Quetiapine and Essential Tremor

Clinical Neuropharmacology Vol. 25, No. 6, pp. 303–306 © 2002 Lippincott Williams & Wilkins, Inc., Philadelphia

Quetiapine and Essential Tremor Federico Micheli, Marı´a Graciela Cerso´simo, Gabriela Raina, and Emilia Gatto Parkinson’s Disease and Abnormal Movements Program, Institute of Neurosciences, “Jose´ de San Martı´n” Hospital de Clı´nicas, Buenos Aires, Argentina

Summary: The safety and tolerability of quetiapine (up to 75 mg/day) as monotherapy on essential tremor were investigated in an open-label study in 10 patients. Five men and 5 women, with a mean age of 66.3 years, affected by essential tremor participated in the trial. They were treated with increasing doses of quetiapine to 75 mg/day over a 6-week period. Side effects included a paradoxical psychiatric reaction in one and angor in another, and in both cases quetiapine was discontinued. In two other patients, somnolence led to dose reduction. There were no pre- versus post-treatment differences, but 3 out of 10 patients benefited (improvement >20%). Although the study was not powered to assess efficacy, quetiapine seems to be a safe drug for the treatment of essential tremor. Key Words: Essential tremor—Quetiapine—Antipsychotic drugs

approaches by lesion or deep brain stimulation in the ventral intermediate nucleus of the thalamus have been reported to be efficacious even in the most severe cases (5,8). Nevertheless, the latter alternative is neither widely available nor devoid of side effects. In several open studies, clozapine, an atypical neuroleptic drug, has been reported to improve resting and postural Parkinson’s disease (PD) tremor (9,10), tardive tremor, and even ET (Class III evidence)(11,12). Clozapine was effective in reducing both the amplitude and frequency of tremor (12) in roughly 75% of patients with ET. In this series, the most common side effects were drowsiness, sedation, and weight gain (11). Although its mechanism of action remains unknown, sedation appears unrelated to its antitremor effect. However, frequent monitoring of the white blood cell count makes the use of this drug cumbersome and expensive. Quetiapine, a dibenzothiazepine derivative, is an atypical antipsychotic agent closely resembling clozapine, but its use does not require blood monitoring (13). Quetiapine is associated with hardly any risk of causing or exacerbating extrapyramidal symptoms (14) and does not worsen motor function in patients with PD due to its greater binding affinity for serotonin 5-HT2 receptors than for dopamine D2 receptors (15–17). The present open study was conducted to evaluate the safety and tolerability of quetiapine in ET.

As the most common movement disorder, essential tremor (ET) presents a wide range of clinical severity (1). Although regarded as a benign condition, it may give rise to physical handicap or social embarrassment. The anatomic basis and pathophysiology of ET remains debatable, but the most widely accepted hypothesis supports a central oscillator that may be enhanced or suppressed by reflex pathways (2). Despite the fact that the inferior olivary nucleus, which may be a major structure in the genesis of ET, receives serotoninergic input, several pharmacologic trials have failed to show a selective serotonin, as well as GABA or dopaminergic neurotransmitter, impairment (3,4). The first-line treatment for ET includes propanolol and primidone as isolated or adjunctive therapy, though in both cases the antitremor mechanism remains unknown (5,6). Although GABAergic medications such as gabapentin, alprazolam, clonazepam, topiramate (6,7), and botulinum toxin A (in some forms of tremor) may be of benefit in ET to date, these drugs constitute the secondline therapies in nonresponders. Interestingly, surgical Address correspondence and reprint requests to Dr. Federico Micheli, Parkinson’s Disease and Abnormal Movements Program, Institute of Neurosciences, Hospital de Clı´nicas “Jose´ de San Martı´n”, Juncal 1695P 5 Dpto J (1062), Buenos Aires, Argentina. E-mail: Fmicheli@ fibertel.com.ar.

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F. MICHELI ET AL. TABLE 1. Clinical data of patients

Patients

Age

Sex

1 2 3 4 5 6 7 8 9 10 Mean age ± SD

62 79 60 76 79 66 67 59 35 80 66.3 ± 13.7

F F M M F M F M M F

Disease duration (years)

Family history (Yes/No)

30 10 3 3 6 10 2 2 7 2 Mean 7.5 ± 8.51

Yes Yes Yes No No Yes Yes No No No

ments, and drawing Archimedes spirals). Each of these six tests was performed with the dominant and the nondominant arm. The same physician (G.R.) performed all evaluations but the rater’s test-retest reliability was not assessed. In addition, careful questioning for adverse effects including other movement disorders was carried out at each visit. Statistical analysis results were analyzed using Statistica 5.0 software. Statistical data was obtained using ANOVA ␹2. A p value of 20%) was detected in 3 patients, but only in one case was the improvement significant. In five patients, no changes were detected and two patients worsened (Table 2). TABLE 2. Tremor scores and side effects in ET patients on quetiapine Patient 1 2 3 4 5 6 7 8 9 10

BasePercentage of line Visit 3 Variability improvement 18 27 27 33 27 36 12

7 24.5 28 32 21.5 35 17

18–7.0 27–24.5 27–27 33–32 27–21.5 36–35 12.0–17.0

61.2% 9.3% 0% 3.04% 20.4% 2.8% Worse

22.5 12 14

23 15 12

22.5–15.5 12.0–15 14.0–12.0

31.2% Worse 14.3%

Side effects — — — Somnolence — — Somnolence/ Angor — Somnolence Hallucinations/ delusions

