C-1 9309

Case Reports
Potentiation of Haloperidol Neurotoxicity in
Acute Hyperthyroidism: Report of a Case
Hsin Chu1,2, Jiann-Chyun Lin1, and Yaw-Dong Hsu1 Abstract- Haloperidol has been used extensively for the treatment of many psychiatric illnesses as well as
for control of agitated patients. Side effects including anticholinergic, extrapyramidal, sedative side effects
as well as neuroleptic malignant syndrome are not unusual. Many factors may contribute to these complica-
tions including withdrawal or toxicity, concomitant use of other medications or the underlying illness itself.
We report a case without previous history of thyroid disorder sufferring acute manic episode. Haloperidol
was prescribed to control psychotic symptoms. Symptoms and signs of extrapyramidal syndrome, catatonia
and hyperthyroidism ensued. Prescription of anti-thyroid agents and discontinuation of haloperidol were
essential in the successful treatment of this patient. It is hypothesized that underlying hyperthyroidism might
have precipitated haloperidol neurotoxicity. Haloperidol might play a role in the exacerbation of hyperthy-
roidism.
Key Words: Haloperidol, Hyperthyroidism, Neuroleptic-induced catatonia
Acta Neurol Taiwan 2004;13:126-130 INTRODUCTION
oral route were used for longer than 6 days before the development of neurotoxicity. We describe a patient in Traditional neuroleptics such as haloperidol had whom neuroleptic-induced side effect was greatly exag- been associated with the development of extrapyramidal gerated by the presence of hyperthyroidism. Catatonia side effects as well as neuroleptic malignant syndrome.
developed within 48 hours after intramuscular injection Dose, prescription interval and duration were believed to of haloperidol. Possible mutual influences between thy- determine the occurrence of these side effects. Certain roid state and haloperidol as well as clinical implication concomitant illness had also been shown to precipitate the development of neuroleptic-induced side effects. For example, several cases of haloperidol neurotoxicity pre- CASE REPORT
cipitated by hyperthyroidism had been published(1-3).
However, in those cases, low dose of haloperidol by the A 21 year-old male soldier was well before. Two From the 1Department of Neurology, Tri-Service General Reprint requests and correspondence to: Hsin Chu, MD, PhD.
Hospital, 2Institute of Aerospace Medicine, National Defense Department of Neurology, Tri-Service General Hospital, No.
325, Sec. 2, Cheng-Kung Road, Taipei, Taiwan.
Received May 5, 2004. Revised June 7, 2004. Acta Neurologica Taiwanica Vol 13 No 3 September 2004 weeks prior to current hospitalization, he presented with moist and warm. His blood pressure was 167/78 mmHg, unusual behaviors including absence without permission with a pulse rate of 140-150/min, and body temperature from work, hypertalkative, negative thinking and at 36.7 ˚C. The neurological examination revealed roving increased sexual drive. He was brought to emergency eyes, normoactive tendon reflexes with plantar respons- room of a local hospital for help where blood, urine bio- es. Although no response to pain stimulation, his limbs, chemical studies, and brain CT revealed unremarkable if hold in the air, would be maintained in position and findings. Later, as the condition persisted, he was admit- then gradually fall. Intermittently, generalized tremor ted to acute psychiatric ward and treated with low dose over limbs was observed. Laboratory studies revealed benzodiazepine and paroxetine (a selective serotonin elevated CPK (392 U/L) and ALT (77 U/L). Urine drug reuptake inhibitor). During psychiatric interview, he screen showed negative response to amphetamine, opiate admitted suffering from failed personal investment, wor- and benzodiazepine. Brain CT revealed unremarkable rying about future career and unstable relationship with findings. EKG showed atrial fibrillation with rapid ven- girlfriend. He was discharged with the impression of tricular response. The differential diagnoses included adjustment disorder. Two days later, he was brought to thyrotoxicosis, neuroleptic malignant syndrome, neu- another psychiatric hospital because of unstable mood roleptic withdrawal and non-convulsive status epilepti- and agitation. Diaphoresis was noted at arrival but his cus. He was admitted to ICU. Intravenous fluid supple- vital signs were stable and he was afebrile. Results of ment was initiated to prevent dehydration and rhabdomy- routine laboratory studies including complete blood olysis. After a single dose of bromocriptine and biperi- count and blood biochemistry were unremarkable.
