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PubMed1985

Chronic administration of type A monoamine oxidase inhibitors increases duration of thiopentone anaesthesia in the rat.

Daily intraperitoneal administration for fifteen days of the mixed type A and type B monoamine oxidase inhibitors phenelzine, isocarboxazid, iproniazid and tranylcypromine caused a marked increase in the duration of thiopentone anaesthesia ('sleeping time') tested 48 hours after the last drug injection. This effect was not due to accumulation of drug or other carryover since it failed to occur after 5 days of daily administration. Similar prolongation of anaesthesia was seen after 15, but not 5 days of administration of the selective type A monoamine oxidase inhibitors clorgyline and LY 51641 but not with the type B inhibitors pargyline and deprenyl.

Anesthesia↗

PubMed1989

Action of antidepressants on the septal nuclei of the rat.

Studies on neuronal firing have shown a decrease in frequency of firing in structures not directly related to emotional processes. However, studies of the hippocampus have shown increases in firing rate. Other limbic structures not yet explored in regard to the action of antidepressants include the septal nuclei. The present work describes a common effect of various therapeutic antidepressant models. Extracellular unit recordings were obtained from the septal nuclei of rats exposed to different acute treatments: clomipramine, isocarboxazid, trazodone, sleep deprivation, and electroshock. Frequencies and firing intervals were analyzed. After treatment, an increase in firing frequency in cells of the dorsolateral septal nucleus was found. This supports the hypothesis that brain structures related to the phenomenon of self-stimulation participate in the mechanism of antidepressant treatments.

Animals↗

PubMed1983

Effects of selected drugs on spontaneously occurring abnormal behavior in beagles.

A sub-population of beagles with abnormal behavioral patterns has been identified, isolated and tested for responsively to selected classes of psychoactive drugs. The abnormal behavior was ameliorated by anxiolytics and antidepressants but not by antipsychotics, an antihistaminic, an alpha-adrenergic blocker, a beta-adrenergic blocker, or an anticholinergic drug. Improvement occurred after a single dose of the anxiolytic drugs but did not occur until 10-18 days after daily dosing with standard tricylic antidepressants and the MAO inhibitor isocarboxazid. This delayed onset in beagles resembles that seen on use of these drugs in humans. The results with these drugs suggest that the abnormal behaviors of the beagles are related to anxiety and are in part depressive in nature. This colony provides an animal model of abnormal behavior which allows evaluation of the anxiolytic and antidepressant effects of drugs and estimates of the onset of action of antidepressant drugs.

Amobarbital↗

PubMed1998

Clozapine and several other antipsychotic/antidepressant drugs preferentially block the same 'core' fraction of GABA(A) receptors.

Clozapine and several other antipsychotic/antidepressant drugs that fully or partially block GABA(A) receptors were tested at concentrations that reversed the inhibitory effect of 1 microM GABA on 35S-t-butylbicyclophosphorothionate ([35S]TBPS) binding to rat forebrain membranes only about 20-30%, here designated "core" fractions. Clozapine at 10 microM reverses 1 microM GABA 25+/-4.0% (n = 23) (its "core" fraction). Fourty three compounds were tested alone, and pairwise together with 10 microM Clozapine. The "core" fractions of some of the compounds yielded significant additive reversals together with 10 microM Clozapine, while others did not. A group of 14 compounds of which 7 are clinically effective antipsychotic drugs, including Chlorprothixene, Clomacran, Clopipazan, Fluotracen, Sulforidazine, Thioproperazine, and cis-Thiothixene, were statistically non-additive with 10 microM Clozapine, suggesting that all of these drugs selectively block the same core population of GABA(A) receptors as Clozapine. These non-additivities also suggest that Clozapine at 10 microM fully saturates a subset of GABA(A) receptors blocked by 1 microM GABA. Therefore, Clozapine probably blocks 2 or more types of GABA(A)receptors, but only half of the receptors that are sensitive to 1 microM GABA. A second group of 12 compounds of which 6 are clinically active antidepressant/antipsychotic drugs including Amoxapine, Clothiapine, Dibenzepine, Inkasan (Metralindole), Metiapine and Zimelidine were slightly, but significantly, additive with Clozapine suggesting that these compounds block most of Clozapine's core fraction, plus a small additional fraction. A third group consisted of ten compounds that yielded larger (R > 80) and statistically highly significant additivities with Clozapine. Complete additivity was obtained with Bathophenanthroline disulfonate, and Isocarboxazid, suggesting that they block GABA(A) receptors other than those blocked by 10 microM Clozapine. Seven "classical" GABA(A) receptor blockers, also tested at concentrations yielding 21 to 33% reversal alone, were all significantly additive with 10 microM Clozapine, but in no case was the additivity complete. The largest additivity was obtained with Pitrazepine (21%) and the smallest with Tubocurarine (9%). These results provide further support for the notion that selective blockade of the same subset of GABA(A) receptors may contribute to the clinical antipsychotic/antidepressant effects of Clozapine. The deltaB(opt) values for Clozapine are 50+/-1.7% and 26+/-2.6% (n = 3) in whole rat forebrain and cerebellum, respectively, confirming that clozapine-sensitive GABA(A) receptors are unevenly distributed in the brain. The sedative and anxiolytic properties of Clozapine and other antipsychotic drugs may be due to selective blockade of GABergic disinhibition at certain interneurons.

