Clinical pharmacology of phenelzine.

There is renewed interest in the clinical pharmacology of phenelzine sulfate and other monoamine oxidase (MAO) inhibitors. Newer clinical and analytic techniques recently have been applied to investigations of this class of drugs in man. The results show that drugs such as phenelzine are effective in nonendogenous depression and phobic disorders. Clinical response to phenelzine is related to platelet MAO inhibition and dosage per unit body weight. High percent MAO inhibition in platelets at two weeks is associated with greater improvement after a six-week course of treatment. Our data show that a safe, effective phenelzine dose in 1 mg/kg body weight per day. These results have delineated the pharmacologic and therapeutic effects of phenelzine and support a continuing role for MAO inhibitors in psychopharmacology.     

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.     

Monoamine oxidase inhibitors. A review of antidepressant effectiveness.

Data from double-blind, placebo-controlled trials of the monoamine oxidase (MAO) inhibitors show that phenelzine is clearly effective in neurotic or atypical depressives, but the findings concerning its effect in endogenous depressives are inconclusive. Although few controlled studies have been done with tranylcypromine, similar conclusions are warranted. Studies have contrasted MAO inhibitors and tricyclic antidepressants (TCAs) to gain further information about the type of patients likely to respond to MAO inhibitors. We believe that simply contrasting the relative efficacy of TCAs and MAO inhibitors is outdated. Neurotic or atypical depression is probably a heterogeneous syndrome, and delineation of subtypes responsive to specific antidepressants is needed. The implications of fast acetylation, selective MAO inhibitors, types MAOA and MAOB, and measures of platelet MAO inhibition are discussed in this article.     

Response of psychotic and nonpsychotic depression to phenelzine

The authors studied 52 depressed inpatients to examine treatment response to phenelzine, a monoamine oxidase (MAO) inhibitor. All patients were classified into one of three RDC categories (definitely psychotic, probably psychotic, and nonpsychotic). For the entire sample, the mean platelet MAO inhibition level achieved with phenelzine was greater than 80%. Response to treatment was determined by independent clinical assessment and by the change in rating scores from baseline; 68% of the nonpsychotic, 43% of the probably psychotic, and 21% of the definitely psychotic patients were classified as responders. This differential response rate is similar to that reported in the literature for tricyclic antidepressants.     

Phenelzine treatment of melancholia

Monoamine oxidase (MAO) inhibitor antidepressants are widely thought by clinicians and researchers to be ineffective in the treatment of endogenous depression. This study reports an open clinical trial in which seven of eight outpatients (88%) with melancholia responded to phenelzine treatment. This response rate is comparable to the response to tranylcypromine in a previous study at our clinic. These results suggest that MAO inhibitors are effective for outpatients with endogenous depressive syndromes. The use of MAO inhibitors may be an alternative treatment for patients who cannot tolerate or who have not responded to tricyclic antidepressants.     

Inhibition of platelet monoamine oxidase in depressed subjects treated with phenelzine.

The authors treated 19 depressive inpatients double-blind with a mean dose of 78 mg/day of phenelzine for 3 weeks to determine the possible relationship between monoamine oxidase (MAO) inhibition and the effectiveness of phenelzine. Clinical ratings made on the Hamilton Depression Rating Scale, the Beck Depression Inventory, and the SCL-90 indicated a minimum of 60% MAO inhibition had to be achieved for the drug to be consistently beneficial.     

Urinary amine metabolite excretion in a patient with adrenergic hyperactivity state: reaction to phenelzine withdrawal and combined treatment

Urinary MHPG (3-methoxy-4-hydroxyphenylglycol) amounts increased threefold during a toxic delirious state in a 57-year-old bipolar patient 3 days after phenelzine treatment was stopped. This norepinephrine metabolite was not expected to rise as monoamine oxidase (MAO) was completely blocked. In addition, the delirious state appeared as a rebound phenomenon and not an acute toxic state during drug administration. It seems that phenelzine acts more through catecholamine release phenomenon than by inhibition of MAO.     

