Am J Psychiatry. 1980 Oct;137(10):1183-7.
Urinary MHPG and clinical response to amitriptyline in depressed patients.

Spiker DG, Edwards D, Hanin I, Neil JF, Kupfer DJ.

The authors treated 18 rigorously diagnosed depressed patients with amitriptyline after baseline urine samples were collected for the measurement of 3-methoxy-4-hydroxphenylglycol (MHPG). Neither age nor severity of depression before treatment correlated with MHPG excretion. There was also no significant correlation between baseline MHPG excretion and clinical response at the end of at least 25 days' treatment with amitriptyline. The authors discuss the relevance of amitriptyline and nortriptyline plasma levels to MHPG and the noradrenergic/serotonergic theories of depression.

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Electroencephalogr Clin Neurophysiol. 1977 Jun;42(6):769-75.
Individual variations in response of human REM sleep to amitriptyline and haloperidol.

Nakazawa Y, Kotorii M, Kotorii T, Ohshima M, Hasuzawa H.

The effect of amitriptyline and haloperidol on REM sleep was investigated in healthy human adults, with special attention to individual variations in these drugs' effects. In addition, an investigation was made of the rebound elevation of REM sleep occurring on the following night of partial differential REM deprivation (PDRD), again with emphasis being placed on individual variations in that effect. The administration of amitriptyline in a single oral dose of 25 mg was followed by an inhibition of REM sleep in all subjects. The per cent decrease in REM sleep was found to have a significant negative correlation with the per cent increase in REM sleep following PDRD in individual subjects. The amount of REM sleep during the recovery night following the night of amitriptyline medication tended to correlate with the per cent increase in REM sleep following PDRD in individual subjects. Haloperidol in a single oral dose of 1.5 mg caused REM sleep to augment in some subjects but inhibit in others. A significant correlation was noted to exist between drug-induced change in REM sleep and the per cent increase in REM sleep following PDRD.

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Neurosci Biobehav Rev. 1981 Summer;5(2):265-71.
Amitriptyline and scopolamine in an animal model of depression.

Katz RJ, Hersh S.

Adult male Sprague-Dawley rats were subjected to acute (95 dB white noise) or chronic stress, or their combination. In comparison with unstressed controls, stressed rats were more active upon several measures of open field activity. A history of chronic stress eliminated the acute stress induced activation. Concurrent treatment of chronically stressed rats with amitriptyline or scopolamine, or with a combination of both drugs resulted in selective behavioral improvement (i.e., in motor activity, latency, defecation) for amitriptyline and combined treatment rats, with significant restoration of the normal behavioral response. Scopolamine however was only marginally effective. A higher dose of scopolamine proved effective, but only with a marked disruption of baseline activity. Examination of plasma corticosterone titers indicated that chronic stress induced an elevation of basal levels and that this was reversed by amitriptyline, scopolamine, and combined drug treatment. Thus while behavioral depression and elevated corticosteroids may covary they are not identically mediated.

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Neuropharmacology. 1986 Dec;25(12):1301-6.
Down-regulation of serotonin2, but not of beta-adrenergic receptors during chronic treatment with amitriptyline is independent of stimulation of serotonin2 and beta-adrenergic receptors.

Scott JA, Crews FT.

Antidepressant drugs down-regulate beta-adrenergic, alpha 2-adrenergic and serotonergic 5-HT2 receptors with a time course that parallels their clinical efficacy, i.e. chronic administration is required (Crews and Smith, 1978; Svensson and Usdin, 1978; Banerjee, Kung, Riggi and Chanda, 1979; Bergstrom and Keller, 1979; Peroutka and Snyder, 1980). In the present study, it was found that the 5-HT2 receptor antagonist, nefazadone (50 mg/kg per day) did not prevent the downregulation of 5-HT2 receptors in the cerebral cortex produced by amitriptyline (10 mg/kg per day), when administered for 3 weeks. Moreover, treatment with nefazadone (50 mg/kg per day) alone for 3 weeks decreased binding to 5-HT2 receptors in cerebral cortex. In contrast, administration of propranolol, the beta receptor antagonist, (10 mg/kg per day) with amitriptyline (10 mg/kg per day) for 3 weeks prevented the down-regulation of beta receptors, but did not alter the decrease in binding to 5-HT2 receptors. In addition, the depletion of central stores of norepinephrine and serotonin by a 4-day treatment with reserpine (5 mg/kg per day) increased binding to beta receptors in the cerebral cortex and hippocampus, but did not affect binding to 5-HT2 receptors in either region. These results suggest that the 5-HT2 receptor is not down-regulated by direct stimulation by serotonin agonists and that the down-regulation of 5-HT2 receptors by amitriptyline is independent of down-regulation of beta-adrenergic receptors.

