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At least 19 recordsLinked to original sources
PubMed1981

Relationship between response to phenelzine and MAO inhibition in a clinical trial of phenelzine, amitriptyline and placebo.

This report examines the hypothesis that for phenelzine to be more effective than placebo it is necessary to achieve at least 80% inhibition of platelet MAO activity. This hypothesis was examined in the context of a double-blind comparison of phenelzine, amitriptyline and placebo in depressed patients. When phenelzine became significantly more effective than placebo at 4 weeks, the average MAO inhibition was 85%. By the 5th week, with MAO inhibition greater than 90%, phenelzine was significantly more effective than amitriptyline. A highly significant correlation was noted between improvement and MAO inhibition within the phenelzine group.

Amitriptyline↗
PubMed1984

Effects of chronic phenelzine in the rat: altered tissue weights and metabolism of 14C-phenelzine.

Phenelzine (2-phenylethylhydrazine, PZ, Nardil) a clinically important antidepressant, inhibits several enzyme systems including monoamine oxidase (MAO). Since PZ is itself a known substrate for MAO, it is possible that its metabolites will differ according to the functional status of MAO. We have, therefore, examined aspects of the metabolism of 14C-PZ in the rat after multiple (15 days) treatments with nonlabelled PZ and compared results to those obtained from drug naive animals. In addition, we have examined the effects of PZ treatment upon total body weight and the weights of selected organs. Total body weights and weights of lungs, livers and kidneys were reduced from controls after repeated injection with PZ. The excretion of radioactivity was also altered. The PZ-pretreated animals excreted less (p less than 0.05) radioactivity in urine (41.1 +/- 5.6 vrs 59.2 +/- 3.7% of dose in controls) and more in expired air (p less than 0.05) than did controls. These data suggest that prior treatments with PZ alter the metabolism and excretion of subsequently administered 14C-PZ.

Animals↗
PubMed1988

Effect of chronic deuterated and non-deuterated phenelzine on rat brain monoamines and monoamine oxidase.

The effects of phenelzine and 1,1-dideuterophenelzine (0.5 or 2.5 mg/kg/day) administered s.c. via miniosmotic pumps for 13 days were compared. Striatal levels of p-tryrosine and tryptophan were unaffected by either treatment. The concentrations of DOPAC, HVA and 5-HIAA were dose-dependently decreased by phenelzine and deuterated phenelzine; furthermore, the deuterated compound decreased the amounts of these acids more than the same dose of phenelzine. Dopamine levels were increased by a rather small amount by all drug treatments; no effects of drug dose or drug type (deuterated or nondeuterated) were observed. With the exception of phenylethylamine, qualitatively similar effects were found with all other amines measured; their amounts were increased dose-dependently and the effects of deuterated phenelzine were greater than those of phenelzine. Rat cerebral MAO activity was inhibited dose-dependently by phenelzine and by deuterated phenelzine. Type A MAO was inhibited more than type B, and deuterated phenelzine inhibited both types more than did phenelzine. The present study shows that the efficacy of phenelzine was increased about 5-fold by deuteration, that deuterated phenelzine increased tryptamine, m-tyramine and p-tyramine levels much more than it did the other monoamines, that phenylethylamine levels were least affected by the drug treatments, and that deuterated phenelzine inhibited MAO more than did phenelzine.

Animals↗
PubMed1983

Analgesic properties of meperidine, amitriptyline and phenelzine in mice.