Acetylation phenotype, platelet monoamine oxidase inhibition, and the effectiveness of phenelzine in depression.

The authors treated 16 depressed patients with up to 90 mg/day of phenelzine. After acetylation phenotype was determined and platelet monoamine oxidase (MAO) activity measured, no significant relationship was observed between clinical improvement and acetylation phenotype or between MAO inhibition and acetylation. Discrepant findings regarding acetylation phenotype and the effects of phenelzine are discussed. The authors do not recommend a sulfamethazine phenotype test as a predictor of outcome for phenelzine.     

Interactions of non-selective monoamine oxidase inhibitors, tranylcypromine and nialamide, with inhibitors of 5-hydroxytryptamine, dopamine or noradrenaline re-uptake

Rats pretreated with tranylcypromine and given clomipramine, developed head and body twitches, forelimb flexor-extensor movements and wet dog shakes, phenomena which failed to develop when pretreatment incorporated p-chlorophenylalanine (PCPA) but were unabated when this included alpha-methyl-p-tyrosine (AMPT). Locomotor activity, itself enhanced by tranylcypromine, was further and significantly elevated compared to saline, by clomipramine or imipramine in grouped rats (n = 3) but not in single or paired rats; desipramine lacked such action. This effect of clomipramine was prevented when PCPA was incorporated into the pretreatment and that of imipramine by including PCPA or AMPT. Brain monoamine oxidase (MAO) A inhibition was 92% and that of MAO B, 80%. Cortical hydroxytryptamine (5-HT) and noradrenaline concentrations as well as hypothalamic 5-HT, were significantly elevated by tranylcypromine, as was dopamine in the striatum, nucleus accumbens and tuberculum olfactorium. Hyperthermia developed in tranylcypromine pretreated rats given paroxetine or fluoxetine. Myoclonic phenomena were elicited by paroxetine, fluoxetine, clomipramine or imipramine in nialamide pretreated rats but these were less intense than in rats pretreated with phenelzine or tranylcypromine. Fatalities were fewer than in rats pretreated with tranylcypromine or phenelzine. Brain MAO A inhibition was 92% and that of MAO B, 69%.     

Translating the evidence on atypical depression into clinical practice

Although the introduction of selective serotonin reuptake inhibitors ushered in an era of relative comfort among clinicians in treating major depressive disorder (MDD), no one antidepressant is appropriate for all patients with depression. In patients with atypical symptoms, efficacy of therapeutic agents may be greatest for monoamine oxidase inhibitors (MAOIs). The first-generation MAOIs such as phenelzine and isocarboxazid were largely nonselective inhibitors of both subtypes of MAO, MAO(A) and MAO(B). These medications carried with them dietary restrictions, medication restrictions, a need for titration, and a substantial side effect burden, including weight gain, cardiovascular effects (i.e., hypertension and hypotension), and sexual side effects. The second-generation MAOI selegiline is selective for MAO(B) at oral doses of up to 10 mg/day. At higher doses, selegiline loses selectivity and inhibits both MAO(A) and MAO(B). Because the antidepressant effects of selegiline occur with the higher doses that impact tyramine pressor effects, an ideal formulation would optimize dose while minimizing adverse effects of MAO(A) inhibition in the gastrointestinal mucosa. Efforts in this direction led to formulation of the selegiline transdermal system (STS). The most common side effects are irritation at the patch site and insomnia. Drugs to be avoided with the STS include some pain medications, antidepressants, muscle relaxants, and any form of sympathomimetic amines, which include amphetamines, cold products with pseudoephedrine, phenylephrine, phenylpropanolamine, ephedrine, and stimulant-containing weight-reduction agents. Although no tyramine-restricted diet is required for the 6-mg/24-hour patch, a restricted diet is recommended for the higher-dose patches to reduce the risk of hypertensive crisis.     

