Tranylcypromine

Addiction to Tranylcypromine (Parnate): A Case Report

ABSTRACT

The monoamine oxidase inhibitors are increasingly prescribed for several disorders today, after a hiatus of nonuse lasting a decade. One case of excessive MAOI use and two cases of MAOI withdrawal are reported in the literature. This case report adds a fourth instance and suggests patient characteristics which should alert the clinician to the risk of MAOI abuse or addiction.

INTRODUCTION

MAO inhibitors are increasingly important in the case of patients with several disorders, including major depression, panic disorder, obsessive-compulsive disorder, peptic ulcer disease, enuresis, chronic pain, migraine, bulimia, and attention deficit disorder[1-7].

Unlike most anxiolytic medications, antidepressant medications (including the monoamine inhibitors or MAOI) are generally presumed to be free of addictive potential. Thus, the development of increasing dosage, drug seeking, and withdrawal from tranylcypromine (Parnate) in the patient reported here were unexpected.

Originally used in the early 1960s, tranylcypromine and other MAOI's were taken off the American market for over a decade due to life-threatening hypertension and several cases of cerebrovascular accident[8]. MAOI's were reintroduced after a decade due to continued pressures by clinicians, who observed that some patients who had responded to MAOI's would not respond (or respond as well) to other antidepressants. Available now for several years, many clinicians have gradually employed tranylcypromine and other MAOI's when tricyclic or other antidepressants fail to alleviate severe, disabling, or life-threatening conditions.

CASE REPORT

A 34-year-old Caucasian married man was referred by his physician because of "taking more than prescribed amounts of Parnate." The patient lived in a rural area of northern Wisconsin where he had worked at various seasonal jobs; currently he was unemployed. Over the past 3 months he had increased his dose of Parnate from 20 to 120 mg daily, without the advice of his physician. This required that he manipulate prescriptions in order to obtain the greater-than-prescribed amounts of drugs. Two weeks prior to evaluation the patient had tried to discontinue tranylcypromine on his own. This had led to abdominal cramps, vomiting, diarrhea, irritability, fatigue, a "shakey feeling inside," trouble falling asleep and broken sleep, restlessness while awake, and trouble concentrating. A year previously he had been treated with the MAOI phenelezine (Nardil), 30 mg daily, but had increased his dose to 90 mg daily over a period of weeks without his physician's permission. At that time, tranylcypromine had also been prescribed at 40 mg daily, but was discontinued when the patient on his own increased his dose over a few weeks to 80 mg daily. Withdrawal symptoms to the MAOI's at that time were milder than those presently being experienced.

The patient had a history of chronic recurrent dysphoria going back to his late adolescence. Over the previous 8 years he had been unemployed; welfare and his wife's episodic work supported him and their two children. During this period he had increasing problems with multisystem somatic complaints, loss of libido, impotence, weight fluctuation, sleep disturbance, trouble concentrating, and problems with recent memory. He had been briefly hospitalized on psychiatric units twice, and there had been one suicide attempt. Five psychiatrists in Wisconsin and Minnesota had been him, assigning him several diagnoses including atypical depression, dysthymia, generalized anxiety, and adult residual of attention deficit disorder (although he had not been diagnosed as ADD during childhood). He had been unsuccessfully treated with three tricyclics (amitriptyline, protriptyline, nortriptyline), trazodone (Desyrel), chlorazepate (Tradene), chlordiazepoxide (Librium), and thiothixene (Navane), none of which provided him with relief. Pemoline (Cylert) improved his concentration, but failed to relieve his fatigue and other symptoms. Nonetheless, he took the pemoline in an excessive dose of 750 mg daily over a month. A course of methylphenidate (Ritalin) had been previously tried for presumed ADD, adult residual, followed by a course of dextroamphetamine (Dexedrine). The patient abused both of these drugs, taking in excess of 100 mg daily. Unable to obtain more Dexedrine, he experienced symptoms similar to his current MAOI withdrawal symptoms (i.e., agitation, irritability, insomnia, diarrhea). This led to a brief hospitalization, but the patient signed himself out of the hospital after several hours. An EEG at that time was consistent with stimulant withdrawal, but otherwise negative.

