MAO Inhibitor Anti-Depressants

The monoamine oxidase inhibitor medications is another group of older but quite effective anti-depressant medications which has become largely forgotten. They work quite differently from other anti-depressants, which means that an MAO inhibitor might work when others are not. The medicines block the enzyme, monoamine oxidase, that breaks down monoamine, such as serotonin and norepinephrine.

The biggest concern with these medications is that you have to avoid certain foods that are high in tyramine, another monoamine. On occasion, if these foods are eaten, they will cause a sudden rise in blood pressure and a throbbing headache. There is also the fear that if the blood pressure remains high, it may cause a blood vessel to burst and a stroke. This side-effect is fairly easily prevented by avoiding specific foods including aged cheese and red wine. Patients may also carry a tablet of a blood pressure medication, nifedipine, which can very quickly bring the blood pressure back down if a high tyramine food was consumed by accident. With these precautions, these are very safe medications.

Research is currently being done on a selegiline patch which is said to have few side-effects. Since selegiline itself has a fair number of side-effects, it is hard to believe that the patch will be that much different. The most popular MAO inhibitor has been phenelzine (Nardil) which unfortunately causes frequent weight gain. However, another MAO inhibitor, isocarboxazid (Marplan), actually causes a little weight loss. Thus, isocarboxazid might be the preferred medication for most patients needing an MAO inhibitor, at least until the patch is available. Some research suggests that MAO inhibitors work better than other anti-depressants for "atypical" depression. In atypical depression, the patient has increased sleep, increased appetite, and irritability. MAO inhibitors can not be taken within several weeks of taking an SSRI medication or several other anti-depressants.

MAO Inhibitors Do Well for Atypical Depression: In a meta-analysis of 8 studies using MAO inhibitors, placebos, and other anti-depressants for atypical depression, a significant effect size of 0.45 for a comparison of MAOIs vs. placebo with an insignificant effect size of 0.02 for MAOIs vs. selective serotonin reuptake inhibitors. There was a significant effect size for MAOIs vs. tricyclic antidepressants was 0.27. Treatment of depression with atypical features: A meta-analytic approach. Henkel V, et al. Ludwig-Maximilians-University Munich, Germany. Psychiatric Res 2005 Nov 28.

Bipolar: Tranylcypromine Recommended for Resistant Depression: "Bipolar I depressions should initially be treated with a mood stabilizer (carbamazapine, divalproex, lamotrigine, lithium, or an atypical antipsychotic); antidepressant monotherapy is contraindicated. More severe or "breakthrough" episodes often require a concomitant antidepressant, such as bupropion or a selective serotonin reuptake inhibitor (SSRI). For refractory depressive episodes, venlafaxine, the monoamine oxidase inhibitor tranylcypromine, and ECT are most widely recommended." Bipolar depression: issues in diagnosis and treatment. Thase ME. University of Pittsburgh Medical Center. . Harvard Rev Psychiatry 2005 Sep-Oct;13(5):257-71.

Toxicity with Venlafaxine, SSRI, MAOI Switch: With venlafaxine, Lancet 1995 Nov 11;346(8985):1298-9. Serotonin syndrome with SSRI: J Clin Psychopharmacol 1994 Apr;14(2):144-5; Toxicity has occurred when abruptly switching from one MAOI to another, even with subtherapeutic doses. Therefore, maybe allow washout. Also sensitivity to one MAOI suggests sensitivity to others. Ann Pharmacother 1992 Mar;26(3):337-8. Case of death with sudden switch one MAOI to another. Drug Intell Clin Pharm 1986 Dec;20(12):954-6

Withdrawal Mania: 2 cases with mania on stopping an MAOI. J Clin Psychopharmacol 1985 Dec;5(6):340-2

