and 51% of the variance in xanthine were explained by HVA and 5HIAA. The scored magnitude of memory disturbance during depression was positively correlated to hypoxanthine, xanthine, HVA, and 5HIAA, while the degree of somatic anxiety as well as worrying was or tended to be negatively correlated to the same biochemical markers. The conspicuous relationship observed between purine and monoamine metabolite concentrations in CSF during depressive illness might indicate a parallel purinergic and monoaminergic activation of the brain. The observation that certain isolated depressive symptoms appear to relate to hypoxanthine/xanthine in CSF is consistent with the hypothesis of a central role of purines in behaviour.     

Phenylethylamine and monoamine metabolites in CSF of schizophrenics: Effects of neuroleptic treatment

Phenylethylamine (PEA) and the monoamine metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) have been measured in the cerebrospinal fluid (CSF) of nine paranoid schizophrenics before and after three weeks of neuroleptic treatment. Patients were classified according to the Research Diagnostic Criteria and rated by means of the Brief Psychiatric Rating Scale. A significant increase was seen in HVA CSF concentrations during neuroleptic treatment (p less than 0.01). No influence was found on levels of PEA, 5-HIAA, and MHPG. Concentrations of both MHPG and 5-HIAA correlated positively with those of HVA. These results in combination with previous findings do not support the contention that PEA and NA metabolisms are grossly disturbed in paranoid schizophrenics whereas involvement of other neurotransmitters i.e. dopamine, seems more probable.     

Catecholamine response to methamphetamine is related to glucocorticoid levels but not to pleasurable subjective response

INTRODUCTION: Corticosteroids may modulate addiction. We previously described subjective, physiological, and endocrine effects of 0.5 mg/kg of intravenous methamphetamine after augmenting cortisol level with hydrocortisone or blocking cortisol response with the corticosteroid synthesis inhibitor metyrapone in a double-blind, balanced crossover study. Although the pharmacologic manipulations produced the expected hormonal changes, pleasurable subjective effects of methamphetamine were unchanged. Metyrapone was followed by frequent premature ventricular complexes (PVCs) in two subjects during methamphetamine administration. In order to better understand these results, we examined changes in two plasma catecholamine metabolites, homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), and their relationship to the previously reported hormonal changes and physiological and subjective responses. METHODS: Plasma from 10 methamphetamine subjects from the earlier study was assayed for HVA and MHPG by high performance liquid chromatography. RESULTS: HVA levels were greater after hydrocortisone or metyrapone pretreatment compared to placebo, and MHPG levels were greater after metyrapone pretreatment. Hydrocortisone pretreatment diminished HVA and MHPG increases after methamphetamine (perhaps explaining the lack of expected increase in pleasurable effects), but metyrapone did not. HVA and MHPG concentrations were not correlated with pleasurable drug effects but were inversely related to reports of "Bad Drug Effect." Increases in MHPG and DHEA concentrations were positively correlated. Metyrapone pre-treated subjects with PVCs had lower HVA and MHPG concentrations. CONCLUSION: Raising cortisol concentration and blocking cortisol synthesis did not produce opposite effects, perhaps because of metyrapone's effect on the hypothalamic-pituitary-adrenal axis, its stress-like effects, and its effects on neurosteroids.     

Neurotransmitter metabolites and endocrine responses in depression

1. Urinary 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), 3–4-dihydroxyphenylethylene-glycol (DHPG), 5-hydroxyindoleacetic acid (5-HIAA), plasma thyroid stimulating hormone (TSH), prolactin (PRL) and growth hormone (GH) were measured before and after the injection of thyrotropin releasing hormone (TRH) in healthy subjects and depressed patients with primary affective disorder.

2. The TSH response to TRH did not differ in depressed compared with control subjects. A trend (.05 < p < .10) toward a lower PRL response appeared in male depressed compared with male control subjects. GH levels did not consistently change after TRH.

3. In all subjects the TSH response correlated positively with pre- and post-TRH urinary MHPG. The PRL response correlated negatively with pre-TRH urinary 5-HIAA. Pre-TRH daytime urinary 5-HIAA levels were elevated in depressed subjects.