Animals↗

PubMed1982

Genotoxic activity of five antidepressant hydrazines in a battery of in vivo and in vitro short-term tests.

Five antidepressant agents (monoamine oxidase inhibitors) having a hydrazino group--phenelzine, nialamide, mebanazine, isocarboxazid, and iproniazid--were assayed in four in vivo or in vitro short-term tests predictive of the potential carcinogenicity of chemicals. (1) All the compounds tested except iproniazid, produced DNA fragmentation, as evaluated by the alkaline elution technique, in liver and/or lung cells of mice treated ip or po. (2) All the compounds except mebanazine (which was no longer available for testing) were weak inducers of sister chromatid exchanges in bone marrow cells of mice treated ip. (3) Phenelzine and nialamide elicited base-pair substitutions and mebanazine elicited frameshift errors in his- Salmonella typhimurium. S9 mix containing rat liver, mouse liver, or mouse lung S9 fractions had variable effects on mutagenicity. (4) The same three compounds were positive in a DNA repair bacterial test with five trp- Escherichia coli strains lacking a variety of repair mechanisms (uvrA, polA, recA, lexA) or incorporating plasmids (R391).

Animals↗

PubMed1981

Comparison of peripheral anticholinergic effects of antidepressants: dry mouth.

Twenty-one healthy volunteers were given single doses of placebo or antidepressants corresponding to average daily doses of patient medications. Spontaneous whole mouth and parotid salivation was measured two, six, and ten hours after drug administration in session 1; in session 2 after ten hours. The results indicate that a subdivision of antidepressants into four groups can be made according to inhibitory effect on salivation: (a) isocarboxazide and lithium citrate with no effect, (b) zimelidine and nomifensine with slight effect, (c) imipramine oxide and mianserin with moderate effect and (d) maprotiline, nortriptyline, clomipramine, imipramine, and amitriptyline with pronounced effect. Research implications and predictive value for new antidepressants are discussed.

Adult↗

PubMed1990

Comparison of monoamine oxidase-A inhibition by moclobemide in vitro and ex vivo in rats.

Inhibition of MAO activity was measured in rat brain homogenates using 5-HT as MAO-A substrate and phenylethylamine as MAO-B substrate. Moclobemide rather selectively inhibited MAO-A. Its inhibitory potency is rather low, like that of toloxatone, whereas clorgyline, harmaline, cimoxatone and brofaromine were all found to be at least 100 times more potent. Phenelzine, isocarboxazid and tranylcypromine were nonspecific, inhibiting MAO-A and MAO-B to about the same extent. The same drugs were also tested ex vivo. Here again moclobemide preferentially inhibited MAO-A; it was equipotent to clorgyline and brofaromine in these tests, and 2-4 times as potent as cimoxatone and harmaline. Moclobemide is a relatively weak MAO-A inhibitor in vitro and yet more potent in vivo than other reversible inhibitors, suggesting that the compound may be converted in vivo to an active form. Nevertheless, it has not been possible so far to identify activated derivatives, and recent findings that moclobemide markedly inhibits liver MAO-A within 5 min of an intravenous injection strongly suggests that the compound itself is responsible for the inhibition.

Animals↗

PubMed1966

An electrophysiological study of 5-hydroxytryptamine receptors of neurones in the molluscan nervous system.

1. 5-Hydroxytryptamine (5-HT) has been iontophoretically applied to the membrane of central neurones of Cryptomphallus aspersa; CILDA neurones (cells with inhibition of long duration) (Gerschenfeld & Tauc, 1964) are the only cells sensitive to 5-HT. The responses to 5-HT is always a depolarization. The CILDA cells studied were also depolarized by ACh.2. From experiments in which pulses of 5-HT and ACh were applied from a double-barrelled micropipette to the CILDA cell soma, it has been calculated that 5-HT and ACh receptors were located at different distances from the injecting micropipette tip. It has also been calculated from the diffusion equation that in the same CILDA cell a 5-HT concentration of 8.2 x 10(-9)M and a ACh concentration of 1.3 x 10(-8)M caused a similar peak depolarization.3. CILDA neurones show ;anomalous' rectification. 5-HT increases the membrane conductance of CILDA.4. 5-HT receptors of CILDA neurone are desensitized by repeated application of 5-HT. The desensitization lasts for ca. 40 sec.5. 5-HT receptors are blocked by lysergic acid diethylamide and its derivatives. Morphine chlorhydrate blocks them non-competitively.6. Some inhibitors of monoamine oxidase (trancylpromine, isocarboxazide, iproniazide and nialamide) have been tested. They do not prolong the action of 5-HT, but block the 5-HT receptors.7. No crossed desensitization between 5-HT and ACh has been observed. Atropine blocks both ACh-receptors and 5-HT receptors, 5-HT receptors appear to be blocked to a greater extent.8. The data presented support the assumption of a excitatory transmitter role of 5-HT to CILDA neurones, but further evidence is necessary to confirm this hypothesis.

