5HT2A receptor gene and bipolar affective disorder

5HT2A receptor gene and bipolar affective disorder

response effect as change from baseline. Furthermore, it is evident from the dose-response curves that no ceiling in response to salbutamol was attain...

160KB Sizes 0 Downloads 28 Views

response effect as change from baseline. Furthermore, it is evident from the dose-response curves that no ceiling in response to salbutamol was attained and so by definition any small difference in baseline would not have a confounding effect on the subsequent delta-response. Our study therefore differs from that of Ullman et al’ in which baseline FEV was significantly increased 12 h after the last dose of salmeterol and a ceiling in response was reached during the salbutamol dose-response curve. Furthermore, that study was not placebo controlled and included no run-in or washout without &bgr;z-agonist. The power of our study was calculated on the basis of delta-response and not absolute response; thus any conclusions drawn from absolute values are invalid. To make a crude comparison of the absolute values for FEV, and PEFR from our data is misleading. Pharmacologically and clinically, the important finding from the shift in the doseresponse curve is that patients will require up to a four-fold greater dose of salbutamol, when used as repeated puffs for rescue therapy during an acute asthma attack. This finding assumes even more importance since patients may be lulled into a false sense of security as a consequence of their higher PEFR diary recordings while taking salmeterol, as we observed at 12 h after chronic dosing. We also showed that compared with placebo at 12 h after dosing, salmeterol showed only 0’7-fold doubling-dose protection against histamine reactivity, which would also support the hypothesis that airway (32 receptor subsensitivity had occurred. We, therefore, remain firmly convinced that twice-daily salmeterol produces sub sensitivity of airway f32-receptor function and associated receptor downregulation, even in patients already receiving inhaled corticosteroids. This effect is predictable in view of the 24 h receptor occupancy that occurs during twice-daily dosing with salmeterol. Indeed, previous placebo-controlled studies with another long-acting P2-agonist (formoterol) also showed that bronchodilator subsensitivity occurs during twice-daily treatment.2,3 These potential problems with long-acting P2-agonists require further investigation, in particular of such issues as drug-free dosing intervals as well as corticosteroidl&bgr;z-receptor interactions. *Brian

Lipworth, Alison Grove

Department of Clinical Pharmacology, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK 1 Ullman A, Hedner J, Svedmyr N. Inhaled salmeterol and salbutamol in asthmatic patients: an elevation of asthma symptoms and the possible development of tachyphylaxis. Am Rev Respir Dis 1990; 142: 571-75. 2 Newnham DM, McDevitt DG, Lipworth BJ. Bronchodilator subsensitivity after chronic dosing with eformoterol in patients with asthma. Am J Med 1994; 97: 29-37. 3 Newnham DM, Grove A, McDevitt DG, Lipworth BJ. Subsensitivity of bronchodilator and systemic beta-2 adrenoceptor responses after regular twice daily treatment with eformoterol dry powder in asthmatic patients. Thorax 1995; 504: 497-504.

5HT2A receptor gene and bipolar affective disorder SIR—The

serotonergic system has been implicated in the of affective disorders through the action of aetiology therapeutic agents and their role in affective and perceptual states. Thus 5-hydroxytryptamine (serotonin) type 2 (5-HT,) receptor down-regulation is a common mechanism of antidepressant action and increased densities of 5-HT2 receptors have been reported in the brains of depressed patients and suicide victims. 5-HT-mediated endocrine responses are also impaired in depressed patients, and may involve postsynaptic dysfunction of 5-HT,A and the closely

*Family history of major affective disorders, unipolar or/and bipolar disorder PsyFH+/-: positive/negative psychiatric family history. Table: Frequencies of T102C polymorphism in 5-HT2A gene in bipolar patients according to family psychiatric history

related 5-HT subtypes. We have investigated the potential role of the 5-HTzA receptor in the aetiology of bipolar affective disorder using a case-control allelic association study. Bipolar affective disorder has a substantial genetic component and it is possible that heritable alterations in the serotonergic system may have a major aetiological role. In this study, we have used a polymorphic variant of the 51 HT ZA receptor described by Warren et al.’ This polymorphism was recently associated with prediction of clinical response to the drug clozapine in schizophrenia2 although it does not cause an aminoacid change in the protein. We have analysed this polymorphism in 88 subjects with bipolar affective disorder and 113 controls using Warren’s assay based on the polymerase chain reaction. All patients had a severe and long history of bipolar affective disorder (mean 12 years since diagnosis) and were all ethnically Spanish. 85 had bipolar type I and three bipolar type II. Controls were from the same geographic area and had no history of psychiatric illness, either themselves or in their first degree relatives. All subjects were diagnosed according to DSM-IIIR and gave informed consent. Allele frequencies for the 5-HTZA polymorphism did not differ between subjects (T102, 415%; C102 58-5%) and controls (T102 41-6%; C102 58-4%). No significant differences in genotype were found between the subject and control group (table), and genotypes for both populations were in Hardy-

Weinberg equilibrium (not shown). Furthermore, frequencies of genotypes did not differ if the subjects were divided according to whether or not they had family history of psychiatric illness, or a family history of affective illness only (table). Family history of psychiatric illness was defined using a structured interview3 with two healthy relatives. This study indicates that genetic variation in the 5-HTzA receptor is unlikely to have a major role in the aetiology of bipolar affective disorder. However, it is possible that additional variants of the gene, not detected by analysis of the T102C polymorphism, may influence the development of bipolar affective disorder. B Gutiérrez, M Arranz, *L Fañanás, V J van Os, D Collier

Vallès, R Guillamat,

*Unitat d’Antropologia, Facultad de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain; Institut Universitari de Salut Pública de Catalunya, Barcelona, Clínica Mental Santa Coloma, Barcelona; and Institute of Psychiatry, London, UK

1

2

3

Warren J, Peacock M, Rodriguez L, et al. An MspI polymorphism in the human serotonin receptor gene (HTR2): detection by DGGE and RFLP analysis. Hum Mol Genet 1993; 2: 338. Arranz M, Collier D, Sodhi M, et al. Association between clozapine response and allelic variation in 5-HT2A receptor gene. Lancet 1995; 346: 281-82. Endicott J, Andreasen N, Spitzer R. Family history research diagnostic criteria. New York: New York State Psychiatric Insitute, 1978.

969