Sixty-three white Swiss Webster mice were divided into seven equal groups. Their tolerance to pain (heat applied to the tail by a test tube containing hot water at a temperature measured by telethermometry) was assessed before and after intraperitoneal injection of (1) physiologic saline; (2) meperidine 14 micrograms X g-1; (3) amitriptyline 6 micrograms X g-1 (4) amitriptyline 12 micrograms X g-1; (5) phenelzine 1.5 micrograms X g-1; (6) phenelzine 3 micrograms X g-1; and (7) amitriptyline 6 micrograms X g-1 plus phenelzine 1.5 micrograms X g-1. All post-injection tests were conducted 45 and 90 minutes after administration, and repeated 24 hours later. No significant difference in pain threshold was noted in any pre-injection test or in any test conducted with physiologic saline. By 90 minutes post-injection, all groups receiving drugs developed increased tolerance to pain. Mice which had received phenelzine plus amitriptyline, or either dose of phenelzine were more tolerant to pain for up to 24 hours than mice which had received physiologic saline. The most marked increases in tolerance to pain were seen with 1.5 micrograms X g-1 and 3 micrograms X g-1 of phenelzine and phenelzine plus amitriptyline. However, phenelzine was more effective and had a longer-lasting effect than either dose of amitriptyline, or meperidine. The combination of phenelzine plus amitriptyline was no more effective than phenelzine alone.

Amitriptyline↗
PubMed1981

Mechanism of the inhibitory action of phenelzine on microsomal drug metabolism.

Aminopyrine N-demethylase was inhibited by phenelzine in vitro and in microsomes isolated from rats treated with phenelzine in vivo. The inhibition was greater if phenelzine was incubated with the microsomal suspension before the addition of the substrate. In vitro, the addition of phenelzine produced immediate decrease in cytochrome P-450. This initial decrease was found to be due to the direct binding of phenelzine to the ferrous heme of cytochrome P-450. Further decrease in cytochrome P-450 occurred upon incubation of microsomes with phenelzine in the presence of NADPH. This secondary decrease in cytochrome P-450 was found to be paralleled by a loss of the home content in cytochrome P-450. The decrease in cytochrome P-450 with concomitant loss of heme can be partially inhibited by a substrate (aminopyrine) or by an inhibitor (metyrapone) of the microsomal enzymes, indicating the possible involvement of the metabolism of phenelzine to a reactive intermediate. The comparison of the effect of phenelzine to that of phenylhydrazine strengthened the possibility that a reactive metabolic intermediate of phenelzine can cause heme destruction in cytochrome P-450. Thus, phenelzine exerts its inhibitory action on microsomal drug metabolism most likely by decreasing the cytochrome P-450 content largely through heme destruction.

Aminopyrine N-Demethylase↗
PubMed1986

Inhibition of aromatic L-amino acid decarboxylase and tyrosine aminotransferase by the monoamine oxidase inhibitor phenelzine.

The concentration of p-tyramine in the rat striatum was increased significantly by intraperitoneal injection of phenelzine (5 or 100 mg/kg). Unlike other monoamine oxidase (MAO) inhibitors, phenelzine had no effect on p-tyramine levels in the first 1-2 h following injection. The high dose of phenelzine increased the p-tyramine levels much more than the low dose. In addition, the high dose of phenelzine increased striatal p-tyrosine levels significantly 12 h after injection. Further studies showed that phenelzine inhibited the tyrosine aminotransferase activity of rat liver homogenates; the IC50 was 50 microM. Phenelzine also inhibited the aromatic L-amino acid decarboxylase activity of rat brain homogenate with an IC50 of 25 microM. Following intraperitoneal injection of 100 mg/kg phenelzine, the initial concentration of phenelzine in the striatum appears to be high enough to inhibit aromatic L-amino acid decarboxylase. It is suggested that the multiple enzyme inhibition caused by administration of high doses of phenelzine accounts for its unusual effects on striatal p-tyramine levels compared with other MAO inhibitors, i.e., its initial lack of effect on p-tyramine levels followed later by very large increases in p-tyramine levels.

Animals↗
PubMed2005

In vivo evidence for reduced cortical glutamate-glutamine cycling in rats treated with the antidepressant/antipanic drug phenelzine.

