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Brief Report   |    
Lack of Association Between Neuroleptic Malignant Syndrome and Polymorphisms in the 5-HT1A and 5-HT2A Receptor Genes
Chiaki Kawanishi, M.D., Ph.D.; Tokiji Hanihara, M.D.; Yoshikazu Shimoda, M.D.; Kyoko Suzuki, Ph.D.; Naoya Sugiyama, M.D., Ph.D.; Hideki Onishi, M.D., Ph.D.; Tomohiro Miyakawa, M.D.; Yoshiteru Yamada, M.D., Ph.D.; Kenji Kosaka, M.D., Ph.D.
Am J Psychiatry 1998;155:1275-1277.

Abstract

Objective: The molecular basis of neuroleptic malignant syndrome is unclear, but studies suggest that genetic factors are involved in its pathogenesis. Considering possible involvement of the serotonergic system in neuroleptic malignant syndrome, the authors examined the association between neuroleptic malignant syndrome and polymorphisms of the 5-HT1A and 5-HT2A receptor genes.Method: The authors examined the frequencies of gene polymorphisms in the 5-HT1A (Arg219Leu) and 5-HT2A (Thr25Asn and His452Tyr) receptor genes in 29 patients previously diagnosed with neuroleptic malignant syndrome, 94 neuroleptic-treated patients with schizophrenia who had no history of neuroleptic malignant syndrome, and 94 healthy comparison subjects. Polymerase chain reaction and restriction fragment length polymorphism analyses were used to screen gene mutations.Results: No polymorphic allele was detected in the patients who had experienced the neuroleptic malignant syndrome. Conclusions: The authors cannot conclude that polymorphisms in the 5-HT1A and 5HT2A receptor genes are factors determining susceptibility to the neuroleptic malignant syndrome. Am J Psychiatry 1998; 155: 1275-1277

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The neuroleptic malignant syndrome is a severe side effect of psychotropic drug therapy R221559CEBBBFBA. Although the physical conditions of patients are risk factors for neuroleptic malignant syndrome R221559CEBDHFDE, the mechanism of this syndrome is still unclear. Some clinical aspects of neuroleptic malignant syndrome suggest that constitutional factors controlled by genetics may determine susceptibility in some patients with neuroleptic malignant syndrome. It is known that once patients have experienced neuroleptic malignant syndrome it is likely to recur. Deuschl et al. R221559CEBDJBEA reported cases of twin patients with schizophrenia who experienced the neuroleptic malignant syndrome, and Otani et al. R221559CEBDJBEA reported familial cases of neuroleptic malignant syndrome. Lazarus et al. R221559CEBDJBEA reported a case of recurrence of the syndrome in a patient with a chromosome abnormality. Iwahashi R221559CEBCHJGB and Ram et al. R221559CEBCJICJ7 reported cases of neuroleptic malignant syndrome in patients with mutations in the debrisoquine 4-hydroxylase and dopamine D2 receptor genes, respectively.

Another potentially lethal side effect, serotonin syndrome, which is induced by serotonin receptor agonists or serotonin reuptake inhibitors, has been well characterized R221559CEBCJICJ. The serotonergic system mediates various autonomic and hormonal responses through serotonin receptor subtypes, and exaggerated serotonergic function causes serotonin syndrome. Clinically, serotonin syndrome resembles neuroleptic malignant syndrome, and some investigators regard neuroleptic malignant syndrome and serotonin syndrome as representing different aspects of a generalized hyperthermic spectrum R221559CEBBGIHG, R221559CEBDHJGJ. We hypothesized that the serotonergic system might be involved in the pathogenesis of neuroleptic malignant syndrome. Therefore, our study was designed to examine the influence of serotonin receptor gene polymorphisms on the occurrence of neuroleptic malignant syndrome. We used neuroleptic-treated patients with schizophrenia who had no history of neuroleptic malignant syndrome as well as healthy subjects for experimental comparison subjects.

