Clin Pharmacol Ther. 1979 Jun;25(6):844-56.
A method for the determination of amitriptyline and its metabolites nortriptyline, 10-hydroxy amitriptyline, and 10-hydroxynortriptyline in human plasma using stable isotope dilution and gas chromatography-chemical ionization mass spectrometry (GC-CIMS).

Garland WA, Muccino RR, Min BH, Cupano J, Fann WE.

A gas chromatography--mass spectrometry (GC-MS) method has been developed to measure amitriptyline and its metabolites nortriptyline, 10-hydroxy amitriptyline, and 10-hydroxynortriptyline in human plasma. Deuterated analogs of each compound were synthesized as internal standards. Isobutane was used as both gas chromatography (GC) carrier gas and chemical ionization (CI) reagent gas. In order to obtain compounds with satisfactory GC and mass spectrometry (MS) properties, the two alcohol metabolites were dehydrated without loss of label during sample preparation. Selective ion monitoring of the MH+ ions of the protio- and deuterio- compounds gave ion ratios which were converted to plasma concentrations using standard curves. For amitriptyline and nortriptyline, which are assayed using multiple deuterated analogs as internal standards, the curves are straight lines. For 10-hydroxy amitriptyline and 10-hydroxynortriptyline, which are assayed using monodeuterated analogs as internal standards, the curves are nonlinear and are analyzed using an iterative computer procedure. Assay sensitivity is 0.5 ng/ml for amitriptyline, nortriptyline, and 10-hydroxy amitriptyline and 1 ng/ml for 10-hydroxynortriptyline. Assay precision and accuracy in terms of percent error are both less than 5%. Following oral administration of a single 75-mg dose of amitriptyline to two subjects, the mean plasma levels of amitriptyline, nortriptyline, 10-hydroxy amitriptyline, conjugated 10-hydroxy amitriptyline, 10-hydroxynortriptyline, and conjugated 10-hydroxynortriptyline were 36, 8, 10, 66, 16, and 46 ng/ml, respectively, at 2 hr after dosing and 3, 4, 0.5, 1, 6, and 17 ng/ml, respectively, at 72 hr after dosing. Analyses of plasma samples from 12 subjects who had been receiving 50 mg amitriptyline therapy three times a day for an average +/- SD of 32 +/- 5 days gave a mean concentration of 81 +/- 40 ng/ml for amitriptyline, 71 +/- 57 ng/ml for nortriptyline, 12 +/- 5 ng/ml for 10-hydroxy amitriptyline, 91 +/- 30 ng/ml for conjugated 10-hydroxy amitriptyline, 82 +/- 27 ng/ml for 10-hydroxynortriptyline, and 176 +/- 64 ng/ml for conjugated 10-hydroxynortriptyline.

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J Pharmacol Exp Ther. 1982 Aug;222(2):424-9.
Protective action of diazepam and of sympathomimetic amines against amitryptyline-induced toxicity.

Follmer CH, Lum BK.

Factors that contribute to the lethality of amitriptyline overdosage were studied in cats. Amitriptyline (50 mg/kg) given i.p. to unanesthetized cats produced convulsions in all of the animals and death in five of six animals; pretreatment with diazepam (5 mg/kg) protected against the convulsions and death. Respiratory depression contributed to the mortality when amitriptyline was given i.v. in cats anesthetized with pentobarbital as indicated by the finding that artificial respiration delayed the time of death induced by a continuous i.v. infusion of the drug. The i.v. infusion of amitriptyline in pentobarbitalized cats under artificial respiration produced death due to cardiovascular collapse. The latter was characterized by hypotension, bradycardia, depression of myocardial contractile force, atrioventricular block, intraventricular conduction delay and cardiac arrhythmias. These effects appear to be due to a direct membrane (quindine-like) cardiotoxic action of amitriptyline. Dopamine and dobutamine were effective in protecting the animals against the acute cardiovascular collapse induced by amitriptyline. The protection was associated with a diminution of the hypotension, the negative inotropic and chronotropic actions and the incidence of atrioventricular block produced by the tricyclic antidepressant drug. The results suggest that the positive chronotropic, inotropic and dromotropic actions of the amines may all be contributory factors in their protection action. Isoproterenol and norepinephrine were less effective than the other two amines.