Converging evidence has indicated that hyperglutamatergic activity and GABAergic dysfunction may play important roles in the neurobiology and treatment of depression and other mood disorders. In this study, in vivo 1H[13C] magnetic resonance spectroscopy was used to quantify the effects of acute phenelzine administration on cortical energetics, glutamate neurotransmission, and GABA synthesis flux. The time-resolved kinetics of cortical [4-13C]glutamate, [4-13C]glutamine, and [2-13C]GABA turnover from i.v.-infused [1,6-13C2]glucose was measured at 11.7 T in alpha-chloralose anesthetized rats four hours after phenelzine treatment (10 mg/kg, i.p.) and in non-treated controls. The rate of the tricarboxylic acid cycle flux was not affected by phenelzine treatment compared with the non-treated group (0.46+/-0.05 vs. 0.50+/-0.05 micromol/g/min, respectively). The rate of the glutamate-glutamine cycling flux between neurons and glia in the phenelzine-treated group was significantly reduced (from 0.16+/-0.04 to 0.10+/-0.03 micromol/g/min), providing in vivo evidence that phenelzine attenuates glutamate neurotransmission. Following phenelzine treatment, the cortical GABA concentration increased significantly (from 1.02+/-0.17 to 2.30+/-0.26 micromol/g), while the GABA synthesis flux was unchanged (from 0.07+/-0.02 to 0.06+/-0.02 micromol/g/min). The possible role of augmented GABAergic function resulting from elevated GABA levels in the observed modulatory effect of phenelzine on the glutamate-glutamine cycling flux was discussed. The reduced glutamate-glutamine cycling flux observed in this study suggests that, in addition to its effects on monoaminergic and GABAergic systems, the attenuation of glutamate neurotransmission resulting from phenelzine administration may also contribute to its efficacy in the treatment of depression. This study is the first demonstration that the glutamate-glutamine cycling flux, which can be measured non-invasively in the human brain in vivo, was altered due to the action of a psychotropic drug.

Animals↗
PubMed1989

Monoamine oxidase inhibition by phenelzine and brofaromine in healthy volunteers.

The two monoamine oxidase (MAO) inhibitors phenelzine and brofaromine given for 2 to 3 weeks were compared in six volunteers. Blood pressure sensitivity to intravenous tyramine increased 2.6-fold during phenelzine (60 mg/day) and 4.8-fold during brofaromine, whereas sensitivity to oral tyramine increased more during phenelzine (15.7-fold vs 8.5-fold). After withdrawal of phenelzine, pressor sensitivity to oral tyramine returned to control values within 2 and for more than 8 weeks. Relative bioavailability of conjugated tyramine was elevated sixfold by brofaromine and 11.6-fold by phenelzine. Urinary elimination of tryptamine increased during phenelzine and brofaromine to 12.7-fold and threefold, respectively. 3-Methoxy-4-hydroxyphenylglycol (MHPG) and 3-methoxy-4-hydroxymandelic acid (VMA) excretion decreased during brofaromine significantly by 72% and 49%, respectively. The nonsignificant decrease of MHPG excretion and the increase of intravenous tyramine pressor sensitivity caused by phenelzine are significantly related. The data suggest that the selective reversible MAO-A inhibitor brofaromine has a larger therapeutic safety than phenelzine.

Adult↗
PubMed2003

Phenelzine efficacy in refractory social anxiety disorder: a case series.

Several effective treatments for social phobia are now available, notably cognitive behavioural therapy and some antidepressant medications. Controlled trials indicate that 25-45% of patients fail to respond to the initial treatment. To my knowledge, nothing has yet been published on the treatment of refractory cases. Phenelzine is effective in social phobia, and no treatment has been shown to be superior to phenelzine. Hence, phenelzine is a reasonable option for patients unresponsive to other treatments. This report presents the results of naturalistic, open-label phenelzine treatment of a series of seven consecutive, previously unresponsive patients treated with a mean dose of phenelzine 66 mg. Six patients were classified as responders according to Clinical Global Impression (CGI) ratings. Some experienced dramatic improvement and regained ability to function in school or work. Two patients experienced re-emergence of social phobia while on maintenance therapy. The majority of patients had a sustained response and elected to stay on the medication. There were no serious adverse events. Two patients discontinued due to side-effects. The drawbacks of phenelzine therapy may be more than outweighed by its potential utility in relieving social anxiety disorder. Phenelzine appears to be effective in treating social phobia that has been unresponsive to other treatments. No patient should be considered treatment resistant without being offered a trial of phenelzine.

