James W. Maas

An improved procedure of 3-methoxy-4-hydroxyphenyl-ethylene glycol determination by gas-liquid chromatography

Abstract A method for the quantitative determination of MHPG from urine by gas-liquid chromatography is described. Conditions for the hydrolysis of conjugated MHPG and isolation of free MHPG by organic extraction is discussed. High recovery, reproducibility, and specificity are obtainable with this method. The mean 24 hour MHPG urinary excretion for 5 males was 1600 ± 380 μg and for 6 females 1320 ± 360 μg.

Urinary catecholamine metabolites during behavioral changes in a patient with manic-depressive cycles.

3-Methoxy-4-hydroxyphenylglycol and normetanephrine were analyzed in daily urine specimens of a patient with manic-depressive cycles who was studied longitudinally. The quantities of these catecholamine metabolites excreted into urine were decreased during periods of depression as compared with periods of mania. Urinary excretion of 3-methoxy-4-hydroxyphenylglycol varied cyclically with a period length of approximately 20 days. Changes in this metabolite, and perhaps in normetanephrine, preceded the affective and behavioral shifts.

Excretion of catecholamine metabolites following intraventricular injection of 6-hydroxydopamine in the Macaca speciosa☆

Abstract Seven non-human primates ( Macaca speciosa ) were stereotaxically implanted with Kopf cannulae with the tip being placed at the junction of the lateral and third ventricles. Following a recovery period, 2 24-hr baseline urine specimens were collected from each animal. 4 of the animals were given intraventricular (i. vent.) injections of 1, 2, 4 and 8 mg of 6-hydroxy-dopamineṡHBr (6-OH-DAṡHBr) at 12-hr intervals ( in 1 ml of artifical CSF) and 7 days later a final injection of 16 mg of 6-OH-DAṡHBr. 3 control animals were given artificial CSF + equimolar NaBr injections on a similar schedule. Following the i. vent. injections 24-hr urine specimens were collected at periodic intervals. Urines were assayed for normetanephrine (NM), metanephrine (M), 3-methoxy-4-hydroxy-mandelic acid (VMA), and 3-methoxy-4-hydroxyphenylglycol (MHPG). All animals were sacrificed 16 days after the final i. vent. injections and 14 areas of brain, adrenal gland, heart, and thoracic sympathetic chain were removed and assayed for norepinephrine (NE). It has been found that it is possible with this schedule of injection of 6-OH-DA to produce animals which have significantly reduced levels of brain NE (70% depletion) without decreasing NE in tissues outside the CNS. Such experimental animal preparations should be of particular use in studies in which a separation of peripheral from central noradrenergic systems is desirable. No differences in the excretion of NM, M, VMA, and MHPG between baseline and post-injection periods were found in those animals which were injected with artificial CSF only. In all animals which were given intraventricular 6-OH-DA and in which there was a decrement in brain NE without a depletion of NE in tissues outside the central nervous system, there was a significant decrement in urinary MHPG between the baseline and post-injection periods while no differences in the excretion of NM, M, or VMA were found. Based upon these data calculations were made which suggest that a significant fraction of urinary MHPG has its origin in metabolism of NE in brain.

Lithium treatment of mania: Clinical characteristics, specify of symptom change, and outcome

The effects of lithium treatment and prediction of response in 18 manic patients were studied as part of the National Institute of Mental Health Collaborative Study of the Psychobiology of Depression. Patients were rated using the Mania Diagnostic and Severity Scale (MADS) and an additional battery of behavioral constructs developed for measurement of state and drug response in depressed patients. About 67% of the patients had good treatment outcome after 26 days of lithium treatment. Responders did not differ from nonresponders before treatment with respect to delusions, hallucinations, or irritable-paranoid symptoms. Nonresponders were rated as more anxious than responders before treatment and had higher scores on the Hamilton Rating Scale for Depression. Improvement on the MADS, however, did not correlate with pretreatment behavioral ratings. Patients with relatively high ratings for aspects of behavior not specific to mania tended to improve in these regardless of change in MADS score. Manic patients who were also depressed (44%) had higher mania ratings than manic patients who were not depressed. Patients with concomitant depression and mania had significantly worse overall treatment outcome, although their depression ratings improved during lithium treatment.

Cerebrospinal fluid HVA, central brain atrophy, and clinical state in schizophrenia

In 16 patients with chronic schizophrenia, cerebrospinal fluid (CSF) concentrations of homovanillic acid (HVA) showed a significant negative correlation with computed tomographic measures of brain third ventricle size. Clinical state during a drug-free period was also significantly correlated with CSF HVA level, but not with third ventricle size when the effect of CSF HVA was partialed out. The authors propose that these findings may reflect an atrophic process involving structures around the third ventricle and a decrease in dopaminergic activity.

