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Tutkimustyö

Toimin psykiatrian dosenttina Tampereen yliopistossa. Tutkimusaiheeni on ollut farmakogenetiikka psykiatriassa. Lisäksi olemme tutkineet geenien yhteyttä sairastumisriskiin ja sairastumisikään. Väitöskirjassa tutkimuksen kohteena oli perinteisten psykoosilääkkeiden tehon ennustaminen geenejä tutkimalla. Väitöskirjan lehdistötiedote ja yhteenveto-osa löytyvät allaolevista linkeistä.

http://www.uta.fi/laitokset/kirjasto/vaitokset/2004/2004094.html

http://acta.uta.fi/pdf/951-44-6140-1.pdf

Väitöskirjatyön ohessa aloitimme Pitkäniemen sairaalassa tutkimuksen, joka keskittyy masennuksen genetiikkaan. Pyrimme löytämään geenien vaihtelua tutkimalla keinoja ennustaa etukäteen, saako potilas vastetta ECT-hoidosta. Koska ECT-hoitoon päätyneet potilaat ovat käytännössä aina myös lääkehoidolle resistenttejä, antaa tutkimus mahdollisesti vastauksia siihen, voidaanko hoitoresistenttiä masennusta ennustaa geneettisen vaihtelun pohjalta.

Dosentuurini pohjalta mm. ohjaan kahta psykiatrian farmakogenetiikkaan liittyvää väitöskirjatyötä. Toinen väittelijä on jo saanut väitöskirjansa valmiiksi ja sen yhteystiedot ovat Tampereen yliopiston sivulla: http://www.uta.fi/laitokset/kirjasto/vaitokset/2009107.html

Julkaisuluettelo

1. Anttila Sami, Mattila Aino, Niskanen Pekka. Uusien masennuslääkkeiden yhteisvaikutukset muiden psyykenlääkkeiden kanssa. Suomen Lääkärilehti 1999;1-2:39-44.

2. Anttila SAK, Leinonen EVJ, Seppälä JA. Delirium during clarithromycin treatment: A case report. Nordic Journal of Psychiatry 1999;2:139-40.

3. Anttila Sami, Mattila Aino, Niskanen Pekka. Klotsapiinin metabolia ja yhteisvaikutukset. Novartis news 1999;1:21-24.

4. Anttila SAK, Räsänen I, Leinonen EV. Fluvoxamine augmentation increases serum mirtazapine concentrations three- to fourfold. Ann Pharmacother 2001;35:1221-1223.

5. Anttila SA, Leinonen EV. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev 2001;7:249-264.

6. Anttila S, Leinonen E. Duloxetine Eli Lilly. Curr Opin Investig Drugs 2002;3:1217-1221.

7. Anttila Sami, Leinonen Esa. Psykiatristen sairauksien farmakogenetiikasta. Erikoislääkäri 2002;6:313-6.

8. Anttila S, Kampman O, Illi A, Roivas M, Mattila KM, Lassila V, Lehtimäki T, Leinonen E. NOTCH4 gene promoter polymorphism is associated with the age of onset in schizophrenia. Psychiatr Genet 2003;13(2):61-64.

9. Illi A, Kampman O, Anttila S, Roivas M, Mattila KM, Lehtimäki T, Leinonen E. Interaction between angiotensin-converting enzyme and catechol-O-methyltransferase genotypes in schizophrenics with poor response to conventional neuroleptics. Eur Neuropsychopharmacol 2003;13(3):147-151.

10. Illi A, Mattila KM, Kampman O, Anttila S, Roivas M, Lehtimäki T, Leinonen E. Catechol-O-methyltransferase and Monoamine Oxidase A Genotypes and Drug Response to Conventional Neuroleptics in Schizophrenia. J Clin Psychopharmacol 2003;23(5):429-434.

11. Kampman O, Anttila S, Illi A, Lehtimäki T, Mattila KM, Roivas M, Leinonen E. Dopamine receptor D2 -141C Insertion/Deletion polymorphism in a Finnish population with schizophrenia. Psychiatry Res 2003;121(1):89-92.

12. Anttila S, Illi A, Kampman O, Mattila KM, Lehtimäki T, Leinonen E. Interaction between NOTCH4 and catechol-O-methyltransferase genotypes in schizophrenia patients with poor response to typical neuroleptics. Pharmacogenetics 2004;14(5):303-307.