Adult↗
PubMed1997

Prophylactic efficacy of phenelzine and imipramine in chronic atypical depression: likelihood of recurrence on discontinuation after 6 months' remission.

OBJECTIVE: Demonstration of antidepressant efficacy beyond 6 months has infrequently been addressed, and no long-term efficacy data exist for patients with chronic atypical depression. METHOD: Sixty patients with atypical depression (according to Columbia University criteria) of at least 2 years' duration and who had improved with imipramine or phenelzine were stabilized for 6 months and then randomly continued the same medication or placebo for 6 months. RESULTS: Several baseline differences suggested that patients who entered the discontinuation trial on a regimen of phenelzine were more chronically depressed than the imipramine-treated patients. Survival analysis showed a marked advantage for phenelzine relative to placebo. In addition, patients switched to placebo from phenelzine experienced a recurrence of depressive symptoms significantly more often than patients switched to placebo from imipramine. Patients maintained with imipramine did not have lower relapse rates than those switched from imipramine to placebo. Recurrence rates were 23% for patients maintained on a regimen of phenelzine, 41% for those maintained on a regimen of imipramine, 47% for those switched from imipramine to placebo, and 87% for placebo-treated patients originally treated with phenelzine. CONCLUSIONS: Patients with chronic atypical depression are at high risk of recurrence if phenelzine is withdrawn 6 months after initial improvement. Similar findings were not demonstrated for imipramine; this replicates acute trials demonstrating imipramine's relative ineffectiveness in patients with atypical depression. Differences in recurrence rates after the switch to placebo from phenelzine and imipramine could be due to the two drugs' different mechanisms of action or to baseline differences in the two populations.

Adult↗
PubMed1998

Cognitive behavioral group therapy vs phenelzine therapy for social phobia: 12-week outcome.

BACKGROUND: This article presents results of the acute treatment phase of a 2-site study comparing cognitive behavioral group therapy (CBGT) and treatment with the monoamine oxidase inhibitor phenelzine sulfate for social phobia. METHODS: One hundred thirty-three patients from 2 sites received 12 weeks of CBGT, phenelzine therapy, pill placebo administration, or educational-supportive group therapy (an attention-placebo treatment of equal credibility to CBGT). The "allegiance effect," ie, the tendency for treatments to seem most efficacious in settings of similar theoretical orientation and less efficacious in theoretically divergent settings, was also examined by comparing responses to the treatment conditions at both sites: 1 known for pharmacological treatment of anxiety disorders and the other for cognitive behavioral treatment. RESULTS: After 12 weeks, phenelzine therapy and CBGT led to superior response rates and greater change on dimensional measures than did either control condition. However, response to phenelzine therapy was more evident after 6 weeks, and phenelzine therapy was also superior to CBGT after 12 weeks on some measures. There were few differences between sites, suggesting that these treatments can be efficacious at facilities with differing theoretical allegiances. CONCLUSIONS: After 12 weeks, both phenelzine therapy and CBGT were associated with marked positive response. Although phenelzine therapy was superior to CBGT on some measures, both were more efficacious than the control conditions. More extended cognitive behavioral treatment and the combination of modalities may enhance treatment effect.

Adult↗
PubMed1983

Potentiation of the behavioural effects of the antidepressant phenelzine by deuterium substitution.