The patient had used alcohol heavily and had taken drugs illicitly earlier in his life. During later adolescence he found that an occasional amphetamine (i.e., illicit "white crosses") helped him to "relax" and "concentrate." For several years during his later teenage years and early twenties he had consumed about 4-10 drinks in the average day, with up to 20 drinks on some weekends. He had used alcohol only occasionally for the last 3 years, but did smoke one pack of cigarettes per day and consumed 500-600 mg caffeine daily in soft drinks (i.e., Mountain Dew).

A sister had been treated for depression. The family believed that the father had a chronic depression, but he had never been treated for it. Early in childhood the patient had demonstrated letter reversals; later in childhood he had notable problems with memorization work in school. Although he understood the material, his grades were poor. Several years ago he had injured himself at work, leading to loss of his index finger from his right hand (patient is right handed).

At the time of outpatient assessment the patient was neatly groomed and cooperative with interview. He denied any abuse of his drugs and saw nothing amiss in his setting his own dosages of prescribed drugs. He appeared slightly depressed and mildly anxious, but thinking, memory, and concentration were grossly intact. He was able to repeat 9 numbers forward, and 4 numbers backward. Hamilton Depression Scale was 25 (moderately elevated), Hamilton Anxiety Scale was 15 (mildly elevated), and Global Assessment Scale was 35 (severely impaired). On self-rating scales, his Beck Depression Scale was 18 (moderately elevated), and two out of ten scales on the SCL-90 were abnormal (i.e., Obsessive-Compulsive 2.30, Depression 1.77).

Neurophysiological testing included the WAIS, Porteus Maze, Tactual Formboard, Aphasia Screening Test, Trail Making Test, several Motor Tests, Bender Recall, Verbal Fluency, and Rey Auditory Verbal Learning Test. These tests indicated low average intelligence, with severe impairment in planning and foresight, probably due to a toxic encephalopathy. Verbal IQ of 99, with a much lower performance IQ, suggesting toxicity and/or deterioration over time.

Drug screen of the urine showed only nicotine. Triglycerides were slightly elevated at 260 mg% (normal 36-233). Carotene was also reduced at 24 mg% (normal 80-220). Normal tests included urinalysis, RBC indices, platelets, liver enzymes, amylase, electrolytes, creatinine, uric acid, urea nitrogen, cholesterol, and EKG.

It was our opinion that major depression, panic disorder, and Korsakoff's amnestic syndrome (from a decade of heavy alcohol abuse) should be ruled out after withdrawal from the tranylcypromine and a period of abstinence from all drugs. Further diagnostic studies were also advised. It was recommended to the patient that he be admitted to our inpatient service, to be followed by some months in a halfway house while attending our day program. The patient refused and returned home.

DISCUSSION

One previous case of tranylcypromine abuse had been reported in the world's literature. It involved a case included in a series of prescription drug abusers from the Mayo Clinic, although specific case details were not elaborated[9]. Two withdrawal cases from the MAOI phenelezine are reported as a letter in the British literature, although dosages are not mentioned[10]. In one case the patient reported shivering, while in the other the patient complained of depression, irritability, and shivering.

The mechanisms of MAOI abuse are not clear, although the antidepressants potentiate morphine analgesia[11]. This may involve the serotonin system, since serotinergic agonists have been shown to increase plasma endorphin levels[12]. MAOI's are known to inhibit the degradation of serotonin[7]. Congeners of the amphetamines may act in a similar fashion, but by releasing serotonin[13]. Of course, the tricyclic antidepressants (to which this patient did not become addicted despite multiple exposures) also affect serotonin by blocking its reuptake[7]. It may be that the effect of the MAOI's (i.e., inhibiting degradation of serotonin) is more potent and resembles that of the amphetamines (i.e., releasing serotonin) as compared to the effect of the tricyclics (i.e., blocking its reuptake). The experimental "self-pharmacology" practiced by this patient indicates that this may be the case. The tricyclics (especially amitriptyline) are at times abused in association with other drugs, and even sold on the street[14]. It may be relevant that the tricyclics generally are abused in concert with the opioids.