13. Anttila S, Illi A, Kampman O, Mattila KM, Lehtimäki T, Leinonen E. Association of EGF polymorphism with schizophrenia in Finnish men. Neuroreport 2004;15:1215-1218.

14. Kampman O, Anttila S, Illi A, Mattila KM, Rontu R, Leinonen E, Lehtimäki T. Apolipoprotein E polymorphism is associated with age of onset in schizophrenia. J Hum Genet 2004;49(7):355-359.

15. Anttila S, Illi A, Kampman O, Mattila KM, Lehtimäki T, Leinonen E. Lack of association between two polymorphisms of brain-derived neurotrophic factor and response to typical neuroleptics. J Neural Transm 2005;112:885-890.

16. Kampman O, Anttila S, Illi A, Saarela M, Rontu R, Mattila KM, Leinonen E, Lehtimäki T. Neuregulin genotype and medication response in Finnish patients with schizophrenia. Neuroreport 2004;15:2517-2520.

17. Anttila S. Genetic factors in schizophrenia. Studies on treatment response to typical neuroleptics and age at onset. Doctoral dissertation. Tampere: 2004. Acta Universitatis Tamperensis 1047.

18. Kampman O, Anttila S, Illi A, Mattila KM, Rontu R, Leinonen E, Lehtimaki T. Interaction of tumor necrosis alpha - G308A and epidermal growth factor gene polymorphisms in early-onset schizophrenia. Eur Arch Psychiatry Clin Neurosci 2005;255:279-283.

19. Huuhka M, Anttila S, Leinonen E, Huuhka K, Rontu R, Mattila KM, Huhtala H, Lehtimäki T. The apolipoprotein E polymorphism is not associated with response to electroconvulsive therapy in major depressive disorder. J ECT 2005;21:7-11.

20. Leinonen E, Anttila S, Kampman O, Illi A. Voiko vastetta psyykenlääkkeeseen ennustaa? Duodecim 2005;121:45-52.

21. Kampman O, Illi A, Hänninen K, Katila H, Anttila S, Rontu R, Mattila KM, Leinonen E, Lehtimäki T. RGS4 genotype is not associated with antipsychotic medication response in schizophrenia. J Neural Transm 2006;113:1563-8.

22. Hänninen K, Katila H, Kampman O, Anttila S, Illi A, Rontu R, Mattila KM, Hietala J, Hurme M, Leinonen E, Lehtimäki T. Association between the C957T polymorphism of the dopamine D2 receptor gene and schizophrenia. Neurosci Lett 2006;407:195-8.

23. Hänninen K, Katila H, Anttila S, Rontu R, Maaskola J, Hurme M, Lehtimäki T. Epidermal growth factor A61G polymorphism is associated with the age of onset of schizophrenia in male patients. J Psychiatr Res 2007;41:8–14.

24. Huuhka K, Anttila S, Huuhka M, Leinonen E, Rontu R, Mattila KM, Lehtimäki T. Brain-Derived Neurotrophic Factor (BDNF) polymorphisms G196A and C270T are not associated with the response to electroconvulsive therapy in major depressive disorder. Eur Arch Psychiatry Clin Neurosci 2007;257:31-35.

25. Anttila S, Huuhka K, Huuhka M, Rontu R, Mattila KM, Leinonen E, Lehtimäki T. Interaction between TPH1 and GNB3 genotypes and electroconvulsive therapy in major depression. J Neural Transm 2007;114:461-468.

26. Anttila S, Huuhka K, Huuhka M, Rontu R, Hurme M, Leinonen E, Lehtimäki T. Interaction between 5-HT1A and BDNF genotypes increases the risk of treatment-resistant depression. J Neural Transm 2007;114:1065-1068.

27. Illi A, Kampman O, Hänninen K, Anttila S, Mattila KM, Katila H, Rontu R, Hurme M, Lehtimäki T, Leinonen E. Catechol-O-methyltransferase val108/158met genotype and response to antipsychotic medication in schizophrenia. Hum Psychopharmacol 2007;22:211-215.

28. Anttila S, Kampman O, Illi A, Rontu R, Lehtimäki T, Leinonen E. Association between 5-HT2A, TPH1 and GNB3 genotypes and response to typical neuroleptics: a serotonergic approach. BMC Psychiatry 2007;7:22.