Phenelzine in the rat induced biphasic behavioural stimulation, which was profoundly potentiated by deuterium substitution. Doses of 12.5 or 25.0 mg/kg phenelzine had little or no effect on spontaneous activity, whereas the same doses of deuterated phenelzine produced hyperactivity, wet-dog shakes, forepaw padding, splayed hind limbs, backward walking, sniffing and stereotyped grooming 2-12 h after injection. Similarly, the behavioural response induced by 50.0 mg/kg phenelzine was strongly potentiated by deuterium substitution. It appears likely that the increased behavioural response induced by deuterated phenelzine may be due to its greater potency as a monoamine oxidase inhibitor compared to undeuterated phenelzine. Since phenelzine is an antidepressant that is particularly efficacious in the treatment of severe anxiety, a deuterated analogue of the drug seems likely to be clinically useful.

Animals↗
PubMed1986

Effects of acute and chronic phenelzine on regional monoamine metabolism in rats and its potentiation by deuterium substitution.

Phenelzine is a monoamine oxidase inhibitor with antidepressant properties. The present study investigated effects of acute (1-2 mg kg-1 4 h s.c.) and chronic (0.25-2 mg kg-1 day-1 Alzet miniosmotic pumps, 13 days s.c.) administration of phenelzine on regional monoamine metabolism in rats. The effects of these phenelzine treatments were compared with those of equivalent doses of a deuterated form of the drug (phenelzine-d4). The following brain regions and compounds were assessed using high performance liquid chromatography with electrochemical detection: Striatum: dopamine, DOPAC, HVA, 5-HT, 5-HIAA; hypothalamus: dopamine, 5-HT, 5-HIAA, noradrenaline; hippocampus: 5-HT, 5-HIAA, noradrenaline; frontal cortex: dopamine, noradrenaline, 5-HT, 5-HIAA. Acute drug administration increased levels of dopamine, 5-HT and noradrenaline with the exception of dopamine in the hypothalamus and frontal cortex and 5-HT in the hypothalamus. DOPAC, HVA and 5-HIAA levels were decreased. After chronic administration amine levels increased with the exception of dopamine administration amine levels increased with the exception of dopamine in the hypothalamus. The respective acid metabolites were also decreased. These effects of phenelzine were markedly potentiated by deuterium which was substituted for hydrogen in the side chain. The potentiation of these effects was enhanced with chronic administration, differences between phenelzine and phenelzine-d4 effects being more marked at lower doses.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

The antidepressant drug phenelzine produces antianxiety effects in the plus-maze and increases in rat brain GABA.

Research on the effects of antidepressant/ antipanic drugs in animal models of anxiety has yielded equivocal results, even after chronic drug regimens. In contrast, we found that the antidepressant/antipanic drug phenelzine, given acutely, produced a clear anxiolytic effect in the elevated plus-maze, a widely-used animal model of "anxiety" that is primarily sensitive to benzodiazepine-type anxiolytics (e.g., diazepam). Furthermore, the effective dose of phenelzine (15 mg/kg) administered to rats was associated with more than a 2- fold increase in whole brain levels of gamma-aminobutyric acid (GABA), whereas an ineffective dose of phenelzine (5.1 mg/kg) did not significantly change GABA levels. The N-acetylated metabolite of phenelzine, N2-acetylphenelzine, produced neither an anxiolytic effect in the elevated plus-maze nor a significant change in whole-brain levels of GABA. However, both phenelzine and N2-acetylphenelzine potently inhibited monoamine oxidase, a mechanism commonly thought to be involved in the therapeutic effects of monoamine oxidase inhibitors such as phenelzine in the treatment of depression in humans. These results suggest that the mechanism whereby phenelzine produces anxiolytic effects in the plus-maze model is unique to a facilitatory action on brain levels of GABA, in contrast to classical benzodiazepines, which produce anxiolytic effects by enhancing the affinity of the GABAA-receptor for GABA.

Animals↗
PubMed1989

Deuterium isotope effect of phenelzine on the inhibition of rat liver mitochondrial monoamine oxidase activity.