den treatment, rigidity and waxy flexibility gradually Medications prescribed included clonazepam (6 mg/day subsided. However, signs of autonomic hyperactivity in three divided doses), valporic acid (500 mg/day)and persisted. Initially, he was treated with amiodarone and clothiapine (800 mg/day). Haloperidol (15 mg in three digoxin without significant response. Thyrotoxicosis divided doses on the first day and 10 mg in two doses on with probable thyroid storm was later confirmed by ele- the second day) and lorazepam were given intramuscu- vated T3 (296.8 ng/dl; N 86-187), free T4 (4.39 ng/dl; N larly to sedate the patient. Extrapyramidal side effects 0.8-2.0) and suppressed TSH level (<0.03 µIU/ml; N including orobuccal dyskinesia, akathisia and salivation 0.3-5). Thyroid sonogram revealed diffuse enlargement were noted on the 3rd hospital day, 48 hours since the of both glands. Elevated titers of anti-microsomal and first dose of haloperidol. Tachycardia (PR >120/min) anti-thyroglobulin antibodies (>1:25,600 and >1:320, and elevated blood pressure (159/65 mmHg) developed respectively) indicated autoimmune-mediated hyperthy- later. He became speechless and lethargic. EKG demon- roidism. Propranolol and anti-thyroid agents including strated atrial fibrillation with rapid ventricular response.
propylthiouracil 100 mg and Lugol solution were pre- Elevated CPK (392 U/L; N, 55-170 U/L) was noted. He scribed accordingly. Blood pressure and pulse rate were gradually under control, he returned to euthyroid state The patient was naive to neuroleptics. His elder sis- clinically and by laboratory examination. On the 6th hos- ter had been diagnosed with schizophrenia for five years.
pital day, he was transferred to psychiatric service.
According to his mother, he had a similar episode of vio- Several differential diagnoses including mood disorder lent behavior, negative thoughts and agitation about two secondary to hyperthyroid disease and bipolar disorder years ago. He had the habit of cigarette smoking and with most recent manic episode were impressed.
consumption of alcoholic beverages on social occasions Beginning from the third day after hospitalization, olan- zapine, valproic acid and clonazepam were prescribed to At the emergency room, the patient appeared coma- treat symptoms of increased appetite, ir ritation, tous (GCS E2V1M1). He was generally rigid and pro- increased sexual drive and insomnia. He also tolerated fusely sweating. Mild exophthalmos was suspected. On haloperidol given on p.r.n. basis intramuscularly at a palpation, no obvious goiter was noted. His skin was dose of 10 to 15 mg per day (total 60 mg in 9 days) Acta Neurologica Taiwanica Vol 13 No 3 September 2004 under euthyroid state without untoward reactions. He schizophrenia patients(5). The patient we reported was given 25 mg haloperidol in two days. Whether this reflect high degree of D2 receptor occupancy need fur- DISCUSSION
ther study. It had been shown that altered thyroid state might influence the effects of psychotropic drugs. In the One of the most important adverse effects of literature, only a few cases on possible potentiation of haloperidol is the extrapyramidal syndrome (EPS), a haloperidol neurotoxicity in acute hyperthyroidism had group of movement disorders that include akathisia, dys- been reported (Table)(1-3). The case we presented differs tonia, parkinsonism and tardive dyskinesia. Propensity from previous described cases in the duration, dosage, toward the development of these side effects usually and route of haloperidol given. While in previous depends on the dosage, duration, concurrent medica- reports, haloperidol was given orally in low dose for over tions, underlying medical illness or surgery. Various one week before the development of catatonic neurotoxi- investigations have shown high percentage of EPS city, 25 mg given intramuscularly within 48 hours was among patients treated with haloperidol. For example, enough to provoke severe neurotoxic effects in our Lane et al demonstrated 63% of EPS reaction in acute patient. Indeed, different route of administration affects Chinese schizophrenic patient treated with haloperidol at the toxicity of haloperidol. Riker et al. have reported five 10 mg/day for two weeks(4). It is not surprising to observe euthyroid, delirious patients tolerated intravenous EPS (akathesia and orobuccal dyskinetic reaction) in our haloperidol well at median doses of 250 mg/day but patient after 25 mg of haloperidol in total given intra- developed EPS reaction after medication was discontin- ued(6). It has been suggested that, compared with oral At toxic dose or during withdrawal from neurolep- route, parenteral haloperidol use may be associated with tics, more severe complications such as catatonia or neu- less intense EPS, perhaps related to less f irst-pass roleptic malignant syndrome could occur. In our patient, metabolism and lower concentrations of reduced several hours after the last dose of haloperidol, general haloperidol or other metabolites(7). If this was the case, weakness, rigidity, and catatonic appearance ensued. We the potentiation effect of hyperthyroidism on haloperidol suspect the severe catatonic reaction in our patient was neurotoxicity in our case was obvious.