29. Anttila S, Huuhka K, Huuhka M, Illi A, Rontu R, Leinonen E, Lehtimäki T. Catechol-O-methyltransferase (COMT) polymorphisms predict treatment response in electroconvulsive therapy. Pharmacogenomics J 2008;8:113-116.

30. Huuhka K, Kampman O, Anttila S, Huuhka M, Rontu R, Mattila KM, Hurme M, Lehtimäki T, Leinonen E. RGS4 polymorphism and response to electroconvulsive therapy in major depressive disorder. Neurosci Lett 2008;437:25-28.

31. Huuhka K, Anttila S, Huuhka M, Hietala J, Huhtala H, Mononen N, Lehtimäki T, Leinonen E. Dopamine 2 receptor C957T and catechol-O-methyltransferase Val158Met polymorphisms are associated with treatment response in electroconvulsive therapy. Neurosci Lett 2008;448:79-83.

32. Stewart J, Kampman O, Huuhka M, Anttila S, Huuhka K, Lehtimäki T, Leinonen E. ACE polymorphism and response to electroconvulsive therapy in major depression. Neurosci Lett 2009;458:122-125.

33. Anttila S, Viikki M, Huuhka K, Huuhka M, Hietala J, Huhtala H, Rontu R, Lehtimäki T, Leinonen E. TPH2 polymorphisms may modify clinical picture in treatment-resistant depression. Neurosci Lett 2009;464:43-46.

34. Viikki M, Kampman O, Illi A, Setälä-Soikkeli E, Anttila S, Huuhka M, Nuolivirta T, Poutanen O, Mononen N, Lehtimäki T, Leinonen E. TPH1 218A/C polymorphism is associated with major depressive disorder and its treatment response. Neurosci Lett 2010;468:80-84.

35. Viikki M, Anttila S, Kampman O, Illi A, Huuhka M, Setälä-Soikkeli E, Mononen N, Lehtimäki T, Leinonen E. Vascular endothelial growth factor (VEGF) polymorphism is associated with treatment resistant depression.Neurosci Lett.2010 Apr 22

Kongressiabstraktit

Illi A, Mattila KM, Kampman O, Anttila S, Roivas M, Lehtimäki T, Leinonen E. Catechol-O-methyltransferase and Monoamine Oxidase A Genotypes and Drug Response to Conventional Neuroleptics in Schizophrenia. Scandinavian College of Neuro-Psychopharmacology, 44th Annual- and 3rd Mediterranean Meeting 9.-12.4.2003 Juan les Pins, France.

Kampman O, Anttila S, Illi A, Rontu R, Mattila KM, Lehtimäki T, Leinonen E. Nord J Psychiatry 58:2;98-99. Age of onset in schizophrenia and tumor necrosis factor and epidermal growth factor genotypes. 45th Annual and 4th Mediterranean meeting of SCNP 21.04.2004 - 24.04.2004 Juan-les-Pins, France.

Anttila S, Huuhka K, Huuhka M, Rontu R, Mattila KM, Leinonen E, Lehtimäki T. An association study of tryptophan hydroxylase 1 (TPH1) and G-protein beta3 subunit (GNB3) gene polymorphisms and electroconvulsive therapy in major depressive disorder. The Fourth Annual Pharmacogenetics in Psychiatry Meeting 15.-16.4.05 New York, USA.

Anttila S, Huuhka K, Huuhka M, Illi A, Rontu R, Leinonen E Lehtimäki T. COMT polymorfismi yhteydessä psykiatrisen sähköhoidon (ECT) vasteeseen masennuksen hoidossa. Tampereen Lääkäripäivät 22.-24.3.07 Tampere.

Leinonen E, Illi A, Anttila S, Kampman O, Lehtimäki T. Treatment of depression - Association of response and genetic profile. 'Abstracts', Nordic Journal of Psychiatry 2007;61:6,487-502.

Refereenä olin vuoden 2002 aikana lehdissä European Journal of Clinical Pharmacology (kahdesti) ja Journal of Pharmacy and Pharmacology.

Vuonna 2003 olin refereenä lehdissä Expert Review of Neurotherapeutics ja American Journal of Medical Genetics.

Vuonna 2004 olin refereenä lehdissä American Journal of Medical Genetics, British Journal of Pharmacology, Neuroscience Letters ja Molecular Psychiatry.

