If It Doesn’t Work

• Many patients have only a partial response where some symptoms are improved but others persist (especially insomnia, fatigue, and problems concentrating)

• Other patients may be nonresponders, sometimes called treatment-resistant or treatment-refractory

• Consider increasing dose, switching to another agent, or adding an appropriate augmenting agent

• Consider psychotherapy

• Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

• Some patients may experience apparent lack of consistent efficacy due to activation of latent or underlying bipolar disorder, and require antidepressant discontinuation and a switch to a mood stabilizer

Best Augmenting Combos for Partial Response or Treatment Resistance

✽ Augmentation of MAOIs has not been systematically studied, and this is something for the expert, to be done with caution and with careful monitoring, but may be somewhat less risky with moclobemide than with other MAO inhibitors

✽ A stimulant such as d-amphetamine or methylphenidate (with caution; may activate bipolar disorder and suicidal ideation)

• Lithium

• Mood-stabilizing anticonvulsants

• Atypical antipsychotics (with special caution for those agents with monoamine reuptake blocking properties, such as ziprasidone and zotepine)

Tests

• Patients should be monitored for changes in blood pressure

Moclobemide: side effects How Drug Causes Side Effects

• Theoretically due to increases in monoamines in parts of the brain and body and at receptors other than those that cause therapeutic actions (e.g., unwanted actions of serotonin in sleep centers causing insomnia, unwanted actions of norepinephrine on vascular smooth muscle causing changes in blood pressure)

• Side effects are generally immediate, but immediate side effects often disappear in time

Notable Side Effects

• Insomnia, dizziness, agitation, anxiety, restlessness

• Dry mouth, diarrhea, constipation, nausea, vomiting

• Galactorrhea

• Rare hypertension

Life-Threatening or Dangerous Side Effects

• Hypertensive crisis (especially when MAOIs are used with certain tyramine containing foods – reduced risk compared to irreversible MAOIs)

• Induction of mania

• Rare activation of suicidal ideation and behavior (suicidality) (short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo beyond age 24)

• Seizures

Weight Gain

• Reported but not expected

Sedation

• Occurs in significant minority

What to Do About Side Effects

• Wait

• Wait

• Wait

• Lower the dose

• Switch to an SSRI or newer antidepressant

Best Augmenting Agents for Side Effects

• Trazodone (with caution) for insomnia

• Benzodiazepines for insomnia

✽ Single oral or sublingual dose of a calcium channel blocker (e.g., nifedipine) for urgent treatment of hypertension due to drug interaction or dietary tyramine

• Many side effects cannot be improved with an augmenting agent

MOCLOBEMIDE: DOSING AND USE

Usual Dosage Range

• 300–600 mg/day

Dosage Forms

• Tablet 100 mg scored, 150 mg scored

How to Dose

• Initial 300 mg/day in 3 divided doses after a meal; increase dose gradually; maximum dose generally 600 mg/day; minimum dose generally 150 mg/day

Dosing Tips

✽ At higher doses, moclobemide also inhibits MAO-B and thereby loses its selectivity for MAO-A, with uncertain clinical consequences

✽ Taking moclobemide after meals as opposed to before may minimize the chances of interactions with tyramine

• May be less toxic in overdose than tricyclic antidepressants and older MAOIs

• Clinical duration of action may be longer than biological half-life and allow twice daily dosing in some patients, or even once daily dosing, especially at lower doses

Overdose

• Agitation, aggression, behavioral disturbances, gastrointestinal irritation

Long-Term Use

• MAOIs may lose efficacy long-term

Habit Forming

• Some patients have developed dependence to MAOIs

How to Stop

• Taper not generally necessary

Pharmacokinetics

• Partially metabolized by CYP450 2C19 and 2D6

• Inactive metabolites

• Elimination half-life approximately 1–4 hours

• Clinical duration of action at least 24 hours

Drug Interactions

• Tramadol may increase the risk of seizures in patients taking an MAO inhibitor

• Can cause a fatal “serotonin syndrome” when combined with drugs that block serotonin reuptake, so do not use with a serotonin reuptake inhibitor or for 5 half-lives after stopping the serotonin reuptake inhibitor (see Table 1 after Pearls)

• Hypertensive crisis with headache, intracranial bleeding, and death may result from combining MAO inhibitors with sympathomimetic drugs (e.g., amphetamines, methylphenidate, cocaine, dopamine, epinephrine, norepinephrine, and related compounds methyldopa, levodopa, L-tryptophan, L-tyrosine, and phenylalanine)

• Do not combine with another MAO inhibitor, alcohol, or guanethidine

• Adverse drug reactions can result from combining MAO inhibitors with tricyclic/tetracyclic antidepressants and related compounds, including carbamazepine, cyclobenzaprine, and mirtazapine, and should be avoided except by experts to treat difficult cases

• MAO inhibitors in combination with spinal anesthesia may cause combined hypotensive effects

• Combination of MAOIs and CNS depressants may enhance sedation and hypotension

• Cimetidine may increase plasma concentrations of moclobemide

• Moclobemide may enhance the effects of nonsteroidal anti-inflammatory drugs such as ibuprofen

• Risk of hypertensive crisis may be increased if moclobemide is used concurrently with levodopa or other dopaminergic agents