Eleven normal volunteers were given an acute and two chronic doses of desipramine (DMI). The plasma norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), and dihydroxyphenylglycol (DHPG) ...concentrations were measured before and during drug administration. DMI reduced plasma concentrations of MHPG by 13% and DHPG by 17%. After two weeks of drug administration, the MHPG/NE ratio was reduced, and there was a significant negative correlation with the concurrent drug concentration. These results suggest that DMI: (1) reduces the turnover of NE; and (2) diminishes the oxidative deamination of NE. In addition, the drug concentration response relationship indicates that the effects of uptake inhibition may not be maximal until concentrations in the apparent therapeutic range are achieved.
Deanol (900 mg/day for 21 days) had no effect on learning a list of words when tested at weekly intervals. Tests of simple and complex reaction time and a test of continuous serial decoding of digits ...showed no enhancement with the drug. Several components of evoked potentials recorded from several scalp sites did show enhanced amplitude under drug treatment. These changes were not accompanied by changes in the EEG spectrum as are seen with some other psychoactive drugs. Deanol seems to be an ineffective treatment for the normal slowing of cognitive function seen in the normal elderly person or those elderly with only minimal cognitive decline and free of symptoms of dementia. Contrary to earlier reports, elderly persons were found to be able to benefit from warning signals in a complex reaction time task.
Using a liquid chromatographic assay, we measured serum neuroleptic concentrations in eight middle-aged or elderly female inpatients with tardive dyskinesia (TD) and eight controls. All 16 patients ...were receiving either thioridazine or mesoridazine at stable doses. TD patients were found to have a significantly higher ratio of serum concentration to daily dose of neuroleptics compared with controls. A 1-year follow-up revealed that this ratio did not change appreciably in those patients who continued to receive neuroleptics. Differences in serum neuroleptic levels were not related to peripheral inflammatory activity as indicated by serum alpha-1-acid glycoprotein concentrations. Of the various thioridazine metabolites, sulforidazine (which is reportedly the most potent in terms of affinity for dopaminergic and alpha-noradrenergic receptors) seemed to be significantly elevated in the serum of TD patients as compared with non-TD patients. Our data suggest a need for further pharmacokinetic investigations to study neuroleptic metabolism in patients with TD.
Noradrenergic mechanisms have been postulated to account for the anticonvulsant and psychotropic effects of carbamazepine. In order to assess this possibility in man, cerebrospinal fluid (CSF) was ...obtained from affectively ill patients before and during treatment with carbamazepine (average duration 29 days) at doses averaging 860 mg/day, achieving blood levels of 8.86 micrograms/ml. Neither plasma nor CSF norepinephrine (NE) nor CSF 3-methoxy-4-hydroxy-phenylglycol (MHPG) was significantly altered by carbamazepine. Baseline medication-free values in 21 depressed patients were not predictive of the degree of subsequent clinical antidepressant response. CSF NE decreased in four manic patients treated with carbamazepine. The many effects of carbamazepine on noradrenergic mechanisms in animals are discussed in relationship to these first studies of carbamazepine in man.
Five women with primary major bipolar affective disorders had variable and at times very high urinary phenylethylamine (PEA) excretion rates. The clinical picture of these patients was characterized ...by periodic bizarre behaviors and short psychotic episodes. These patients were generally nonresponsive to the usual treatment modalities, and their symptoms were exacerbated by nonspecific monoamine oxidase inhibitors which further increased PEA excretion rates.
Amiflamine, a drug reported to be a reversible inhibitor of monoamine oxidase type A (MAO-A) selective for serotonergic neurons in rodents, was administered to rhesus monkeys over a 12-fold dosage ...range (0.5-6 mg/kg). Amiflamine produced small, essentially equivalent reductions in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA, 1-28%), 3-methoxy-4-hydroxyphenylglycol (MHPG, 4-26%), and homovanillic acid (HVA, 7-29%), suggesting that the effects of amiflamine are approximately equal on serotonin, norepinephrine and dopamine metabolism in nonhuman primates. Concentrations of amiflamine were very low in CSF 3-6 h after drug administration (less than 7 nmol/l), while those of its two major, biologically active metabolites were higher (22-150 nmol/l) and varied in relative proportions among the monkeys. Further investigation is required of some preliminary observations of a possible association between drug metabolite variations and the substantial individual differences in the amine metabolite changes following amiflamine treatment. MAO-B in platelets was not inhibited by 6 mg/kg amiflamine, indicating that MAO-A selectivity was maintained. At low amiflamine doses, early and transient increases in CSF 5-HIAA and HVA concentrations were observed, suggesting an amine-releasing effect of the drug within brain serotonergic and dopaminergic neurons.
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 explored further.
Twenty healthy subjects took amitriptyline, doxepin, and placebo for 2 wk each in a double‐blind crossover trial, and another 20 subjects similarly took nortriptyline, chlorimipramine, and placebo. ...The antidepressants were given three times daily in doses generally used for neurotic patients. The presence of antidepressants in tissues was checked with the tyramine pressor test. On the seventh and fourteenth days of each period, psychomotor skills (choice reaction, coordination, and attention) were measured after the administration of drugs in combination with an alcoholic or placebo drink. Dose‐response graphs for the tyramine pressor effect were shifted to the right during the antidepressant treatment, indicating a blockade of the membrane pump in peripheral sympathetic terminals. This anti tyramine effect of antidepressants did not correlate with their psychomotor effects. No drug alone importantly impaired psychomotor skills. Amitriptyline in combination with alcohol increased cumulative choice reaction times, and doxepin in combination with alcohol increased both cumulative choice reaction times and inaccuracy of reactions. Coordination was impaired after both of these combinations on the seventh day. It seems as if doxepin and amitriptyline but not nortriptyline or chlorimipramine, in combination with 0.5 gm/kg of alcohol, may be especially dangerous in driving.
We investigated psychobiological substrates of pathological gambling by measuring levels of norepinephrine, monoamine metabolites, and peptides in cerebrospinal fluid, plasma, and urine. Pathological ...gamblers had a significantly higher centrally produced fraction of cerebrospinal fluid levels of 3-methoxy-4-hydroxyphenylglycol as well as significantly greater urinary outputs of norepinephrine than controls. These results suggest that pathological gamblers may have a functional disturbance of the noradrenergic system. This system has been postulated to underlie sensation-seeking behaviors, aspects of which are thought to be abnormal among pathological gamblers.
Personal and family histories of suicidality were gathered in 45 patients who met Research Diagnostic Criteria for major affective disorder (n = 32, bipolar; n = 13, unipolar) and compared to CSF ...values of 5HIAA obtained by two different assays (n = 20, fluorometric; n = 25, high performance liquid chromatography). In separate analyses of the two assay groups, patients who had made a suicide attempt were not significantly different from those who had not in terms of 5HIAA value or family history of suicidality. Furthermore, in suicide attempters, 5HIAA was unrelated to the severity of the attempt.