Vuonna 2006 olin refereenä lehdissä American Journal of Medical Genetics, Neuroscience Research ja Future Neurology.

Vuonna 2007 olen ollut refereenä lehdissä Progress in Neuro-Psychopharmacology & Biological Psychiatry, Journal of Medical Genetics, Neuroscience Letters, American Journal of Medical Genetics ja The International Journal of Neuropsychopharmacology.

Vuonna 2008 olen ollut refereenä lehdissä American Journal of Medical Genetics, Journal of Sexual Medicine ja Pharmacogenomics.

Julkaisujen abstraktit:

1. Anttila Sami, Mattila Aino, Niskanen Pekka. Uusien masennuslääkkeiden yhteisvaikutukset muiden psyykenlääkkeiden kanssa. Suomen Lääkärilehti 1999;1-2:39-44.

Monet uusista masennuslääkkeistä estävät CYP-entsyymejä, ja tämä vaikutus saa muiden samanaikaisesti käytettyjen psyykenlääkkeiden pitoisuudet suurenemaan. Yhteisvaikutuksen seurauksena on esiintynyt vakavia sivuvaikutuksia, kouristelua, sekavuutta, sydämen rytmihäiriöitä ja ekstrapyramidaalisia oireita. Vakavin yhteisvaikutus on serotoniinioireyhtymä, joka syntyy yleensä farmakodynaamiselta pohjalta.

4. Anttila SAK, Rasanen I, Leinonen EV. Fluvoxamine augmentation increases serum mirtazapine concentrations three- to fourfold. Ann Pharmacother 2001;35(10):1221-3.

OBJECTIVE: To report two cases of interaction between fluvoxamine and mirtazapine. CASE SUMMARY: A 17-year-old boy was treated with mirtazapine 30 mg/d. The addition of fluvoxamine 100 mg/d to the regimen caused a threefold increase in the mirtazapine concentration. This interaction was associated with increased anxiety. A second patient, a 43-year-old woman, was treated with mirtazapine 15 mg/d. There was a fourfold increase in her mirtazapine concentration and simultaneous mood improvements after augmentation with fluvoxamine 50 mg/d. DISCUSSION: This is the first report of any interaction between fluvoxamine and mirtazapine. Mirtazapine is mainly metabolized by cytochrome P450 isoenzymes CYP1A2, CYP2D6, and CYP3A4. Fluvoxamine and cimetidine Inhibit the same isoenzymes, but fluvoxamine is probably the only agent that causes a clinically significant interaction. CONCLUSIONS: Adding fluvoxamine to treatment with mirtazapine may cause a significant increase in mirtazapine concentration. This interaction may necessitate adjustment of the mirtazapine dosage.

5. Anttila SA, Leinonen EV. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev 2001;7(3):249-64.

The novel antidepressant mirtazapine has a dual mode of action. It is a noradrenergic and specific serotonergic antidepressant (NaSSA) that acts by antagonizing the adrenergic alpha2-autoreceptors and alpha2-heteroreceptors as well as by blocking 5-HT2 and 5-HT3 receptors. It enhances, therefore, the release of norepinephrine and 5-HT1A-mediated serotonergic transmission. This dual mode of action may conceivably be responsible for mirtazapine's rapid onset of action. Mirtazapine is extensively metabolized in the liver. The cytochrome (CYP) P450 isoenzymes CYP1A2, CYP2D6, and CYP3A4 are mainly responsible for its metabolism. Using once daily dosing, steady-state concentrations are reached after 4 days in adults and 6 days in the elderly. In vitro studies suggest that mirtazapine is unlikely to cause clinically significant drug-drug interactions. Dry mouth, sedation, and increases in appetite and body weight are the most common adverse effects. In contrast to selective serotonin reuptake inhibitors (SSRIs), mirtazapine has no sexual side effects. The antidepressant efficacy of mirtazapine was established in several placebo-controlled trials. In major depression, its efficacy is comparable to that of amitriptyline, clomipramine, doxepin, fluoxetine, paroxetine, citalopram, or venlafaxine. Mirtazapine also appears to be useful in patients suffering from depression comorbid with anxiety symptoms and sleep disturbance. It seems to be safe and effective during long-term use.