The study group included 29 patients (18 men and 11 women with a mean age of 43.4 years, SD=16.7) who had previously experienced neuroleptic malignant syndrome. Twenty-five of these patients had diagnoses of schizophrenia, one had major depressive disorder, one had bipolar I disorder, one had alcohol-induced psychotic disorder, and one had mental disorder caused by viral encephalitis; all diagnoses were made according to DSM-IV. Neuroleptic malignant syndrome was diagnosed retrospectively according to the criteria of Pope et al. R221559CEBBBFBA. Ninety-four healthy subjects (52 men and 42 women with a mean age of 53.2 years, SD=16.0) and 94 patients with schizophrenia who were taking neuroleptics but had not shown signs of the neuroleptic malignant syndrome (37 men and 57 women with a mean age of 43.0 years, SD=16.7) were studied as comparison subjects. The comparison subjects with schizophrenia had taken neuroleptic medicines for more than 6 months. All of the subjects were Japanese and were unrelated to each other. Written informed consent was obtained from all subjects.

Genomic DNA was extracted from peripheral white blood cells by using standard techniques. Polymerase chain reaction and restriction fragment length polymorphism analysis were performed to identify 1) a G-to-T transition at nucleotide position 659 (Arg219Leu) in the 5-HT1A receptor gene, 2) a C-to-A transition at nucleotide position 74 (Thr25Asn) in the 5-HT2A receptor gene, and 3) a C-to-T transition at nucleotide position 1354 (His452Tyr) in the 5-HT2A receptor gene. Oligonucleotide primers for polymerase chain reaction and restriction fragment length polymorphism analysis methods were designed according to Lam et al. R221559CEBDEBIF for 5-HT1A and according to Erdmann et al. R221559CEBDEDAJ for 5-HT2A.

The genotypes of the 5-HT1A and 5-HT2A receptor genes are shown in T1. Neither polymorphic allele was detected in the patients who had experienced neuroleptic malignant syndrome. 659G/T and 74C/A alleles were not detected in any of the subjects. There was no significant difference between the neuroleptic malignant syndrome group and either of the two comparison groups in allele frequency of 1354C/T (T1). No 1354C/T homozygote was observed in either comparison group.

The serotonergic system, which is thought to mediate various physiological and psychological conditions related to certain disease states, including obsessive-compulsive disorders, anety disorders, eating disorders, depression, and schizophrenia, has been the subject of much research in both psychopharmacology and psychiatric genetics. The serotonin syndrome, a severe drug side effect caused by enhanced activity of the serotonergic system, is characterized by symptoms of restlessness, hyperthermia, diaphoresis, myoclonus, hyperreflexia, tremor, and lack of coordination. Insel et al. R221559CEBBHAII first described the serotonin syndrome in a patient with obsessive-compulsive disorder who used clomipramine after discontinuing treatment with clorgyline. Advances in molecular biology have revealed at least 15 subtypes of serotonin receptors in rodents and humans. The 5-HT1A receptor is thought to mediate symptoms of serotonin syndrome based on psycho­pharmacological experiments using rodents R221559CEBEBHHE. The 5-HT2A receptor has a relatively high affinity for various neuroleptics, including clozapine.

In view of the physiological role of the serotonergic system and similarities in the clinical manifestations of the serotonin syndrome and the neuroleptic malignant syndrome, the serotonergic system may be involved in the pathophysiology of neuroleptic malignant syndrome. Some investigators have speculated that a dopamine/serotonin imbalance is responsible for the occurrence of these drug-induced syndromes R221559CEBDHJGJ, R221559CEBCACFE. We designed our experiments to screen well-defined amino acid substitutions in the 5-HT1A and 5-HT2A receptors in patients who had previously suffered from neuroleptic malignant syndrome because we hypothesized that some structural change in the receptor might confer sensitivity to psychotropic drugs and cause these drug side effects. The 659G/T polymorphism of the 5-HT1A receptor gene, which is thought to be a very rare polymorphism in the North American population R221559CEBDEBIF, was not observed in any of the Japanese subjects in our study. The frequencies of the 74C/A and 1354C/T polymorphisms in the 5-HT2A receptor gene were lower than those observed in a German study R221559CEBDEDAJ, and none of our neuroleptic malignant syndrome patients possessed these alleles (no reference was available on 5-HT genotype frequencies in Asian populations). Consequently, there is no evidence of susceptibility to neuroleptic malignant syndrome in terms of three polymorphisms we examined in this small study group. However, we cannot rule out the existence of mutations in serotonin receptor genes that affect drug response, and further studies might be needed. The interindividual variation in psychopharmacological responses, including side effects, could be affected by genetic predisposition, and we think that the study of genetic associations is still a potent tool for investigating the development of neuroleptic malignant syndrome.