Nifedipine for Hypertensive Crisis, Fludrocortisone for Hypotension: Two cases are reported of hypertensive crisis, occurring during monoamine oxidase inhibitor treatment, that successfully responded to sublingual nifedipine 10 mg. Decreases BP in 5 minutes and last 3-5 hours. For patients with BP 200/120, mean reduction was 47/34 mmHg. Pt chews the tab prior to placing it under tongue. S. Clary, U Penn, J Clin Psychiatry 1987 Jun;48(6):249-50; When non-pharmacological interventions fail to alleviate MAOI induced postural hypotension, the use of volume expanders (salt tablets or fludrocortisone) may be effective alternatives to drug discontinuation. For MAOI hypertensive emergencies, use nifedipine, diazoxide, or sodium nitroprusside. Can J Psychiatry 1987 Dec;32(9):803-8

Weight Gain and Excess Sleep Patients Do Well: In DB PC study, patients with weight gain, increased appetite, and increased sleep responded particularly well, with a rapid onset of improvement that was apparent by one week. J Affect Disord 1983 May;5(2):183-9

Atypical Depression MAOI > Imipramine: DB MAOI patients with reactive moods: able to be cheered up, eat and sleep more when depressed, feel better in AM, marked tiredness, sensitive torejection. For lack of sex orgasms due to meds, try leave off meds for day of sex or lower dose. Gets better with time. Quitkin, Columbia.

Isocarboxazid 50mg/d Works Better: In non-melancholic depressions, 50 mg proved to be more effective than 30 mg in symptoms of depression and anxiety. No increase in toxicity. J Clin Psychiatry 1984 Jul;45(7 Pt 2):49-52. The most frequently of isocarboxazid noted side effects were dizziness, headache, dry mouth, insomnia, and constipation.

Isocarboxazid with Amitriptyline for Refractory: 25 patients cautiously tried on combo. 12 responded. Over 3 years, attempted to d/c amitriptyline Q 6 months. Six needed combo, 2 relapsed, 4 OK with monotherapy. Mexico. J Affect Disord 1995 Jun 8;34(3):187-92; 3 cases mania from same combo. J Clin Psychiatry 1986 Jan;47(1):40-1

MAOI-Tricyclic Combo Safe: 150 inpatients and 51 outpatients treated with a monoamine oxidase inhibitor (MAOI)-tricyclic antidepressant combination were reviewed. The incidence and severity of side effects among the patients on the combined regimen were essentially the same as those seen in the control groups. There were no deaths or strokes resulting from use of this regimen. The most frequent troublesome side effect was orthostatic hypotension. Arch Gen Psychiatry 1976 Jul;33(7):828-30

Trimipramine Superior to MAOI or Combo: The tricyclic antidepressant was found to be consistently superior to the MAOIs and the combined treatments of phenelzine + the tricyclic or isocarboxazid plus the tricyclic. 135 pt DB. 6 weeks. Br Med J 1979 Nov 24;2(6201):1315-7

Metaanalyses: of FDA-approved trials MAOIs with both placebo and tricyclic antidepressants. For outpatients, drug-placebo differences were 29.5% (phenelzine; nine studies), 41.3% (isocarboxazid; three studies), and 22.1% (tranylcypromine; three studies). For inpatients, phenelzine was 22.3% (five studies) more effective than placebo, whereas the isocarboxazid-placebo difference was lower (15.3%). Both phenelzine and isocarboxazid were significantly less effective than tricyclics for inpatients, whereas tranylcypromine has not been adequately studied. Both phenelzine and tranylcypromine appear to be more effective than tricyclics in depressed outpatients with atypical features. Monoamine oxidase inhibitors are also effective treatments for outpatients who have failed to respond to tricyclic antidepressants. Thase, U Pitt, Neuropsychopharmacology 1995 May;12(3):185-219

Similar to Clomipramine, Moclobemide in DB: 167 outpatients were allocated to daily treatment with 300 mg moclobemide, 30 mg isocarboxazide or 150 mg clomipramine for 6 weeks. Moclobemide was slightly inferior to clomipramine, whereas isocarboxazide had an intermediate position. There was no interaction between treatment and atypical or nonatypical depression. Anticholinergic symptoms and orthostatic hypotension were most pronounced in the clomipramine group. Larsen, Denmark, Acta Psychiatr Scand 1991 Dec;84(6):564-70

Selegiline Modest Benefit in DB: 289 MDD adult rx patch 20mg/d or placebo x 8 weeks in 16 sites. A double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal system without dietary restrictions in patients with major depressive disorder. Amsterdam JD.

