Side effects MAOIs

As of the mid-1990s, use of MAOIs for the treatment of depression is severely restricted because of potential side effects, the most serious of which is hypertensive crisis, which results primarily from the presence of dietary tyramine. Tyramine, a naturally occurring amine present in cheese, beer, wine, and other foods, is an indirecdy acting sympathomimetic, that is, it potently causes the release of norepinephrine from sympathetic neurons. The norepinephrine that is released interacts with adrenoceptors and, by interacting with a-adrenoceptors, causes a marked increase in blood pressure the resultant hypertension may be so severe as to cause death. 

Normally, dietary tyramine is broken down in the gastrointestinal tract by MAO and is not absorbed. In the presence of MAOI, however, all of its potent sympathomimetic actions are seen. Other side effects of MAOI include excessive CNS stimulation, orthostatic hypotension, weight gain, and in rare cases hepatotoxicity. Because the monoamine oxidase inhibitors exhibit greater toxicity, yet no greater therapeutic response than other, newer agents, clinical use has been markedly curtailed. The primary use for MAOIs is in the treatment of atypical depressions, eg, those associated with increased appetite, phobic anxiety, hypersomnolence, and fatigues, but not melancholia (2). 

Buspirone generally is well tolerated and does not cause sedation. Most common side effects include dizziness, nausea, and headaches. Drugs that inhibit CYP3A4 (e.g., verapamil, diltiazem, itraconazole, fluvoxamine, nefa-zodone, and erythromycin) can increase buspirone levels. Likewise, enzyme inducers such as rifampin can reduce buspirone levels significantly. Bupirone may increase blood pressure when coadministered with an monoamine oxidase inhibitor (MAOI). 

MAO Is have not been evaluated systematically for treatment of PD under the current diagnostic classification and generally are reserved for patients who are refractory to other treatments.48,49 MAOIs have significant side effects that limit adherence. Additionally, patients must adhere to dietary restriction of tyramine and avoid sympathomimetic drugs to avoid hypertensive crisis. 

In addition to this serious diet-drug interaction, irreversible MAOIs also potentiate the effects of sympathomimetic drugs like ephedrine found in over-the-counter cold remedies and recreational stimulants like amphetamine. The MAOIs also interact with drugs that increase synaptic concentrations of 5-HT, such as the tricyclic antidepressant clomipramine and the herbal SSRI antidepressant St John s wort (Hypericum spp.). The resulting serotonin syndrome is characterised by hyperthermia and muscle rigidity. While devoid of these side effects the reversible MAO-A inhibitor moclobemide has yet to establish itself as a first-line alternative to the SSRIs. 

MAOIs are reserved for the most difficult or refractory panic disorder patients. Side effects and dietary and drug restrictions affect patient acceptance (see Chap. 70 for food and drug restrictions). Fluoxetine must be stopped 5 weeks before phenelzine (or another MAOI) is started. Other antidepressants should be stopped 2 weeks before phenelzine is started. 

The SSRIs are first-line pharmacotherapy for PTSD. Venlafaxine, the TCAs, and MAOIs may also be effective, but they have less favorable side-effect profiles. 

In the United States, there are presently three approved MAOis phenelzine (Nardil), tranylcypromine (Parnate), and isocarboxizide (Marplan). These medications are all nonselective, irreversible inhibitors of the MAO enzymes. By nonselec-tive, it is meant that they block the actions of both the MAO-A and MAO-B enzyme subtypes. It is felt that blocking the MAO-B enzyme adds little to the effectiveness of these antidepressants but causes many of the problematic side effects. The MAOis are irreversible in that they deactivate the enzyme permanently. 

The common side effects of MAOis include dizziness from orthostatic hypotension, drowsiness, insomnia, palpitations, rapid pulse, and sexual dysfunction. In addition, phenelzine appears to cause weight gain and fluid retention. 

Like the MAOIs, TCAs are hindered by a delayed onset of action that can be especially intolerable for those with frequent and severe panic attacks. When starting treatment, TCAs, like SSRIs, may also produce a transient nervousness that is especially uncomfortable for those with panic disorder. When this occurs, the starting dose should be reduced by half, and the pace of subsequent dose increases should be even slower than usual. Because they produce prominent side effects and can be dangerous in overdose, TCAs are also now reserved for patients unresponsive to other treatments. Refer to Chapter 3 for a more extensive discussion of the TCAs. 

Buspirone does not share any of the problematic benzodiazepine properties such as sedation, motor impairment, addiction, physical dependence, or withdrawal. The most common side effects of buspirone include dizziness, nausea, headache, fatigue, and dry mouth. Despite its activity in the serotonin system, buspirone is not associated with the sexual side effects that plague the SSRIs, SNRIs, MAOIs, and TCAs. 

The side effects of the MAOIs include, somewhat surprisingly, orthostatic h)rpotension. This is thought to be due to the accumulation of dopamine in the sympathetic cervical ganglia where it acts as an inhibitory transmitter. 

Excessive central stimulation, usually exhibited as tremors, insomnia and hyperhidrosis, can occur following therapeutic doses of the MAOIs, as can agitation and hypomanic episodes. Peripheral neuropathy, which is largely restricted to the hydrazine type of MAOI, is rare and has been attributed to a drug-induced p)n idoxine deficiency. Such side effects as dizziness and vertigo (presumably associated with hypotension), headache, inhibition of ejaculation (which is often also a problem with the TCAs), fatigue, dry mouth and constipation have also been reported. These side effects appear to be more frequently associated with phenelzine use. They are not associated with any antimuscarinic properties of the drug but presumably arise from the enhanced peripheral sympathetic activity which the MAOIs... 