Large genetic studies are needed to investigate the mechanism of neuroleptic malignant syndrome. The goal of these genetic studies should be to predict the response to psychotropic drugs in individuals in order to permit safe and effective drug therapy.

Received Oct. 20, 1997; revision received Feb. 20, 1998; accepted March 6, 1998. From the Department of Psychiatry, Yokohama City University School of Medicine; and Fujisawa Hospital, Fujisawa, Japan.. Address reprint requests to Dr. Kawanishi, Department of Psychiatry, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.

 
Pope HG Jr, Keck PE Jr, McElroy SL: Frequency and presentation of neuroleptic malignant syndrome in a large psychiatric hospital. Am J Psychiatry  1986; 143:1227–1233
[PubMed]
 
Itoh H, Ohtsuka N, Ogita K, Yagi G, Miura S, Koga Y: Malignant neuroleptic syndrome—its present status in Japan and clinical problems. Folia Psychiatr Jpn  1977; 31:565–576
 
Deuschl G, Oepen G, Hermle L: Neuroleptic malignant syndrome: observations on altered consciousness. Pharmaco­psy­chiatry  1987; 20:168–170
 
Otani K, Horiuchi M, Kondo T, Kaneko S, Fukushima Y: Is the predisposition to neuroleptic malignant syndrome genetically transmitted? Br J Psychiatry  1991; 158:850–853
 
Lazarus AL, Moore KE, Spinner NB: Recurrent neuroleptic malignant syndrome associated with inv dup (15) and mental retardation. Clin Genet  1991; 39:65–67
[PubMed]
 
Iwahashi K: CYP2D6 genotype and possible susceptibility to the neuroleptic malignant syndrome. Biol Psychiatry  1994; 36:781–782
[PubMed]
[CrossRef]
 
Ram A, Cao Q, Keck PE, Pope HG, Otani K, Addonizio G, McElroy SL, Kaneko S, Redlichova M, Gershon ES, Gejman PV: Structural change in dopamine D2 receptor gene in a patient with neuroleptic malignant syndrome. Am J Med Genet  1995; 60:228–230
[PubMed]
[CrossRef]
 
Sternbach H: The serotonin syndrome. Am J Psychiatry  1991; 148:705–713
[PubMed]
 
Heyland D, Sauve M: Neuroleptic malignant syndrome without the use of neuroleptics. Can Med Assoc J  1991; 145:817–819
 
Miyaoka H, Kamijima K: Encephalopathy during amitriptyline therapy: are neuroleptic syndrome and serotonin syndrome spectrum disorders? Int Clin Psychopharmacol  1995; 10:265–267
 
Lam S, Shen Y, Nguyen T, Messier TL, Brann M, Comings D, George SR, O’Dowd BF: A serotonin receptor gene variant found in a Tourette’s syndrome patient. Biochem Biophys Res Commun  1996; 219:853–858
[PubMed]
[CrossRef]
 
Erdmann J, Shimron-Abarbanell D, Rietschel M, Albus M, Maier W, Korner J, Bondy B, Chen K, Shih JC, Knapp M, Propping P, Nothen MM: Systematic screening for mutations in the human serotonin-2A (5-HT2A) receptor gene: identification of two naturally occurring receptor variants and association analysis in schizophrenia. Hum Genet  1996; 97:614–619
[PubMed]
[CrossRef]
 
Insel TR, Roy BF, Cohen RM, Murphy DL: Possible development of the serotonin syndrome in man. Am J Psychiatry  1982; 139:954–955
[PubMed]
 