6. Anttila S, Leinonen E. Duloxetine Eli Lilly. Curr Opin Investig Drugs 2002;3(8):1217-21.

Duloxetine is a serotonin (5-HT) and norepinephrine (NE) uptake inhibitor in pre-registration for depression. In vivo studies demonstrate that duloxetine inhibits 5-HT and NE transporters and this may induce an antidepressant effect [159168]. In humans, duloxetine has a low affinity for most 5-HT subtypes and for muscarinic, histamine H1, alpha1-adrenergic, alpha2-adrenergic and dopamine D2 receptors [444103]. Thus, it is not surprising that the meta-analysis of four recent clinical studies suggests duloxetine is a potent and well-tolerated antidepressant [429723]. By December 2001, Lilly had filed an NDA for depression. The launch of duloxetine is planned for the second half of 2002 [434250], [436220]. In April 2002, filing for stress urinary incontinence was anticipated for later in 2002 [456894]. Analysts at Banc of America predicted in April 2002, that the drug will be launched in the first quarter of 2003. The company projects US $400 million in revenue in 2003 and anticipates duloxetine to reach peak sales of over US $1 billion [450920]. Analysts at Morgan Stanley, projected US $25 million in sales in the fourth quarter 2002, rising to US $900 million in 2006 [450937]. At the same time, Credit Suisse First Boston anticipated launch for late 2002, with US $220 million in duloxetine revenues in 2003 and US $457 million in 2004 [450936].

8. Anttila S, Kampman O, Illi A, Roivas M, Mattila KM, Lassila V, Lehtimaki T, Leinonen E. NOTCH4 gene promoter polymorphism is associated with the age of onset in schizophrenia. Psychiatr Genet 2003;13(2):61-64.

OBJECTIVES: The NOTCH4 gene has a promoter polymorphism at position -25, which leads to the three genotypes TT, CT and CC. These have been suggested to present a novel independent genetic risk factor for schizophrenia. We conducted a prospective case-control study to explore the impact of NOTCH4 T-25C polymorphism on the factors associated with schizophrenia. METHOD: NOTCH4 gene promoter T-25C polymorphism was determined by polymerase chain reaction among 94 patients with schizophrenia and 94 healthy age-matched and sex-matched blood donors. RESULTS: The T allele was highly associated with an earlier age of onset in male patients of schizophrenia (Kaplan-Meier log-rank test P<0.0001). Moreover, the male patients carrying the T allele were born significantly more often in June-November compared with other months of the year [odds ratio=3.92 (95% confidence interval=1.025-15.018), P=0.046]. No association was determined, however, between the NOTCH4 gene polymorphism under study and schizophrenia. CONCLUSION: The NOTCH4 T-25C polymorphism has an important effect on the age of onset in schizophrenia and thus may be related to an early pathogenesis of schizophrenia in young patients. Alternatively, these findings may represent a significant genetic marker for managing subgroups and etiological clues in schizophrenia.

9. Illi A, Kampman O, Anttila S, Roivas M, Mattila KM, Lehtimaki T, Leinonen E. Interaction between angiotensin-converting enzyme and catechol-O-methyltransferase genotypes in schizophrenics with poor response to conventional neuroleptics. Eur Neuropsychopharmacol 2003;13(3):147-51.

Angiotensin-converting enzyme (ACE) modulates dopamine turnover in the brain and catechol-O-methyltransferase (COMT) enzyme is an important agent in the metabolic inactivation of dopamine and norepinephrine. Functional polymorphism in the COMT and ACE genes causes variation in enzyme activities. We investigated the relationship of COMT and ACE gene polymorphism with response to conventional neuroleptic treatment in schizophrenia. In this study population we had earlier detected that COMT genotype is associated with unsatisfactory drug response. A total of 94 schizophrenic patients were evaluated either as responders (n=43) or non-responders (n=51). The responders had experienced a fair and steady response to conventional neuroleptics. The non-responders had failed to achieve an acceptable response to conventional neuroleptics. We also used a control population of 94 age- and gender-matched blood donors. Genotyping of the COMT and ACE genes was performed by polymerase chain reaction. The risk of having both low activity COMT and high activity ACE genotypes was over 10 times higher (odds ratio=10.89, 95%CI 1.14-103.98, P=0.04) in the non-responders compared to responders. ACE genotype alone did not differ between any groups. This finding may suggest a possible interaction with low activity COMT and high activity ACE genotype in association with poor response to conventional neuroleptics.