Acetylcholine↗

PubMed1988

Severe daytime somnolence in patients treated with an MAOI.

Eight patients with hypersomnolent, anergic major depression benefited markedly from treatment with relatively high doses of phenelzine or tranylcypromine but experienced intense afternoon somnolence and disrupted sleep. Reducing the dose of monoamine oxidase inhibitor (MAOI) or substituting isocarboxazid sometimes provided relief, but altering the schedule of drugs or meals did not. Bedtime sedation alleviated the disrupted sleep but had little effect on daytime somnolence. The mechanism underlying this side effect is unknown; sleep deprivation, narcolepsy, or hypotension does not account for it. Patients given an MAOI should be assessed for this disturbance and cautioned to avoid risk of injury when it occurs.

Adult↗

PubMed2002

Body weight changes associated with psychopharmacology.

OBJECTIVE: The authors discuss changes in body weight associated with various psychopharmaceuticals. METHODS: A large number of articles and books about drug-induced changes in body weight, selected on the basis of various literature searches and the authors' clinical experiences with psychopharmaceuticals, were reviewed. RESULTS: Many psychotropic drugs with antipsychotic, mood stabilizing, and antidepressant properties are associated with weight gain. Others, such as fluoxetine, isocarboxazid, nefazadone, topiramate, and psychostimulants, may cause weight loss. The antipsychotic drugs chlorpromazine, clozapine, and olanzapine are often associated with weight gain. Among antidepressants, amitriptyline and mirtazapine are known to cause weight gain. However, reductions are sometimes observed, and each antidepressant has its own unique weight-effect profile. Mood stabilizers, especially valproate-related products, are also associated with weight gain. CONCLUSIONS: Careful monitoring and consideration of alternative therapies are essential.

Humans↗

PubMed1988

Monoamine oxidase inhibitors and weight gain.

Weight gain associated with antidepressant therapy is a common problem that often results in noncompliance. Some authors suggest that monoamine oxidase inhibitors (MAOI) are less likely to produce weight gain than tricyclic antidepressants. This paper addresses the relative potential for weight gain with the MAOI. Assessing the potential for antidepressant-induced weight gain necessitates separating the weight changes associated with alterations in mood disorders from those due to drug-induced alterations in appetite control. The mechanisms of appetite control are reviewed briefly followed by proposed mechanisms by which the MAOI may alter this control. A literature review suggests that phenelzine is the MAOI most likely to induce weight gain; reports of isocarboxazid-induced weight gain are less common. There are no cases of tranylcypromine-induced weight gain in the literature that are clearly associated with the drug. The MAOI probably have different effects on the mechanisms of appetite control.

Humans↗

PubMedDate not supplied

Monoamine oxidase inhibitors and elective surgery.

Monoamine oxidase inhibitor use is considered a contraindication for elective surgery. We reviewed 32 patients on a regimen of isocarboxazid 10 mg daily who underwent elective surgery. Their anesthetic management, postanesthesia outcome, and pharmacology are described.

Adult↗

PubMed1975

Activation of tryptophan pyrrolase by benzylhydrazine.

The mechanism responsible for the activation of tryptophan pyrrolase (TP) by benzylhydrazine (BZH) was investigated. The increase in holo/apo ratio of rat TP activity after addition of BZH in concentration of 1 x 10(-4)M, which is a major metabolite of isocarboxazid (ISOC), was higher than those in mice and guinea pigs. In addition, treatment with ISOC to rats (50 mg/kg i.p.) resulted in a significant increase in TP activity. These results suggested that the BZH-induced elevation of TP is at least in part due to a stimulation of conjugation step of TP activity.

Animals↗

PubMed1992

Suicide and fatal antidepressant poisoning.