Goodwin GM, De Souza RJ, Green AR, Heal DJ: The pharmacology of the behavioural and hypothermic responses of rats to 8-hydroxy-2-(di-n-propylamino) tetralin. Psychopharmacology (Berl)  1987; 91:506–511
[PubMed]
[CrossRef]
 
Ames D, Wirshing WC: Ecstasy, the serotonin syndrome, and neuroleptic malignant syndrome—a possible link? (letter). JAMA  1993; 269:869
[PubMed]
[CrossRef]
 
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References

Pope HG Jr, Keck PE Jr, McElroy SL: Frequency and presentation of neuroleptic malignant syndrome in a large psychiatric hospital. Am J Psychiatry  1986; 143:1227–1233
[PubMed]
 
Itoh H, Ohtsuka N, Ogita K, Yagi G, Miura S, Koga Y: Malignant neuroleptic syndrome—its present status in Japan and clinical problems. Folia Psychiatr Jpn  1977; 31:565–576
 
Deuschl G, Oepen G, Hermle L: Neuroleptic malignant syndrome: observations on altered consciousness. Pharmaco­psy­chiatry  1987; 20:168–170
 
Otani K, Horiuchi M, Kondo T, Kaneko S, Fukushima Y: Is the predisposition to neuroleptic malignant syndrome genetically transmitted? Br J Psychiatry  1991; 158:850–853
 
Lazarus AL, Moore KE, Spinner NB: Recurrent neuroleptic malignant syndrome associated with inv dup (15) and mental retardation. Clin Genet  1991; 39:65–67
[PubMed]
 
Iwahashi K: CYP2D6 genotype and possible susceptibility to the neuroleptic malignant syndrome. Biol Psychiatry  1994; 36:781–782
[PubMed]
[CrossRef]
 
Ram A, Cao Q, Keck PE, Pope HG, Otani K, Addonizio G, McElroy SL, Kaneko S, Redlichova M, Gershon ES, Gejman PV: Structural change in dopamine D2 receptor gene in a patient with neuroleptic malignant syndrome. Am J Med Genet  1995; 60:228–230
[PubMed]
[CrossRef]
 
Sternbach H: The serotonin syndrome. Am J Psychiatry  1991; 148:705–713
[PubMed]
 
Heyland D, Sauve M: Neuroleptic malignant syndrome without the use of neuroleptics. Can Med Assoc J  1991; 145:817–819
 
Miyaoka H, Kamijima K: Encephalopathy during amitriptyline therapy: are neuroleptic syndrome and serotonin syndrome spectrum disorders? Int Clin Psychopharmacol  1995; 10:265–267
 
Lam S, Shen Y, Nguyen T, Messier TL, Brann M, Comings D, George SR, O’Dowd BF: A serotonin receptor gene variant found in a Tourette’s syndrome patient. Biochem Biophys Res Commun  1996; 219:853–858
[PubMed]
[CrossRef]
 
Erdmann J, Shimron-Abarbanell D, Rietschel M, Albus M, Maier W, Korner J, Bondy B, Chen K, Shih JC, Knapp M, Propping P, Nothen MM: Systematic screening for mutations in the human serotonin-2A (5-HT2A) receptor gene: identification of two naturally occurring receptor variants and association analysis in schizophrenia. Hum Genet  1996; 97:614–619
[PubMed]
[CrossRef]
 
Insel TR, Roy BF, Cohen RM, Murphy DL: Possible development of the serotonin syndrome in man. Am J Psychiatry  1982; 139:954–955
[PubMed]
 
Goodwin GM, De Souza RJ, Green AR, Heal DJ: The pharmacology of the behavioural and hypothermic responses of rats to 8-hydroxy-2-(di-n-propylamino) tetralin. Psychopharmacology (Berl)  1987; 91:506–511
[PubMed]
[CrossRef]
 
Ames D, Wirshing WC: Ecstasy, the serotonin syndrome, and neuroleptic malignant syndrome—a possible link? (letter). JAMA  1993; 269:869
[PubMed]
[CrossRef]
 
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