partly due to underlying hyperthyroidism.
The severe haloperidol neurotoxic response in our Using positron emission tomography as a tool, case does not fulfill criteria of neuroleptic malignant Kapur et al. demonstrated that after 2 mg/day of oral syndrome (NMS). Signs of NMS usually appear two haloperidol for two weeks, high levels of striatal weeks after therapy is begun or the dosage of the med- dopamine D2 receptor occupancy could be achieved in ication is increased. In our patient, the symptom devel- Table. Comparison of reported cases of haloperidol neurotoxicity in hyperthyroidism patients
Acta Neurologica Taiwanica Vol 13 No 3 September 2004 oped only 48 hours after intramuscular haloperidol.
weakness and cloudiness of consciousness.
Hyperthermia, severe muscular rigidity, autonomic insta- Thyrotoxicosis or thyroid storm occurs in uncontrolled bility, and changing levels of consciousness are the four hyperthyroid patients as a result of triggering factors major hallmarks of NMS. Laboratory studies in NMS such as surgery, infection or trauma. In our patient, there patient usually revealed leukocytosis, azotemia and were no obvious stresses prior to current hospitalization extremely elevated CPK level. But our patient was in addition to acute psychiatric illness and haloperidol afebrile and showed normal leukocyte level and only injection. Prospective study by Spratt and colleagues mildly elevated CPK level. Instead, our patient met have shown that 33% of newly admitted psychiatric Woodbury and Woodbury’s criteria for neuroleptic- inpatients have transient elevations in circulating levels induced catatonia (NIC)(8). From a case report of a boy of thyroxine (T4)(13). However, in those with elevated T4 with many features of NMS but did not have fever or level, only 36% had concomitant elevation in T3 levels.
leukocytotic response, Adrian et al developed a concept Most important of all, this “transient hyperthyroxinemia” of NIC-NMS as a spectrum of disorder(9). Using their in acute psychotic patient is to be distinguished from scoring system to evaluate severity of the illness, our true hyperthyroidism by spontaneous resolution over a patient scored 1 in muscle rigidity (moderate rigidity), 2 period of weeks and absence of baseline TSH suppres- in autonomic instability (fulfill 2 of the following: body sion. We proposed that thyrotoxicosis experienced by temperature > 39 ˚C, pulse rate > 110, blood pressure this young man was precipitated by haloperidol injec- > 140/100), 1 in mental status (agitation-confusion) and tion. This is supported by the fact that there was marked 1 in CPK level (200 < CPK < 1,500 U/L), with total deterioration after the drug was started. Also, agitation score of 5. This suggests moderate NIC-NMS. Another and diaphoresis decreased, and his coherence improved line of evidence in the potentiation of haloperidol neuro- about 24 hours after last dose of haloperidol, prior to the toxicity by hyperthyroidism came from the fact that this administration of propylthiouracial and Lugol solution.
patient diagnosed with haloperidol-associated NIC suc- A direct stimulatory effect of haloperidol on the thyroid cessfully tolerated to haloperidol without reemergence of is unlikely, in view of the 7-day half-life of T4 and the symptoms, after he reached euthyroid state.
patient’s improvement within 24 hours after haloperidol The mechanism by which hyperthyroidism might was discontinued. His initial presentation was the sole have potentiated neurotoxicity of haloperidol is not clear.
