Drug Interactions between amitriptyline / perphenazine and selegiline

CONTRAINDICATED: Coadministration of monoamine oxidase inhibitors (MAOIs) and dibenzazepine derivatives (e.g., tricyclic and tetracyclic antidepressants, cyclobenzaprine, carbamazepine) may produce significant adverse reactions including nausea, vomiting, flushing, dizziness, tremor, myoclonus, rigidity, diaphoresis, hyperthermia, autonomic instability, hypertensive crises, disseminated intravascular coagulation, severe convulsive seizures, coma, and death. The exact mechanism of interaction is unknown, but may involve excessive serotonergic activity in the central nervous system (i.e., serotonin syndrome). Clinically, the interaction has been reported primarily in patients treated with MAOIs (including reversible, irreversible, selective, and nonselective) and tricyclic antidepressants, especially imipramine and clomipramine, which are the most potent serotonin reuptake inhibitors of the class. Other dibenzazepine-type drugs may also interact based on their structural and pharmacologic similarities to the tricyclic antidepressants, although data are limited. An isolated case has been reported for phenelzine and cyclobenzaprine, while no cases have been reported with carbamazepine. On the contrary, there have been published reports citing a lack of interaction as well as successful use of carbamazepine with MAOIs.

MANAGEMENT: In general, dibenzazepine derivatives should not be used concurrently with MAOIs or other agents that possess MAOI activity (e.g., furazolidone, methylene blue, procarbazine). At least 14 days should elapse between discontinuation of MAOI therapy and initiation of treatment with tricyclic antidepressants, and vice versa. Although it remains controversial, some experts have suggested that certain MAOIs and tricyclic antidepressants (except imipramine and clomipramine) may be used together for the treatment of refractory depression under special circumstances and close supervision, with the following empirical guidelines: the current tricyclic or MAOI should be discontinued for 10 to 14 days; both drugs should then be started at low dosages; the drugs should not be administered parenterally; dose changes should be made in small increments; serotonin reuptake inhibitors must not be used concurrently; and patients should be closely monitored for signs of adverse serotonergic effects.

MONITOR: Coadministration of a phenothiazine with a tricyclic antidepressant (TCA) may result in elevated plasma concentrations of one or both drugs as well as additive adverse effects. Most phenothiazines and TCAs have been found to undergo metabolism by CYP450 2D6, thus competitive inhibition of the enzyme may occur when more than one of these agents are administered. Although these drugs have been used together clinically, the possibility of increased risk of serious adverse effects such as central nervous system depression, tardive dyskinesia, hypotension, and prolongation of the QT interval should be considered, as many of these agents alone can and have produced these effects. In addition, excessive anticholinergic effects may occur in combination use, which can result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of anticholinergic intoxication commonly include mydriasis, blurred vision, flushed face, fever, dry skin and mucous membranes, tachycardia, urinary retention, and constipation. Central symptoms may include memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching or jerking movements, stereotypy, and seizures.

MANAGEMENT: Concurrent use of phenothiazines and TCAs should be approached with caution, particularly in the elderly and those with underlying organic brain disease, who tend to be more sensitive to the central anticholinergic effects of these drugs and in whom toxicity symptoms may be easily overlooked. Patients should be advised to notify their physician promptly if they experience potential symptoms of anticholinergic intoxication (e.g., abdominal pain, fever, heat intolerance, blurred vision, confusion, hallucinations) or cardiovascular toxicity (e.g., dizziness, palpitations, arrhythmias, syncope). Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A dosage reduction in one or both drugs may be necessary if excessive adverse effects develop.

MONITOR: Coadministration of monoamine oxidase inhibitors (MAOIs) and phenothiazines may result in additive hypotensive effects and central nervous system effects such as dizziness, drowsiness, confusion, disorientation, memory loss, and seizures. MAOIs alone quite commonly produce orthostatic hypotension. This effect may stem from a gradual MAOI-induced accumulation of false neurotransmitters in peripheral adrenergic neurons that have minimal activity at alpha- and beta-adrenergic receptors, resulting in a functional block of sympathetic neurotransmission. Phenothiazines can also cause hypotension (including orthostatic hypotension), reflex tachycardia, increased pulse rate, syncope, and dizziness, particularly during initiation of treatment with parenteral doses. Low-potency agents such as chlorpromazine and thioridazine are more likely to induce these effects, which usually subside within the first couple of hours following administration. Tolerance to the hypotensive effects often develops after a few doses.

MONITOR: An increased incidence of extrapyramidal effects has been reported when some MAOIs and phenothiazines are used concomitantly. Data are limited, and the mechanism of interaction has not been established. There have also been rare reports of suspected neuroleptic malignant syndrome (NMS) in patients treated with irreversible, nonselective MAOIs and certain phenothiazines, although the role of MAOIs is uncertain. Since NMS is thought to be triggered by a sudden decrease of activity at central dopamine receptors, neuroleptics such as phenothiazines alone can cause the syndrome. In one report, a 70-year-old female inpatient of a psychiatric ward developed dyspnea, tachycardia, diffuse muscular rigidity, pyrexia, hypotension, cyanosis, hyperreflexia, coma, and a grand mal seizure while being treated with isocarboxazid and chlorpromazine. Laboratory findings included a mild neutrophil leucocytosis and elevated serum potassium and creatine phosphokinase. The patient improved within 24 hours after discontinuation of psychotropic medications and initiation of supportive measures and anticonvulsants, but she subsequently died from acute renal failure secondary to rhabdomyolysis. Another patient developed symptoms of NMS one week after initiating treatment with a tranylcypromine-trifluoperazine combination, immediately after the dose was doubled. The case was complicated by rhabdomyolysis and disseminated intravascular coagulation, but was treated successfully with dantrolene sodium and generous fluid therapy. In other reports, rare cases of fatal hyperthermia occurred during treatment with methotrimeprazine and pargyline or tranylcypromine. Again, the relationship to MAOIs is unknown, since phenothiazines alone have been associated with hyperpyrexia.

MANAGEMENT: Although often safe and effective, caution is advised during coadministration of MAOIs and phenothiazines, especially during the first few weeks of treatment. Close monitoring for development of hypotension is recommended. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Ambulatory patients should also be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities. Alcohol should be avoided, since it may increase hypotensive and CNS effects.