Pre-treatment neurotransmitter metabolites and response to imipramine or amitriptyline treatment

Preliminary data are presented from the NIMH Collaborative Study on the psychobiology of depression, biological studies, dealing with relationships between the pre-treatment levels of the neurotransmitter metabolites 3-methoxy-4-hydrophenethyleneglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) and the subsequent therapeutic response of depressed patients to imipramine or amitriptyline. Eighty-seven depressed patients were studied during pre-treatment and treatment periods. It has been found that (1) both low pre-treatment urinary MHPG and low CSF 5-HIAA values are associated with a response to imipramine; these relationships were not artefacts due to sex or age; (2) there were no significant relationships between pre-treatment urinary MHPG, CSF MHPG, 5-HIAA, or HVA values and the subsequent response, or failure of response, to amitriptyline; (3) there was not a bimodal distribution for CSF 5-HIAA. For both males and females, there were positive and statistically significant correlations between CSF MHPG and urinary MHPG; for the females, there were positive and significant correlations between both urinary and CSF MHPG and CSF 5-HIAA. The theoretical and practical implications of these findings are discussed.

Biochemistry and suicidal behavior in depressed patients

The present study was undertaken in order to further explore the relationship between monoamine levels and hypothalamic-pituitary-adrenocortical (HYPAC) functioning and suicidal behavior in depressed patients. One hundred and thirty-two depressed inpatients participated in the NIMH Collaborative Study on the Psychobiology of Depression. Similar to previous reports, our suicide attempters were younger, more likely to be bipolar, had an earlier age at onset, and displayed more psychotic features. No correlation between cortisol hypersecretion or Dexamethasone Suppression Test (DST) nonsuppression and suicide attempts were found. Only the pre-DST evening plasma cortisol distinguished the groups, being lower in the attempter group. We were unable to confirm the previously reported correlation between cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and suicide attempts. Of the monoamines examined, only urinary and plasma 3-methoxy-4-hydroxphenylglycol (MHPG) differed between suicide attempters and nonattempters, showing lower levels in the attempter group. There was a trend for CSF MHPG in the same direction. This latter reduction was restricted to the bipolar group.

Biological component of the NIMH clinical research branch collaborative program on the psychobiology of depression: I. Background and theoretical considerations.

There are many reports which suggest that patients with effective illness (mania and/or depression) have abnormalities in the functioning of one or more neurobiological systems. At a conference convened by the Clinical Research Branch, Division of Extramural Research Programs, National Institute of Mental Health, these findings were reviewed and some of the factors impeding movement towards a more complete and integrated view of the functioning of neurobiological systems in patients with mania or depression were identified. As a result, a multi-research centre, collaborative approach to the study of the psychobiology of affective disorders was developed. In this collaborative programme, which has now been underway for several years, the focus has been upon: (a) the assessment of the functioning of several different types of biological systems in the same patient, both before and during treatment; (b) obtaining a reasonably large number of patients and comparison subjects; and (c) the use within and across centres of standardized diagnostic categories and behavioural rating methodologies. In this paper the history, background, and rationale for this collaborative effort are reviewed. Those biological systems chosen for study are noted, and issues such as reliability and validity of diagnoses, measurement of state variables, assessment of change with treatment, and logistical and coordinating problems are discussed.

Urinary Catecholamines in Attention-Deficit Hyperactivity Disorder with and without Comorbid Anxiety

OBJECTIVE To determine whether there are differences in noradrenergic or adrenergic functioning in children with attention-deficit hyperactivity disorder (ADHD) with and without anxiety. METHOD ADHD children with and without a comorbid overanxious (ANX) disorder were compared to each other and to normal controls in terms of 2-hour urinary excretion of norepinephrine (NE), epinephrine (EPI), and their metabolites. All subjects performed a fixed series of mentally stressful tasks during the collection period. RESULTS Children with ADHD, regardless of comorbid anxiety, excreted more normetanephrine (NMN), the chief extracellular metabolite of NE, than controls, as well as more vanillylmandelic acid. Children with ADHD alone had lower NE/NMN and EPI/metanephrine ratios compared to controls. Children with ADHD/ANX excreted more EPI than ADHD children without anxiety. CONCLUSIONS Children with ADHD may have a higher tonic activity of the noradrenergic system than controls, while children with comorbid ADHD/ANX may be differentiated from those with ADHD alone by higher adrenergic activity.

Effects of amitriptyline and imipramine on brain amine neurotransmitter metabolites in cerebrospinal fluid

The effects of amitriptyline (AMI) or imipramine (IMI) on levels of 3‐methoxy‐4‐hydroxyphenylethyleneglycol (MHPG), 5‐hydroxyindoleacetic acid (5‐HIAA), and homovanillic acid (HVA) (the major brain metabolites of the neurotransmitters norepinephrine [NE], serotonin [5‐HT], and dopamine [DA]) in cerebrospinal fluid were determined in 66 subjects with unipolar and bipolar depression. There were significant reductions in MHPG and 5‐HIAA levels for the depressed group taken as a whole, but levels of HVA did not change significantly. The changes were similar when subjects were grouped as treated with AMI and IMI and with unipolar and bipolar depression. Reductions in MHPG and 5‐HIAA levels were greater in women than in men. In all subjects with depression and in those treated with AMI and IMI, amine metabolite changes did not differ significantly between those who had a positive clinical response to drug therapy and those who did not. Responders with bipolar depression had smaller reductions in MHPG levels than did responders with unipolar depression. The similar effects of AMI and IMI on MHPG and 5‐HIAA differ from the dissimilar effects of the two drugs on NE and 5‐HT amine uptake systems reported in animal and in in vitro studies. Results provide conclusive evidence of the effects of AMI and IMI on noradrenergic and serotonergic (but not dopaminergic) systems in patients with depression.