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Acta Psychiatr Scand Suppl. 1989;354:47-53.
Why do amitriptyline and dothiepin appear to be so dangerous in overdose?

Montgomery SA, Baldwin D, Green M.

St. Mary's Hospital Medical School, London, United Kingdom.

Data from different analyses of reported deaths from overdose with antidepressants in the U.K. reveal that amitriptyline and dothiepin are the antidepressants most likely to be associated with death from overdose. All widely used tricyclic antidepressants (TCAs) except clomipramine and lofepramine appear to be dangerous in overdose, whereas the newer antidepressants such as mianserin, trazodone, viloxazine and the TCA lofepramine appear to be relatively safe. The toxicity of amitriptyline and dothiepin appears to be greater than all antidepressants including other TCAs and it is important to try to understand why. A number of explanations will be considered: 1. Dothiepin and amitriptyline may be inherently more toxic than other TCAs. 2. Dothiepin and amitriptyline may induce suicide more than other antidepressants. It is assumed that antidepressants are neutral with regard to inducing suicide but this may not be true. There is, for example, evidence that alprazolam and other benzodiazepines induce suicidal behaviour. 3. Amitriptyline and dothiepin are often presented in subtherapeutic and ineffective doses and it is possible that increased suicides may result from inadequately treated depression. 4. There may be a selective overreporting of deaths with amitriptyline and dothiepin. 5. Amitriptyline and prothiaden may be selectively given to the suicide prone on the mistaken assumption that they are safe.

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Arzneimittelforschung. 1988 Mar;38(3):332-40.
Electroencephalographic effects of the new antidepressant paroxetine in the rabbit.

Watanabe S, Ohta H, Ohno M, Tani Y, Furuya Y, Ueki S, Man'no K, Sugihara K.

Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.

The electroencephalographic (EEG) effect of (-)-trans-4-(4'-fluorophenyl)-3-(3',4'-methylene-dioxyphenoxy-met hyl)piperidine hydrochloride (paroxetine, BRL 29060A) a new antidepressant, was investigated in conscious rabbits with chronic electrode implants and was compared with those of imipramine and amitriptyline. Paroxetine induced an arousal pattern of the spontaneous EEG consisting of low voltage fast waves in the cortex and synchronization of hippocampal theta waves with decreased amplitude, while imipramine and amitriptyline elicited drowsy patterns of the spontaneous EEG. Paroxetine failed to suppress the EEG arousal responses induced not only by auditory stimulation but also by electrical stimulation of the mesencephalic reticular formation, centromedian thalamus and posterior hypothalamus, whereas imipramine and amitriptyline markedly inhibited these responses. The EEG arousal response induced by i.v. injection of physostigmine 0.2 mg/kg was slightly enhanced by paroxetine, while the response was significantly suppressed by imipramine and amitriptyline. Paroxetine, imipramine and amitriptyline showed no significant effect on the photic driving response and recruiting response. Paroxetine did not show any effects on the limbic afterdischarges elicited by either hippocampal or amygdaloid stimulation, while imipramine and amitriptyline caused an initial suppression followed by slight enhancement of these afterdischarges. These results indicate paroxetine to be an antidepressant of a new type which induces a sustained arousal pattern of the spontaneous EEG and has no central anticholinergic action.

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Nippon Yakurigaku Zasshi. 1987 Jun;89(6):339-54.
[Electroencephalographic effect of quinupramine in the rabbit]

[Article in Japanese]

Watanabe S, Ohta H, Yamashita K, Ohno M, Tani Y, Furuya Y, Ueki S.