MAO inhibition and clinical response in depressed patients treated with phenelzine

The authors studied clinical response in 47 depressed inpatients treated with the monoamine oxidase (MAO) inhibitor phenelzine. Improvement on ratings for depression at Week 2 of treatment was correlated with percent MAO inhibition at Week 2 (r = .35, p less than .03), and the modest positive correlation that was found remained after the authors adjusted for the effects of baseline scores on the Hamilton Rating Scale for Depression, dose (mg/kg), and psychosis (partial correlation = .49, p less than .002). Further, the 23 patients ultimately classified as responders had a significantly greater percent MAO inhibition at Week 2 than did the 24 nonresponders (t = 3.02, p less than .005). Thus, the rate of MAO inhibition at Week 2 was significantly correlated with clinical improvement at Week 2 and final response status. These findings could not be explained by other potentially moderating variables such as sex, age, endogenicity, recurrence, and incapacitation.     

Enzymatic N-methylation of phenelzine catalyzed by phenylethanolamine N-methyltransferase

1. Phenelzine has been found to be methylated by enzymes obtained from bovine adrenal and some rat tissues in the presence of S-adenosylmethionine (SAM) as methyl group donor. 2. The methylated product was chromatographically (TLC and HPLC) identical with chemically synthesized N-methylphenelzine. The structure of this methylated phenelzine has been confirmed by a GC-MS procedure. 3. The phenelzine methyltransferase in the bovine adrenal has a molecular weight and isoelectric point identical with that of bovine adrenal phenylethanolamine N-methyl-transferase (PNMT). 4. Methylated phenelzine possesses much reduced inhibitory activity towards monoamine oxidase (MAO). It can, however, be deaminated by MAO to produce phenylacetaldehyde, and subsequently phenylacetic acid. 5. Other hydrazine compounds, such as hydralazine, have also been found to be methylated by the adrenal enzyme. 6. Our finding of enzymatic methylation of hydrazine compounds is novel, and it may play a role in the metabolism of hydrazine drugs.     

Platelet MAO inhibition, urinary MHPG, and leukocyte beta-adrenergic receptors in depressed patients treated with phenelzine

The authors investigated three biochemical indices of peripheral catecholamine activity in 36 depressed inpatients treated with the monoamine oxidase (MAO) inhibitor phenelzine. Platelet MAO activity, urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), and leukocyte beta-adrenergic receptor functions were measured before and during the 4th week of phenelzine treatment. There were significant reductions in platelet MAO activity, urinary MHPG excretion, and depressive symptoms in all of the patients. Responders had the same decrease in MHPG as nonresponders. There were no changes in leukocyte beta-receptor function in a small subgroup of the patients.     

Tyramine sulfate excretion may be a better predictor of antidepressant response than monoamine oxidase activity

The tyramine sulfate excretion test was performed on 62 nonmelancholic depressed outpatients who then took part in a 6-week double-blind trial comparing imipramine, phenelzine, and placebo. In a double-blind design, nonresponders were switched to one of the active medications. Tyramine sulfate excretion failed to differentiate response from nonresponse to placebo. By contrast, phenelzine responders excreted significantly less tyramine sulfate than did phenelzine nonresponders, while there was a trend in the same direction for imipramine-treated patients. The presence of only eight phenelzine nonresponders dictates caution in interpreting these results. Baseline monoamine oxidase (MAO) activity did not distinguish responders from nonresponders or correlate with tyramine sulfate excretion. Although males had significantly lower MAO activity than females, controlling for sex did not alter these negative findings. These results fail to confirm a previous report of a significant correlation between MAO activity and treatment response in older, mainly melancholic patients.     