This case raises some important clinical and pharmacological issues. Was this patient escalating his dose for its therapeutic effects in relieving his chronic anxiety-depression symptoms, to obtund himself and seek a euphoric state, or some combination of these? At least in part he was seeking relief, but in part also he was accustomed to managing his affect, his autonomic nervous system, his relationships with others and his view of the world by taking a variety of psychoactive substances-of-potential-abuse. Although he was taking a licit MAOI drug, he was consuming it in an illicit fashion by determining his own dosage and not responding to physicians' orders to reduce his dose to therapeutic levels. He consumed drugs for "symptom relief" even when his anxiety and depression or panic attacks were short of being severe and disabling. In regard to his symptoms following cessation of MAOI (i.e., gastrointestinal symptoms, irritability, fatigue, insomnia, poor concentration, "shaking inside"), were these withdrawal symptoms or were they a rebound of underlying psychopathological symptoms? Several of his "cessation symptoms" (e.g., insomnia, fatigue, trouble concentrating) were exacerbations of symptoms that he experienced off medications or illicit drugs. However, gastrointestinal symptoms were not ordinarily present in this patient and were closely tied in time to his withdrawal experiences (i.e., earlier with dextroamphetamine and currently with tranylcypromine). Animal studies may aid in clarifying this issue.

Increased prescribing of the MAOI's for several conditions has led to greater exposure of the population to these drugs. They are prescribed especially for people who may be at risk to abuse, including depressed individuals who somatize, bulimic patients, and patients with conditions which occur in association with alcoholism and/or drug abuse (i.e., peptic ulcer, chronic pain, attention deficit disorder, panic disorder, and treatment-resistant depression). Evaluation for previous substance abuse and close monitoring of MAOI prescriptions are warranted.

REFERENCES

[1]Sargent, W., The effect of anxiety states and atypical depressions by the MAOI drugs, J. Neuropsychiatry 3:96-103 (1962). [2]Jenike, M. A., Surman, O. S., Cassem, N. H., et al., Monoamine oxidase inhibitors in obsessive-compulsive disorder, J. Clin. Psychiatry 44:131-132 (1983). [3]Akil, H. J., and Liebeskind, J. C., Monoaminergic mechanisms of stimulation-produced analgesics, Brain Res. 94:279-296 (1975). [4]Anthony, M., and Lance, J. W., Monoamine oxidase inhibition in the treatment of migraine, Arch. Neurol. 21:263-268 (1969). [5]Liebowitz, M. R., Quitkin, F., Stewart, J. W., et al., Phenelzine and Imipramine in atypical depression, Psychopharamcol. Bull. 17:159-161 (1981). [6]Walsh, B. T., Stewart, J. W., Wright, L., et al., Treatment of bulimia with monoamine oxidase inhibitors, Am. J. Psychiatry 139:1629 (1982). [7]Goodman, W. K., and Charney, D. S., Therapeutic applications of mechanisms of action of monoamine oxidase inhibitor and heterocyclic antidepressant drugs, J. Clin. Psychiatry 4:6-22 (1985). [8]Council on Drugs, Paradoxical hypertension from tranylcypromine sulfate, J. Am. Med. Assoc. 186:854 (1963). [9]Swanson, D. W., Weddige, R. L., and Morse, R. M., Abuse of prescription drugs, Mayo Clin. Proc. 48:359-367 (1973). [10]Pitt, B., Withdrawal symptoms after stopping phenelzine?, Br. Med. J. 2:332-333 (1974). [11]Hynes, M. D., Lochner, M. A., Bernis, K. G., et al., Thioxetine, a selective inhibitor of serotonin uptake, potentiates morphine analgesia without altering its discriminative stimulus properties or affinity for opioid receptors, Life Sci. 36:2317-2323 (1985). [12]Petraglia, F., Facchinetti, F., Martignonni, E., et al., Serotinergic agonists increase plasma levels of B-endorphin and B-lipoprotein in humans, J. Clin. Endocrinol. Metab. 59:1138-1142 (1984). [13]Jespersen, S., and Scheel-Kruger, J., Evidence for a difference in mechanism of action between fenfluramine- and amphetamine-induced anorexia, J. Pharm. Pharmacol. 25:49-54 (1973). [14]Westermeyer, J., A Clinical Guide to Alcohol and Drug Problems, Praeger, Philadelphia, 1986.

Joseph Westermeyer, MD, PhD Department of Psychiatry Alcohol-Drug Treatment Program University of Minnesota Hospital and Clinics Minneapolis, Minnesota 55455

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