Electroencephalographic (EEG) effect of quinupramine was investigated in unanesthetized rabbits with chronic electrode implants, and it was compared with those of imipramine and amitriptyline. Quinupramine (0.56-3.2 mg/kg) induced a marked drowsy pattern of spontaneous EEG: high voltage slow waves increased in the cortex, while the hippocampal theta rhythm was desynchronized. Imipramine (1.0-5.6 mg/kg) and amitriptyline (0.56-3.2 mg/kg) also elicited similar EEG effects. The EEG arousal response to auditory stimulation and to electric stimulation of the mesencephalic reticular formation, posterior hypothalamus and centromedian thalamus was markedly suppressed by quinupramine, imipramine and amitriptyline. The EEG arousal response induced by i.v. injection of physostigmine was markedly suppressed by quinupramine, amitriptyline and imipramine. Quinupramine showed no significant effect on the photic driving response and recruiting response. Quinupramine slightly enhanced the limbic afterdischarges elicited by either hippocampal or amygdaloid stimulation, while amitriptyline and imipramine caused an initial suppression followed by a quick recovery. The EEG effects of quinupramine were similar to those of amitriptyline in both qualitative and quantitative aspects.

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Nippon Yakurigaku Zasshi. 1976 Mar;72(2):153-68.
[Electroencephalographic effects of lopramine]

[Article in Japanese]

Watanabe S, Ueki S, Kawasaki H.

Electroencephalographic (EEG) effects of lopramine, a new antidepressant, were investigated in rabbits with chronic electrode implants, and compared with those of imipramine and amitriptyline. All drugs were administered i.v. Lopramine (10, 20 mg/kg) induced a drowsy pattern of spontaneous EEG consisted of high voltage slow waves in the cortex and amygdala, and desynchronization of hippocampal thetha waves. Imipramine and amitriptyline (1-5 mg/kg) also elicited similar EEG changes but were much more potent than lopramine in this effect. Lopramine (10, 20 mg/kg) failed to suppress the EEG arousal responses induced by not only auditory stimulation but also electrical stimulation of the mesencephalic reticular formation, centromedian thalamus and posterior hypothalamus, whereas imipramine and amitriptyline (1 approximately 5 mg/kg) markedly inhibited these responses. The EEG arousal response induced by i.v. injection of physostigmine 0.1 mg/kg showed no change after lopramine (20 mg/kg), while the response was significantly suppressed by imipramine (2, 5 mg/kg) and amitriptyline (1, 2 mg/kg). Lopramine showed no effect on the recruiting response induced by electrical stimulation (8 Hz) of the centromedian thalamus and slightly enhanced the limbic afterdischarges elicited by either hippocampal or amygdaloid stimulation, while imipramine (2, 5 mg/kg) and amitriptyline (1--5 mg/kg) caused an initial depression followed by sustained enhancement of these afterdischarges. These results demonstrate lopramine to be an antidepressant of a new type which has no effect on the ascending reticular activating system and no central anticholinergic action.

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Psychopharmacology (Berl). 1990;101(4):481-5.
Evidence for feeding elicited through antihistaminergic effects of tricyclic antidepressants in the rat hypothalamus.

Ookuma K, Sakata T, Fujimoto K.

First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.

We studied central mechanisms of antidepressants that affect feeding behavior in rats. The tricyclic compounds amitriptyline, doxepin and imipramine significantly induced feeding after their infusion into the third cerebral ventricle in the light phase, but the tricyclic, desipramine, and the dicyclic zimelidine, did not. Drinking was not affected by any compound tested. The relative order of potency in eliciting feeding was: amitriptyline and doxepin greater than imipramine greater than desipramine and zimelidine. To clarify the involvement of neuronal histamine in antidepressant-induced feeding, alpha-fluoromethylhistidine (FMH), a "suicide" inhibitor of histidine decarboxylase, was intraperitoneally administered before infusion of amitriptyline. FMH attenuated the amitriptyline's effect. Bilateral microinfusion of amitriptyline into the ventromedial hypothalamus or the paraventricular nucleus verfied that these are loci for the modulation of feeding by amitriptyline. In the lateral hypothalamus, amitriptyline was less effective. These findings indicate that tricyclic antidepressants directly facilitate feeding, which is, at least in part, mediated by histamine in the hypothalamus.

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