result of haloperidol is also unlikely, since diaphoresis, Hyperthyroidism might have impeded the metabolism of tremor and palpitation are not known to be side effects of haloperidol, allowing toxicity to develop. However, this haloperidol. Hordiienko et al provided evidence in birds seems unlikely as there was no difference in plasma that dopaminergic agents inhibited hypothalamo- haloperidol concentration under different thyroid states hypophyseal-thyroid system(14). It is possible that by in human(10). In animal studies, thyroxine has sensitizing blocking dopaminergic transmission in the brain, effect on the rats’ central nervous system to the toxic haloperidol indirectly potentiated thyroid state, causing effects of haloperidol(11), and hyperthyroidism increases hyperthyroidism. The synergism between asymptomatic the receptivity of dopamine receptors in guinea pigs(12).
hyperthyroid state and toxic effects of haloperidol pre- Whether these mechanisms apply to human need further sumably resulted in a clinical picture of thyrotoxicosis.
Hoffman and his colleagues had reported a patient with The case we presented have had no prior history of hyperthyroidism. Thyroid hyperactivity was suggested Another possible explanation for clinical presenta- by mild ophthalmos for unknown period of time and tion was thyrotoxic psychosis. Although the relationship diaphoresis, irritability developed three days before he between thyroid disease and psychiatric symptomatology was sent to this hospital. Full-blown thyrotoxicosis has always been close, thyroid psychosis has been developed later, with typical clinical features of observed and reported rarely in the literature. A prospec- diaphoresis, tachycardia, fine tremor of limbs, muscle tive study showed only three cases in a total of 3,011 Acta Neurologica Taiwanica Vol 13 No 3 September 2004 admissions to a large mental hospital(16). In contrary to dol treatment: a PET study. Am J Psychiatry 1996;153:948- what happened in our patient, several case reports had pointed to the beneficial effect of haloperidol in alleviat- 6. Riker RR, Fraser GL, Richen P. Movement disorders asso- ing acute psychosis in hyper thyroid patient(17,18).
ciated with withdrawal from high-dose intravenous Interestingly, in those reports, oral form of haloperidol haloperidol therapy in delirious ICU patients. Chest was used, suggesting the possibility that thyroid state might affect haloperidol neurotoxicity in route-specific 7. Menza MA, Murray GB, Holmes VF, et al. Decreased manner. Persistence of certain symptoms such as irrita- extrapyramidal symptoms with intravenous haloperidol. J tion, increased sex drive and insomnia after he was treat- ed to euthyroid state suggested mechanisms other than 8. Woodbury MM, Woodbury MA. Neuroleptic-induced cata- tonia as a stage in the progression toward neuroleptic In conclusion, hyperthyroidism, adverse reaction to malignant syndrome. J Am Acad Child Adolesc Psychiatry haloperidol (and other neuroleptics), and acute manic or psychotic state share some common clinical features 9. Hynes AF, Vickar EL. Case study: neuroleptic malignant such as palpitations, sweating, tremors, irritability and syndrome without pyrexia. J Am Acad Child Adolesc emotional liability. Careful differential diagnosis is essential for proper management of such patients.
10. Crocker AD, Carson JA, Crocker JM, et al. Radioreceptor Thyrotoxicosis should be considered in the differential assay of antipsychotic drugs and prolactin levels in the diagnosis of behavioral changes with hyperactivity.
serum of schizophrenic patients. Clin Exp Pharmacol Unusual adverse response to short term use of neurolep- tics such as haloperidol should raise the suspicion of 11. Selye H, Szabo S. Protection against haloperidol by cata- underlying provoking events, such as hyperthyroidism in toxic steroids. Psychopharmacologia 1972;24:430-4.
our case. In such cases one would rule out hyperthy- 12. Klawans HL Jr, Goetz C, Weiner WJ. Dopamine receptor roidism before introducing haloperidol into the treatment site sensitivity in hyperthyroid and hypothyroid guinea 13. Spratt DI, Pont A, Miller MB, et al. Hyperthyroxinemia in REFERENCES
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Acta Neurologica Taiwanica Vol 13 No 3 September 2004

Source: http://www.neuro.org.tw/magz/doc/13-3P126.pdf