Abstract
A 34-year-old man with a history of multiple substance abuse (now abstinent for six years) became addicted to tranylcypromine, consuming up to 240 mg/day. After discontinuing the drug, he developed thrombocytopenia (52,000/ul) and delirium; there were no other anticholinergic signs. The delirium was unresponsive to haloperidol and diazepam. Intravenous administration of physostigmine (2 mg) on hospital day 6 resulted in prompt, but temporary, clearing of the delirium. Following a recurrence of the delirium after 30 minutes, he was started on an intravenous infusion of physostigmine (2 mg/hr) with good results. Physostigmine administration did not produce any cholinergic signs. By hospital day 8, he did not require any more physostigmine. Thrombocytopenia resolved on hospital day 9 without therapeutic intervention. On hospital day 10, the patient was asymptomatic and left the hospital on his own recognizance.
Case report
A 37-year-old man with a history of drug abuse (heroin, amphetamines, ethanol) had been abstinent for six years. His neurologist prescribed tranylcypromine 40 mg daily for the treatment of his migraine headaches. Tranylcypromine relieved the migraines, and the patient also reported that he could concentrate better, think more clearly, and felt less distracted by daily worries. Within eight weeks he increased the dose to 240 mg/day. After 12 weeks of taking these high doses he reported the abuse to his neurologist because he had “collapsed several times,” probably due to tranylcypromine, but he had not sought help at that time. The neurologist recommended detoxification in a hospital. Instead, the patient chose to taper the daily dose on his own to 160 mg. It is not known if he had stopped tranylcypromine completely when he was brought to a psychiatric hospital with delirium. Over two days of observation, the delirium worsened, he became combative, and was transferred to our facility after sedation with diazepam. On arrival he was talking to imaginary policemen using the English language (despite being a native German speaker) and began to sing. Nevertheless, he followed simple commands. He had no anticholinergic signs and no other symptoms of withdrawal; his pupils were mid-sized and reactive to light. His BP was 136/76 mmHg, pulse 98 beats/min, and temperature 37.1°C. Laboratory tests were normal except for a blood glucose of 50 mg/dl (insulin <2 μIU/ml, C-peptide 0.6 ng/ml), thrombocytes 84,000/μl, alanine aminotransferase (ALT) 65 U/l, aspartate aminotransferase (AST) 80 U/l, and creatine kinase (CK) 2150 U/l. ALT and AST values normalized within 4 days and the CK level fell to 354 U/l (normal <174 U/l) after 3 days. A urine drug analysis was negative except for benzodiazepines and tranylcypromine (opiates, benzodiazepines, barbiturates, cocaine, amphetamines, and tricyclic antidepressants were analyzed using CEDIA®; alcohol was analyzed using an ADH-method; screening utilized an automated HPLC (Remedi®)). The plasma concentration of tranylcypromine was below its detection limit (<40 μg/l) (GC-MS analysis performed by Institut für Rechtsmedizin, University of Munich). Intravenous glucose (4 g) increased the blood glucose to 110 mg/dl. After one hour, the blood glucose dropped to 60 mg/dl and a continuous infusion of glucose was started (24g over 6 hours), followed by parenteral nutrition. Parenteral nutrition was necessary because the patient's delirium prevented oral feeding and placement of nasogastric tube. Since two intravenous doses of haloperidol 5 mg did not improve his mental status, he was sedated with diazepam 20 mg, which was followed by a continuous infusion with midazolam (3 to 10 mg/h) and additional diazepam (20 to 60 mg/day). Thrombocytopenia reached its nadir (52,000/μl) on day five, resolving spontaneously in four days and leading to reactive thrombocytosis (553,000/μl) on day ten. Global coagulation parameters (PTT, INR, D-dimers) were monitored and remained within normal limits. The delirium did not resolve within five days of its onset and further attempts with haloperidol were unsuccessful. On day six, we gave an intravenous dose of physostigmine 2 mg. Within five minutes the patient was completely oriented, admitted his abuse of tranylcypromine, and reported having dreamt of being in London for business. After 30 minutes he became delirious again. He was treated with an infusion of physostigmine (2 mg/h). The physostigmine infusion was interrupted every six hours in order to test the patient's mental state and with each cessation the delirium returned. No sedation was necessary while the patient was receiving physostigmine and no adverse effects from the physostigmine were observed. Eight days after its beginning the delirium did not return after stopping the physostigmine. The patient left the hospital on his own recognizance on day ten. One year later, he appeared well with no sequellae of the episode and no signs of a psychiatric disorder. He was abstinent from tranylcypromine and other addictive substances, and his migraine was under control with frovatriptan.
Discussion
Addiction to tranylcypromine was first reported in 1963, three years after its introduction into the market (Citation1). Seven cases of high-dose consumption (120 to 600 mg/day) with delirium after discontinuation are presented in . At least six patients had a history of substance abuse, but were abstinent. Four reports mention a stimulant effect of tranylcypromine. In four cases, the delirium was accompanied by thrombocytopenia. Since the number of thrombocytes prior to hospitalization was not known, it is not clear if thrombocytopenia is caused by withdrawal of tranylcypromine or by its misuse. The latter is supported by the fact that thrombocytopenia is a consequence of intoxication (Citation2). However, in our case, as with others (Citation3–5), thrombocytopenia reaches its nadir several days after cessation of tranylcypromine. This implies an influence of tranylcypromine withdrawal on the thrombocytes. Since in our case the global coagulation parameters were normal, the thrombocytopenia was not caused by a consumption coagulopathy like DIC, but rather may have been caused by reduced platelet synthesis or by enhanced sequestration or pooling of platelets in the spleen (Citation5). The elevation of CK was probably due muscular efforts in the delirious states in which he was combative, although a myotoxic effect cannot be ruled out. However, CK elevation was observed in a similar case (Citation4). Moderately elevated liver enzymes in cases of tranylcypromine abuse also are documented in the literature (Citation4,Citation6,Citation7) and may reflect hepatotoxicity. The role of tranylcypromine in our patient's hypoglycemia remains unclear. Hypoglycemia was not reported in other cases and may have been related to our patient's fasting due to the delirium. The delirium typically starts about 20 hours after discontinuation of tranylcypromine and lasts three to twelve days, which may be the time the CNS needs to enough MAO for normal functioning. Treatment with haloperidol and benzodiazepines produce a helpful sedative effect but does not affect the delirium. The pathopharmacology leading to the delirium is unclear. However, most probably the delirium was caused by tranylcypromine withdrawal: 1) there was a clear temporal relationship between cessation of tranylcypromine consumption and the onset of the delirium; 2) the patient recovered to a normal mental state; 3) consumption or abuse of other psychogenic substances were ruled out to the greatest possible extent; and 4) the course in our case was nearly identical with those known from literature with coincidence of delirium and short-duration thrombocytopenia. The similarity of amphetamine and tranylcypromine withdrawals suggests a common mechanism (Citation8). A novel feature in our case was the effect of physostigmine on the delirium. The effect of physostigmine was too prompt and too reproducible to be attributed to the natural waxing and waning of a fading delirium. The effect of physostigmine was remarkable since our patient had no other anticholinergic signs.
Table 1. Tranylcypromine – abuse, delirium, and thrombocytopenia – review from literature
Prescribers of tranylcypromine, especially when prescribed for off-label use as in our case, should be aware of the addictive properties of tranylcypromine. The risk of misuse may be higher in patients with a history of substance abuse, particularly with stimulants.
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