QUETIAPINE AND ESSENTIAL TREMOR Total mean scores before and after treatment were 22.85 ± 8.59 and 21.5 ± 8.87, respectively. DISCUSSION Essential tremor has been considered a chronic and often progressive and disabling disorder for which few effective pharmacologic treatments are available (6). It has even been suspected that the reason why many ET patients fail to show up at movement disorder clinics is attributable to the belief that there are no effective therapies for this disorder. Recently, the beneficial effects of thalamic DBS have been highlighted (8,20); however, an antisurgical bias is both evident in most patients and their families as well as in many neurologists. In this setting, new drugs apt to treat ET are needed. Like clozapine, quetiapine is active on mesolimbic but not nigrostriatal dopaminergic neurons, a property conferring a similar pharmacologic profile to both drugs (17,21,22). These findings may further explain its ability to provide antipsychotic effects with no worsening of extrapyramidal symptoms. Although clozapine has been shown to be effective to treat ET in refractory patients by a mechanism that remains to be elucidated, it needs periodic blood cell count monitoring because of the well-known occurrence of serious hematological side effects (11,12). Conversely, quetiapine appears as a safe drug without this requirement. Although it has been acknowledged to be well accepted due to its relatively benign adverse profile (23), this only holds true for psychotic patients. In this study on nonpsychotic patients, somnolence was the most common adverse event (13,16); on increasing the dosage, two patients experienced somnolence, severe enough to require dose reduction. In addition, one patient with a negative personal and family history for psychiatric disturbances had a paradoxical psychiatric reaction and another developed angor. Whether the latter was related to quetiapine cannot be ascertained. Although the patient had a previous normal cardiological evaluation, quetiapine has been reported to increase heart rate but not the QT interval (24). However, despite these side effects, all patients were available for the last visit evaluation, as the most serious adverse effects occurred just prior to the last visit. As expected, no adverse extrapyramidal effects occurred. In the present study, quetiapine failed to provide clinical improvement in ET. We may hypothesize that the different response to clozapine and quetiapine is attributable to variable binding and affinity for the dopamine, serotonin, adrenergic, or muscarinic receptors. In agreement with this hypothesis, the affinity for D1

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receptors is higher for clozapine than for quetiapine (21). Moreover, the antitremor action of clozapine has been related to serotoninergic central antagonism and probably a diverse antagonism on serotoninergic 5-HT1, 5-HT2, and 5-HT3 receptors between clozapine and quetiapine could be posited (10). However, some authors suggest that the antitremor action of clozapine is unrelated to antidopaminergic or antiserotoninergic activity (10,11). Relevantly, the role of peripheral components in modulating ET is strongly supported by the sustained improvement after the administration of beta-2 antagonists (25). Thus, clozapine and quetiapine exhibit potent alpha-1 and alpha-2 adrenergic antagonistic activity (12,13) that could account for reduction of ET. However, our study has several limitations, as it is open-label with a small sample, not powered to test efficacy, and a brief evaluation period (maximum 6 weeks). Further double-blind studies with higher doses and longer treatment schedules are required to assess the therapeutic potential of quetiapine in ET. REFERENCES 1. Brin MF, Koller W. Epidemiology and genetics of essential tremor. Mov Disord 1998;13(suppl 3):55–63. 2. Deuschl G, Elble RJ. The pathophysiology of essential tremor. Neurology 2000;54(suppl 4):S14–S20. 3. Koller WC, Gupta S. Pharmacologic probe with progabide of GABA mechanism in essential tremor. Arch Neurol 1987;44:905–7. 4. Koller WC. Trazodone in essential tremor. Probe of serotoninergic mechanisms. Clin Neuropharm 1987;12:134–7. 5. Evidente VGH. Understanding essential tremor. Postgrad Med 2000;108:138–49. 6. Koller WC, Hristova A, Brin M. Pharmacologic treatment of essential tremor. Neurology 2000;54(suppl 4):S30–S38. 7. Galvez-Jimenez N, Hargreave M. Topiramate and essential tremor. Ann Neurol 2000;47:837–38. 8. Louis ED. Clinical practice: essential tremor. N Engl J Med 2001; 345:887–91. 9. Friedman JH, Lannon MC. Clozapine-responsive tremor in Parkinson’s disease. Mov Disord 1990;5:225–29. 10. Bonnuccelli U, Ceravolo R, Salvetti S, et al. Clozapine in Parkinson’s disease tremor. Neurology 1997;49:1587–90. 11. Ceravolo R, Salvetti S, Piccini P, et al. Acute and chronic effects of clozapine in essential tremor. Mov Disord 1999;14:468–72. 12. Factor SA, Friedman JH. The emerging role of clozapine in the treatment of movement disorders. Mov Disord 1997;4:483–96. 13. Dev V, Raniwalla J. Quetiapine: a review of its safety in the management of schizophrenia. Drug Saf 2000;23:295–307. 14. Worrel JA, Marken PA, Beckman SE, et al. Atypical antipsychotic agents: a critical review. Am J Health Syst Pharm 2000;57:238–55. 15. Meltzer HY. The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 1999;21(suppl 2):106S–115S. 16. Misra LK, Erpenbach JE, Hamlyn H, et al. Quetiapine: a new atypical antipsychotic. S D J Med 1998;51:189–93. 17. Dewey RB Jr, O’Suilleabhain PE. Treatment of drug-induced psychosis with quetiapine and clozapine in Parkinson’s disease. Neurology 2000;55:1753–54. 18. Deustchl G, Bain P, Brin M, et al. Consensus statement of the Movement Disorder Society on Tremor. Mov Disorder 1998;13(suppl 3): 2–23. 19. Louis ED, Ottman R, Ford B, et al. The Washington Heights-

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