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Acta Psychiatr Scand Suppl. 1989;354:55-60.
Fatal poisonings with antidepressants in Finland 1985-1987.

Vuori E, Ruohonen A, Penttila A, Klaukka T, Lahti T.

University of Helsinki.

In Finland the majority of the users of antidepressants are women and old age people. In the 80's the number of fatal poisonings has increased. During the years 1985-1987 58% of these poisonings were women who belonged to the younger age group of the users. The older tricyclic drugs are known to be more toxic, at least in overdose, than the newer antidepressants especially when they are compared to mianserin. Of the latter, however, lately more serious side effects have been reported. For this reason the use of the different kinds of antidepressants in Finland had changed: the sales of doxepin and amitriptyline have increased and those of maprotiline and mianserin have decreased. To study the role of antidepressants in sudden and unexpected deaths the fatality ratio (defined as fatalities divided by defined daily doses per 1000 inhabitants/day) was calculated for four most prescribed antidepressants. As to the sales, amitriptyline has to be considered to be the leading antidepressant followed by doxepin, mianserin and maprotiline. As a detection in the forensic toxicological screening the sales related ratios showed that maprotiline was most commonly found followed by doxepin, amitriptyline and mianserin. When an antidepressant was the cause of death the fatality ratio was highest for doxepin (6.4) followed by maprotiline (4.3), amitriptyline (4.0) and mianserin (1). In cases of established suicides the order was the same again.(ABSTRACT TRUNCATED AT 250 WORDS)

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J Pharm Pharmacol. 1978 Sep;30(9):547-53.
The use of 13C-nmr spectroscopy for the detection and identification of metabolites of carbon-13 labelled amitriptyline.

Hawkins DR, Midgley I.

The antidepressant drug amitriptyline and two of its metabolites, nortriptyline and desmethylnortriptyline, each containing two 13C atoms, have been used to determine the sensitivity and selectivity of 13C-nmr spectroscopy for the detection of unchanged amitriptyline and N-desmethyl metabolites in the urine of animals dosed orally with the labelled drug. The resonance signals from the 13C atoms detected in the 13C-nmr spectrum of entire extract from a control 12 h rat urine sample to which 1 mg of each labelled compound had been added were easily detected, using an instrument accumulation time of 1 h. The 13C-nmr spectrum of an extract of hydrolysed urine from a dog that had received an oral dose of [13C2]amitriptyline (30mg) exhibited signals that could be assigned to metabolites resulting from N-dealkylation and N-oxidation, as well as those bearing the intact amitriptyline side-chain. These assignments were confirmed by analysis of the same extract by g.c.--ms and h.p.l.c.

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Biol Psychiatry. 1987 Apr;22(4):495-507.
Amitriptyline supersensitizes a central cholinergic mechanism.

Dilsaver SC, Snider RM, Alessi NE.

The withdrawal of tricyclic antidepressants produces symptoms characteristic of cholinergic overdrive states. The authors previously proposed that these states are the consequence of the pharmacological induction of cholinergic system supersensitivity by chronic treatment with antidepressants, combined with a reduction in the plasma level of a competitive muscarinic receptor antagonist when the dose of a tricyclic is decreased. This is consistent with the facts that all tricyclic antidepressants are antimuscarinic agents and that classical antimuscarinic compounds, such as scopolamine, up-regulate and supersensitize muscarinic cholinergic systems. The authors present evidence that chronic treatment with amitriptyline supersensitizes a central cholinergic mechanism. Core body temperature is subject to influence by a central (hypothalamic) muscarinic mechanism, which is rendered supersensitive to cholinomimetic challenge by treatment with scopolamine. The authors telemetrically measured the hypothermic responses of adult male rats to various doses of the muscarinic agonist oxotremorine before and in the course of chronic treatment with amitriptyline. Treatment with amitriptyline resulted in marked enhancement of the cholinomimetic-induced hypothermia. Methylscopolamine nitrate, a peripherally active antimuscarinic agent, did not block the hypothermic response to oxotremorine, whereas scopolamine, a centrally active antimuscarinic compound, did. This study indicates that the chronic administration of amitriptyline can produce supersensitivity of a central muscarinic cholinergic mechanism. Clinical and theoretical implications of this finding are discussed.

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