Phenelzine is a suicide monoamine oxidase (MAO) inhibitor with antidepressant properties. The present study compares the inhibition of rat liver mitochondrial MAO by phenelzine and 1,1-dideuterated phenelzine and the metabolism of these drugs by that enzyme. Phenylacetaldehyde, which was measured by a high performance liquid chromatographic procedure, was found to be the major metabolite of phenelzine after incubation with MAO. The time-courses of aldehyde formation were non-linear due to the time-dependent inhibition of MAO. The reaction rate was reduced substantially when the hydrogen atom in the 1-carbon position was replaced by deuterium. The VH/VD value was 3.1, indicating a primary isotope effect. Such a substitution of deuterium in the phenelzine molecule did not affect significantly the initial reversible inhibition of MAO, which was determined by comparison of their Ki values. The irreversible inhibition, as estimated from IC50 values, however, was potentiated substantially by deuteration. These results support the notion that the irreversible inhibition of MAO activity by phenelzine proceeds via a phenylethyldiazene intermediate, which reacts with the enzyme to form a covalent adduct. An alternative pathway involving hydrogen abstraction from carbon-1 of phenelzine or via rearrangement of the diazine on the enzyme surface could occur to form a phenylethylidene hydrazine intermediate which would subsequently be hydrolyzed to phenylacetaldehyde. The reduction in the rate of phenylethylidene hydrazine formation due to the isotope effect could lead to the accumulation of phenylethyldiazene intermediate and thus potentiate the inhibition of MAO activity.

Acetaldehyde↗
PubMed1984

Interactions of a non-selective monoamine oxidase inhibitor, phenelzine, with inhibitors of 5-hydroxytryptamine, dopamine or noradrenaline re-uptake.

Interactions of combined antidepressants which occur in man were reproduced in rats pretreated with phenelzine, features elicited including myoclonic phenomena, an augmented lower limb flexor reflex, muscle fasiculation and fatalities, particularly with combinations incorporating 5-hydroxytryptamine (5-HT) re-uptake inhibitors. Combinations of antidepressants included phenelzine with 5-HT re-uptake inhibitors (paroxetine, fluoxetine, clomipramine); with "mixed" re-uptake inhibitors affecting 5-HT and noradrenaline (imipramine, amitriptyline); with noradrenaline re-uptake inhibitors (desipramine, maprotiline, nisoxetine) and with dopamine re-uptake inhibitors (benztropine, nomifensine). Myoclonic phenomena such as forelimb flexor-extensor movements, head and body twitches, occurred in phenelzine pretreated rats after paroxetine, fluoxetine, clomipramine, imipramine, amitriptyline and desipramine. Wet dog shakes, the most intense phenomenon, were obtained only after paroxetine, fluoxetine, clomipramine and imipramine. Myoclonic features were prevented when pretreatment included p-chlorophenylalanine but were unaffected when this incorporated alpha-methyl-p-tyyrosine; there were attenuated by methysergide, cyproheptadine, clozapine or pimozide. The myoclonic phenomena were reproduced by combination of 5-hydroxytryptophan but not L-3,4-dihydroxyphenylalanine with clomipramine. Electrocortical changes observed included 2-4 Hz, 5-8 Hz, large amplitude potentials unrelated to the myoclonic incidents and unaffected by sensory stimulation. Following phenelzine, brain monoamine oxidase (MAO) A inhibition was 99% and that of MAO B, 88%; 5-HT concentration was significantly elevated in the cortex and hypothalamus, as was hypothalamic noradrenaline. Peak and basal tensions of a lower-limb flexor reflex were elevated in phenelzine pretreated spinal rats by fluoxetine, paroxetine, clomipramine and imipramine, effects attenuated by cyproheptadine. Forelimb flexor-extensor movements and body twitches were elicited by fluoxetine and paroxetine in phenelzine pretreated spinal rats in the presence of electrical stimulation of the central stump of a divided posterior tibial nerve. Pressor responses were observed in phenelzine pretreated spinal rats given 5-HT re-uptake inhibitors, "mixed" re-uptake inhibitors and those affecting noradrenaline re-uptake; ECG anomalies occurred in such rats given clomipramine.

Animals↗