OBJECTIVE: To compare the fatal toxicities of antidepressant drugs in England, Scotland and Wales 1985-1989. METHODS: Epidemiological retrospective study using Department of Health prescription data and mortality data from the Office of Population Censuses and Surveys, and the Registrar General for Scotland, for the years 1974-1989. The fatal toxicity index (FTI) of groups of drugs and individual drugs was compared with the FTI for all antidepressant drugs for the years 1985-1989. RESULTS: Of 3,604 single antidepressant deaths between 1975 and 1989, the majority (70.95%) were from amitriptyline or dothiepin. The mean FTI for all drugs for the years 1985-1989 was 35.6; the FTIs for dothiepin, amitriptyline, nortriptyline and tranylcypromine were significantly higher than the mean of all, while those for clomipramine, lofepramine, fluvoxamine, trimipramine, maprotiline, trazodone, mianserin, protriptyline, isocarboxazid and phenelzine were lower. The FTI for the older tricyclic drugs was higher at 43.03 (p < 0.001). The FTI for the monoamine oxidase inhibitors, of 27.03 (p = 0.045), and for all drugs introduced after 1973, of 5.32 (p < 0.001), were each significantly lower than the mean of all drugs. CONCLUSIONS: Overdose deaths from antidepressants have not decreased over the last 15 years. A trend away from prescribing drugs with a higher fatal toxicity index in favour of those with a lower index, would reduce the number of deaths from antidepressant poisoning.

Acute Disease↗

PubMed1965

[Effect of the activity of an indirect anticoagulant by a monoamine oxidase inhibitor].

The combinations of some anticoagulants (phenindione, chlorphenadione, diphenadione, phenprocoumon, 3-[1-(p-chlorophenyl)propyl]-4-hydroxycoumarin, cumachlor and acenocoumarol) with MAO-inhibitors (phenylcyclopropylamino hydrochloride, isocarboxazid, iproniazid, nialamide and p-chloro-N'-[2-(isopropylcarbamoyl)-1-methylethyl]benzohydrazide) were investigated with regard to modification of the anticoagulant activity in the rat. The activity of some anticoagulants like phenindione may be enhanced by the addition of MAO-inhibitors, whereas others (chlorphenadione, phenprocoumon) are only slightly or not at all influenced. The MAO-inhibitors phenylcyclopropylamino hydrochloride and nialamide show enhancement of activity in most combinations whereas iproniazid never does. The other MAO-inhibitors lie between these two extremes.

Animals↗

PubMed1990

Inhibited female orgasm resulting from psychotropic drugs. A five-year, updated, clinical review.

As of 1989, the psychotropic drugs that have been reported to inhibit female orgasm include antipsychotic agents (thioridazine, trifluoperazine and fluphenazine), the combination drug perphenazine/amitriptyline, antidepressants (phenelzine, isocarboxazid, tranylcypromine, amoxapine, clomipramine, imipramine, nortriptyline and desipramine) and anxiolytic agents (diazepam, flurazepam and alprazolam). The management of psychotropic-drug-induced female anorgasmia includes discontinuation of the offending drug, reduction of the dosage level, a wait for spontaneous remission while the patient remains on the agent and substitution of another medication. The use of bethanechol chloride and cyproheptadine has been successful in resolving anorgasmia while patients continue to receive antidepressants.

Female↗

PubMed1989

Strain differences of rat liver carboxylesterase activities related to the phenotype difference of esterase-3 (egasyn).

It was demonstrated that the inbred strain EHBR had the C phenotype of esterase-3 judging from the absence of liver microsomal beta-glucuronidase and the pattern of esterase activities of liver homogenates after analytical isoelectric focusing. In addition, in the strain EHBR, liver microsomal hydrolase activities of acetanilide and isocarboxazid which are hydrolyzed well by esterase-3 were lower than in outbred Sprague-Dawley rat and inbred LEW rat having the D phenotype of esterase-3. These results suggest that the phenotype difference of esterase-3 is possible to cause the strain differences of liver microsomal carboxylesterase activities.

Animals↗

PubMed1988

Effects of hypophysectomy and pituitary hormones on hepatic microsomal carboxylesterase isozymes in male rats.

Hepatic microsomal carboxylesterase (EC 3.1.1.1) from rat liver microsomes showed a different capacity for the hydrolysis of various substrates. In hypophysectomized male rats, hepatic carboxylesterase activities showed substrate-dependent changes, i.e., an decrease in malathion and p-nitrophenylacetate hydrolases and increase in isocarboxazid hydrolase. When human growth hormone is administered to hypophysectomized male rats, carboxylesterase activities were decreased. Conversely, subcutaneous injection of ovine prolactin to hypophysectomized rats, carboxylesterase activities showed substrate-dependent changes. On the other hand, in hypophysectomized male rats, the amount of carboxylesterase isozymes showed different changes, i.e., an increase in the amount of RL2 contents and decrease in RL1 contents, and the amount of RH1 was not changed. These results suggested that hepatic microsomal carboxylesterases are regulated, at least in part, by some pituitary hormones, and that these hormones have selective effects on the different isozymes of carboxylesterase.

Animals↗