SUMMARY: Biogenic amine synthesis and degradation are involved in the pathogenesis of schizophrenia. Catechol-O-methyltransferase and monoamine oxidase enzymes are important agents in the metabolic inactivation of these neurotransmitters (ie, dopamine, serotonin, and norepinephrine). Functional polymorphism in the catechol-O-methyltransferase and monoamine oxidase A genes causes variation in enzyme activities. We investigated the relationship of catechol-O-methyltransferase Val158Met and monoamine oxidase A promoter repeat polymorphism with response to conventional neuroleptic treatment in schizophrenia. Ninety-four schizophrenic patients formed 2 different study populations. The responders had experienced a fair and steady response to conventional neuroleptics. The nonresponders had failed to achieve an acceptable response to conventional neuroleptics. We also used a control population of 94 age-matched and gender-matched blood donors. Genotyping of the catechol-O-methyltransferase and monoamine oxidase A genes was performed by polymerase chain reaction.Forty-three percent of the nonresponders had a low activity catechol-O-methyltransferase genotype compared with 16% of the responders (P = 0.009). Monoamine oxidase A genotype alone did not differ significantly between the groups. Moreover, the risk of having both low-activity catechol-O-methyltransferase and monoamine oxidase A genotypes was over 6 times more common (odds ratio = 6.16, P = 0.03) in the nonresponders compared with responders. The whole population of patients with schizophrenia did not differ from the controls. The low-activity catechol-O-methyltransferase genotype may be associated with unsatisfactory drug response to conventional neuroleptics or alternatively be involved in a subset of schizophrenics. The role of monoamine oxidase A genotype seems to be additive in this respect.

We examined the occurrence of the -141C Ins/Del polymorphism in 93 Finnish patients with schizophrenia. In comparison with previous studies with Japanese and Caucasian populations, the incidence of this polymorphism was unexpectedly low. The findings suggest that the frequency of the -141C Ins/Del polymorphism is lower in Northern Europe compared to other Caucasian and Japanese populations.

Objective: In this study we attempted to show that the interaction between NOTCH4 and catechol- O -methyltransferase (COMT) polymorphism predicts the response to typical neuroleptics in schizophrenia. Our sample consisted of 94 Finnish patients with DSM-IV schizophrenia and 98 controls.Methods: Several studies have connected COMT and NOTCH4 genes to schizophrenia. We have previously shown that COMT polymorphism is significantly associated with treatment response in schizophrenia. NOTCH4 SNP2 polymorphism has been associated with age of onset in schizophrenia, but there is also a trend that this polymorphism may predict response to typical neuroleptics. In the present sample, there is a strong gene-gene interaction between these genes ( P = 0.003) and they have additive effect in treatment response.Results: Patients carrying both NOTCH4 C/C genotype and COMT low/low genotype, had more than ten times higher risk of being a non-responder than responder to treatment with typical neuroleptics [OR = 10.25 (95% CI 2.21-47.53), P < 0.001]. This combination of genotypes is also more common in patients considered non-responders than in controls [OR = 3.00 (95% CI 1.33-6.76), P = 0.007]. Conclusion: Our results suggest that an interaction between COMT and NOTCH4 genotypes may predict the treatment response to typical neuroleptics in patients with schizophrenia.

13. Anttila S, Illi A, Kampman O, Mattila KM, Lehtimäki T, Leinonen E. Association of EGF polymorphism with schizophrenia in Finnish men. NeuroReport 2004;15(7):1215-1218.

Some recent data suggest that epidermal growth factor (EGF) protein levels are altered in the brain of schizophrenic patients. In addition, a novel polymorphism of the EGF gene is associated with enhanced production of EGF in vitro. We conducted a retrospective study to explore the impact of EGF polymorphism on factors associated with schizophrenia. The sample consisted of 94 patients with schizophrenia who had either responded to treatment with conventional neuroleptics or who were considered non-responders. The control sample consisted of 98 blood donors. In our sample, the G allele was associated with schizophrenia in male patients (OR = 3.594 (95% CI 1.347-9.591), p = 0.008). The G allele was also associated with a later age at onset in male patients with schizophrenia. However, no association was found between treatment response and EGF polymorphism.