Some peculiar aspects of monoamine oxidase inhibition

CN- ions enhance the inhibition of monoamine oxidase by the hydrazine derivatives, phenelzine [2-phenylethylhydrazine] and pheniprazine [(1-methyl-2-phenylethyl)hydrazine]. This involves partial competitive activation of the initial noncovalent enzyme-inhibitor complex with no significant effect on the subsequent reaction to give the irreversibly inhibited species. Whereas the maximum effects on pheniprazine inhibition of rat liver MAO-B occurred at about 5 microM cyanide, concentrations of 5 mM were necessary for maximum stimulation of MAO-A inhibition. A comparison of the behaviour of rat and ox MAO revealed considerable differences in their sensitivities to pheniprazine and the potentiating effects of cyanide. Species differences were also evident in the interactions derivatives of milacemide [2-n-pentylaminoacetamide] as substrates and mechanism-based inhibitors of MAO-B. In one case there was evidence for apparently large difference in inhibitor sensitivities between human brain MAO-B from different individuals.     

Selective inhibition of MAO-A but not MAO-B activity increases rat pineal melatonin

Summary Clorgyline, a selective MAO-A inhibitor, increased (5 times) rat pineal melatonin and N-acetyl-serotonin (NAS) content, and decreased 5-HIAA level by 80%. Deprenyl, a selective MAO-B inhibitor, did not change melatonin or other pineal indoles content. The data obtained show that inhibition of MAO-A but not B enzyme is responsible for pineal melatonin increase caused by MAO inhibitors.It is suggested that the stimulation of melatonin synthesis caused by MAO inhibitors may contribute to their antidepressive effect.     

Pretreatment dexamethasone suppression test as a predictor of response to phenelzine

Twenty inpatients who met Research Diagnostic Criteria and DSM-III criteria for depression underwent a 2-week washout period before the administration of a pretreatment dexamethasone suppression test (DST); the patients then received the monoamine oxidase inhibitor (MAOI) phenelzine. The mean MAO inhibition level achieved during treatment was greater than 80%. On the basis of clinical global evaluation and changes in Hamilton Rating Scale for Depression scores, 7 of the 9 baseline DST suppressors were classified as responders, 1 as a partial responder, and 1 as a nonresponder; of the 11 baseline DST nonsuppressors, 3 were responders, 1 a partial responder, and 7 nonresponders. The Mann-Whitney U test yielded p less than .02, indicating that an abnormally high pretreatment level of cortisol in response to the DST appeared to be predictive of nonresponse to phenelzine.     

The amine oxidase inhibitor phenelzine limits lipogenesis in adipocytes without inhibiting insulin action on glucose uptake

The antidepressant phenelzine is a monoamine oxidase inhibitor known to inhibit various other enzymes, among them semicarbazide-sensitive amine oxidase (currently named primary amine oxidase: SSAO/PrAO), absent from neurones but abundant in adipocytes. It has been reported that phenelzine inhibits adipocyte differentiation of cultured preadipocytes. To further explore the involved mechanisms, our aim was to study in vitro the acute effects of phenelzine on de novo lipogenesis in mature fat cells. Therefore, glucose uptake and incorporation into lipid were measured in mouse adipocytes in response to phenelzine, other hydrazine-based SSAO/PrAO-inhibitors, and reference agents. None of the inhibitors was able to impair the sevenfold activation of 2-deoxyglucose uptake induced by insulin. Phenelzine did not hamper the effect of lower doses of insulin. However, insulin-stimulated glucose incorporation into lipids was dose-dependently inhibited by phenelzine and pentamidine, but not by semicarbazide or BTT2052. In contrast, all these SSAO/PrAO inhibitors abolished the transport and lipogenesis stimulation induced by benzylamine. These data indicate that phenelzine does not inhibit glucose transport, the first step of lipogenesis, but inhibits at 100 μM the intracellular triacylglycerol assembly, consistently with its long-term anti-adipogenic effect and such rapid action was not found with all the hydrazine derivatives tested. Therefore, the alterations of body weight control consecutive to the use of this antidepressant drug might be not only related to central effects on food intake/energy expenditure, but could also depend on its direct action in adipocytes. Nonetheless, phenelzine antilipogenic action is not merely dependent on SSAO/PrAO inhibition.