Hypomania Hypomania has been the most common severe psychiatric side effect reported. This has been largely limited to patients in whom disorders characterized by hyperkinetic symptoms coexist with, but are obscured by, depressive affect. Diabetes There is conflicting evidence as to whether MAOIs affect glucose metabolism or potentiate hypoglycemic agents. Consider this if used in diabetics. Epilepsy The effect of MAOIs on the convulsive threshold may vary. Do not use with metrizamide discontinue MAOl 48 hours or more prior to myelography and resume 24 hours postprocedure. 

Drugs that may increase the effects or side effects of bupropion include levodopa, MAOIs, ritonavir, antidepressants, antipsychotics, beta blockers, type 1C antiarrhythmics. 

MAOI/RIMA Panic disorder Social anxiety disorder PTSD Significant short- and long-term side-effects special dietary requirements moclobemide better tolerated Significant overdose toxicity (less with moclobemide) Reported... 

Answer Because of sertraline s favorable side effect profile and no need for dietary restrictions, it probably should be chosen over the older agents (TCAs and MAOIs). She should be warned about nausea and possibly loose stools, anorgasmia, and insomnia before she begins therapy. It also should be explained that the medication will take at least 2 weeks to begin working and that a complete trial of the medication to assess its efficacy will take 4 to 6 weeks. Since this is her first episode of depression, she should take the medication for 6 to 12 months after her symptoms have remitted before considering discontinuation of drug therapy. 

The inhibition of MAO enzymes increases the concentrations of these neurotransmit-ters at storage sites throughout the CNS. Side effects of MAOIs include hypotensive effects from the inhibition of central vasomotor centers and cholinergic effects. 

Medications with serotonergic activity may also have other monaminergic or sympathomimetic activity. Combining MAOIs with these medications may result in a complex side effect profile. For example, combining meperidine or dextromethorphan with MAOIs may result in respiratory depression, in addition to symptoms of serotonin excess. Furthermore, interactions between MAOIs and tricyclic antidepressants (TCAs) more commonly result in potentiating shared adverse events such as othostatic hypotension, as opposed to hyperadrenergic crises or the serotonin syndrome. 

Although the MAOIs can have serious and potentially life-threatening adverse effects, it is the more common and less dramatic side effects that often lead to the discontinuation of MAOIs. These side effects include orthostatic hypotension, drowsiness, insomnia, edema, weight gain, sexual dysfunction, and precipitation of mania. Rare side effects include hepatitis and leukopenia. Parasthesias may develop secondary to a MAOI-induced pyridoxine deficiency, which responds to oral pyridoxine supplementation. Overall, phenelzine appears to be more sedating, whereas trancylpromine is more activating because of its stimulant-like properties. Meclobomide has more excitatory side effects, such as restlessness and insomnia. 

Two types of the MAO enzymes have been found. They are called MAO-A and MAO-B. MAO-A is found in norepinephrine and serotonin synapses, while MAO-B is found in dopamine synapses. Scientists believe that the therapeutic effects of MAOIs are a result of inhibiting MAO-A, while most of the side effects result from actions at MAO-B. The traditional, older MAOIs cannot select which MAO type they affect, so current studies are investigating drugs that might be more selective. 

New MAOI drugs are being developed that are both selective for MAO-B and reversible. The hope is that these drugs can be effective without causing the serious side effects associated with older MAOIs. Although research is promising, these new MAOIs have yet to be widely used in the treatment of anxiety disorders, possibly because of the overwhelming success of the SSRIs. 

The commonly used classes of antidepressants are discussed in the following sections, and information about doses and half-lives is summarized in Table 2-1. The antidepressant classes are based on similarity of receptor effects and side effects. All are effective against depression when administered in therapeutic doses. The choice of antidepressant medication is based on the patient s psychiatric symptoms, his or her history of treatment response, family members history of response, medication side-effect profiles, and comorbid disorders (Tables 2-2 and 2-3). In general, SSRIs and the other newer antidepressants are better tolerated and safer than TCAs and MAOIs, although many patients benefit from treatment with these older drugs. In the following sections, clinically relevant information is presented for the antidepressant medication classes individually, and the pharmacological treatment of depression is also discussed. The use of antidepressants to treat anxiety disorders is addressed in Chapter 3. 

The following side effects apply to the irreversible, nonselective MAOI antidepressants (phenelzine and tranylcypromine). The most common side effects are orthostatic hypotension, headache, insomnia, weight gain, sexual dysfunction, peripheral edema, and afternoon somnolence. Although MAOIs do not have significant affinity for muscarinic receptors, anticholinergic-like side effects are present at the beginning of treatment. Dry mouth is common but not as marked as in TCA therapy. Fortunately, the more serious side effects, such as hypertensive crisis and serotonin syndrome, are not common. 

The MAOIs cause significant hypotension, which is often the dose-limiting side effect of these drugs. Expansion of intravascular volume through administration of salt tablets or fludrocortisone may be an effective treatment. 

MAOIs are associated with a risk of significant weight gain during treatment. This side effect appears to occur less frequently with tranylcypromine therapy than with phenelzine treatment. 

MAOIs are commonly associated with treatment-emergent sexual dysfunction, including decreased libido, delayed ejaculation, anor-gasmia, and impotence. Some patients become tolerant to this side effect over time, but more often the problem persists unless the dose is reduced or another medication is used to counter the sexual side effects. The treatment of sexual side effects is discussed in the Selective Serotonin Reuptake Inhibitors section earlier in this chapter. 

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