Selegiline Patch Helped Major Depression Somewhat: A six week PC DB study of 177 patients without bipolar, substance abuse, or failures on more than one anti-depressant found that by six weeks 42% selegiline vs. 27% placebo were much improved and had 36% vs. 23% decreases in depression scores (HAM-D and MADRS). Funded by Somerset Drugs. Bodkin J, Amsterdam J. Transdermal selegiline in major depression: a double-blind, placebo-controlled parallel-group study in outpatients. Am J Psychiatry 2002;159:1869-75. McLean Hosp & U Penn.

No Atypical Symptom Response Pattern Found: DB PC 130 out-pt. UNC, Eur Arch Psychiatry Clin Neurosci 1991;241(3):181-6

Reactions with: Dextromethorphan. N Engl J Med 1988 Dec 22;319(25):1671;

Serotonergic Syndrome with SSRIs or Opiates: The serotonin syndrome is an intra-synaptic serotonin concentration-related phenomenon with clonus, hyper-reflexia, hyperthermia and agitation. Combinations of serotonergic drugs acting by different mechanisms can raise intra-synaptic serotonin to a level that is life threatening, especially an MAOI with any SRI. There are a number of lesser-known drugs that are MAOIs, such as linezolid and moclobemide; and some opioid analgesics have serotonergic activity. Treat with 5-HT(2A) antagonists for severe cases. The phenylpiperidine series opioids, meperidine, tramadol, methadone and dextromethorphan and propoxyphene, appear to be weak serotonin re-uptake inhibitors and have all been involved in serotonin toxicity reactions with MAOIs (including some fatalities). Morphine, codeine, oxycodone and buprenorphine are known not to be SRIs, and do not precipitate serotonin toxicity with MAOIs. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Gillman, PK. Australia. . Br J Anesth 2005 Oct;95(4):434-41.

Less Sleep with Isocarboxazid: Daytime sleepiness less common than with phenelzine or tranylcypromine. Am J Psychiatry 1988 Dec;145(12):1552-6; Wt gain more common with phenelzine. Drug Intell Clin Pharm 1988 Oct;22(10):755-9

Lowers Systolic BP Considerably: Systolic blood pressure lowered by isocarboxazid in DB PC. The magnitude was considerable, an average of 14.6 mm in inpatients who received a 50-mg dose, and 18.7 mm in outpatients. There was no evidence for a dose-related orthostatic effect, and greater orthostasis relative to placebo was found only at week 3 in the outpatient study. Significant bradycardia was produced by isocarboxazid in outpatients at weeks 2, 3, and 4 relative to placebo, but no dose-related effect was found among inpatients. Inpatients with a baseline systolic orthostatic drop of greater than or equal to 10 mm showed a significantly better response. J Clin Psychopharmacol 1986 Jun;6(3):139-43

Salt 1-2 g/d for Postural Hypotension: 3 patients rx 0.5-1g salt BID relieved postural dizziness. Two had some bloating and edema. Able d/c after 3 months. Not for pt with HBP or CHF. Kranzler, J Clin Psyc 88;49:366

Phenelzine 60 mg Effective: 30 mg little benefit. but 60mg helps 70% depressed. If no response in 6 weeks, increased to 75-90mg/d for fast acetylators. Lewis Ravaris, U Vermont.

Phenelzine Did as Well as Tranylcypromine: In a 5-week DB PC study of 77 severely Major Depression in-patients, who failed on either tricyclic antidepressants or fluvoxamine found no significant differences between tranylcypromine and phenelzine: 44% responded on tranylcypromine vs. 47% on phenelzine. The mean reduction in HAM-D score was 10.4 for tranylcypromine versus 8.3 for phenelzine. Only 10% used concomitant psychotropic medication. Severe side effects, mainly dizziness, agitation, and insomnia, were the same in both samples (21%). Efficacy and tolerability of tranylcypromine versus phenelzine: a double-blind study in antidepressant-refractory depressed inpatients. Birkenhager TK, et al. Erasmus Medical Centre, Rotterdam, The Netherlands. . J Clin Psychiatry 2004 Nov;65(11):1505-10. Ed: I prefer tranylcypromine due to greater weight gain on phenelzine.

Stimulants OK with MAOIs: No documented reports were found in the recent literature of hypertensive crises or fatalities occurring when the stimulant was cautiously added to the MAOI. Feinberg SS, Albert Einstein. J Clin Psychiatr 2004 Nov;65(11):1520-4.

Subarachnoid Hemorrhage: One Case in 35 Years: Hypertensive crises occur in less than 1%. The authors report an individual with a recent increase in MAOI dosage taking the medicine close to meal time and using a half tablespoon of soy sauce as probably causing the first case of subarachnoid hemorrhage reported in the last 35 years. The patient recovered, apparently fully. Can J Psychiatry 2004 Aug;49(8):573-4. Hay fever and cold remedies have caused hypertensive crises, but spontaneous ones have also occurred.

Antihypertensives Make Tranylcypromine Safer: The authors present uncontrolled evidence that giving MAOI patients anti-hypertensives may help avert hypertensive crises. Do antihypertensives make tranylcypromine safer? Three case reports. Taylor BP, et al. J Clin Psychiatry 2005 May;66(5):657-8.

Modafinil: Used with MAOI: Despite modafinil being listed as contraindicated on theoretical grounds, the researchers report using the combination with no problems. Concomitant use of modafinil and tranylcypromine in a patient with narcolepsy: a case report. Clemons WE, et al. University of Michigan. J Clin Psychiatry 2004 Sep;5(5):509-11.

Bupropion-tranylcypromine Combination for Treatment-refractory Depression: Despite the combination being contraindicated on theoretic grounds, the authors report is to be successful for refractory depression. Pierre JM, et al. J Clin Psychiatry 2000 Jun;61(6):450-1.

Nortriptyline Used with Phenelzine: No cases of adverse interactions from the combination of nortriptyline with either phenelzine or tranylcypromine were found on PubMed.  In fact, one study gave the combination of nortriptyline with phenylzine to 17 patients in a study comparing the combination to ECT. Arch Gen Psychiatry 1978 May;35(5):639-42.

Tranylcypromine Abuse Associated with Delirium and Thrombocytopenia. Single case report. Davids E, et al. J Clin Psychopharm 2000 Apr;20(2):270-1.

Stroke resulting from a Rapid Switch from Phenelzine to Tranylcypromine. Single case report. Mattes J. J Clin Psychiatry 1998 Jul;59(7):382.

Switch MAOIs Less Than 14 Days Done Cautiously With Minor Difficulty: Report of 8 in-patient cases. Only one had a minor problem, either minor serotonergic syndrome or tranylcypromine withdrawal. Rapid conversion from one monoamine oxidase inhibitor to another. Szuba MP, et al. University of Pennsylvania. J Clin Psychiatry 1997 Jul;58(7):307-10.

Successful treatment of Serotonin Syndrome with Chlorpromazine: Gillman PK. Med J Aust 1996 Sep 16;165(6):345-6.

Cases of severe reactions have occurred with single doses of venlafaxine or imipramine added to a patient already on an MAOI. No reactions have been reported on adding an MAOI to a patient on a low dose of venlafaxine or imipramine, although these combinations are contraindicated on theoretic grounds.

Anti-depressants increase the growth of new brain cells in the hypocampus and protect brain cells from cell death.