14. Kampman O, Anttila S, Illi A, Mattila KM, Rontu R, Leinonen E, Lehtimäki T. Apolipoprotein E polymorphism is associated with age of onset in schizophrenia. J Hum Genet 2004;49(7):355-359.

The aims of the study were to investigate the relationship between Apolipoprotein E (APOE) polymorphism, risk of schizophrenia, treatment response to conventional anti-psychotics, and age of onset in schizophrenia. The sample comprised 94 Finnish patients with a DSM-IV diagnosis of schizophrenia. Forty-three of the patients were good responders to conventional anti-psychotics and 51 were classified as non-responders. The control group consisted of 98 healthy blood donors. The APOE allele frequencies (2, 3, and 4) were 4.8, 72.3, and 22.9% in patients and 7.1, 75.0, and 17.9 in controls. None of the differences between groups were statistically significant. No association between treatment response and APOE genotype was found. Patients with APOE 4/4 genotype had a markedly lower age of onset compared with rest of the sample (p=0.0015), which remained significant when controlling for gender (p=0.02). There was an increasing linear trend between the number of 3 alleles (0, 1, or 2) and age of onset in schizophrenia (p=0.08). An inverse trend was found between the number of 4 alleles and age of onset (p=0.07). No relationship between APOE polymorphism and risk for schizophrenia was found. APOE 4/4 genotype may be associated with early onset schizophrenia. APOE 3 allele may function protectively in later onset in this disease.

Summary. Several studies have connected brain-derived neurotrophic factor (BDNF) with treatment response to neuroleptics. In recent studies, the BDNF expression was reduced by typical neuroleptics. We conducted a retrospective study on 94 patients with schizophrenia and 98 controls. The BDNF G196A and C270T polymorphisms are not associated with treatment response to typical neuroleptics or with age at first hospitalization. Moreover, these polymorphisms of the BDNF gene are not associated with the risk of schizophrenia.

16. Kampman O, Anttila S, Illi A, Saarela M, Rontu R, Mattila KM, Leinonen E, Lehtimaki T. Neuregulin genotype and medication response in Finnish patients with schizophrenia. Neuroreport 2004;15(16):2517-2520.

Neuregulin 1 is involved both in neurodevelopment and neurotransmitter mechanisms in the brain. There is evidence of an association between neuregulin 1 genotype and schizophrenia. We compared neuregulin 1 genotypes in patients with schizophrenia (n=94) and control subjects (n=395) of Finnish origin by using one SNP (SNP8NRG221533) as a genetic marker. We also analyzed NRG1 genotype with regard to age at onset and between responders and non-responders to conventional antipsychotics. The NRG1 genotype or allele frequencies showed similar distributions between patient and control groups. Age at onset was not associated with NRG1 genotype. The TT genotype was overrepresented in the non-responders group compared with the responders (p=0.013). Further studies are needed to ascertain the significance of neuregulin genotype in medication response to schizophrenia.

The study population comprised 94 Finnish patients with DSM-IV diagnosis of schizophrenia. The patients were placed into two subgroups according to medication response to conventional neuroleptics. The aim of the study was to examine the frequency of tumor necrosis factor -308 (G > A) polymorphism in these patients and their 98 control subjects who were age- and gender-matched blood donors. Associations between TNFalpha -308 polymorphism alone and between the interaction of TNFalpha and epidermal growth factor gene polymorphisms, and medication response and age at onset of schizophrenia were also studied. The frequencies of TNFalpha A-allele were 11.7 % in patients and 12.8% in controls. The difference was not significant (p = 0.75). TNFalpha -308 polymorphism was not associated with medication response. However, patients with EGF AA and TNFalpha AG/AA genotype had a lower age at onset of schizophrenia compared with the rest of the patients not having this combination (20.0 years, 3.3 vs. 30.2 years, 10.1 mean + SD; p < 0.001). The results support earlier findings according to which TNFalpha polymorphism is not associated with the incidence of schizophrenia. On the other hand, the role of cytokines in schizophrenia may involve genetic interactions predisposing early onset of illness.

The apolipoprotein E (APOE) polymorphism is associated with neurodegenerative diseases. Its role regarding psychiatric disorders is controversial. It has been suggested to affect antidepressant treatment response and response to electroconvulsive therapy (ECT). In the present study, the association between APOE polymorphism and response to ECT in 119 patients with major depressive disorder was investigated. Moreover, a relation between APOE polymorphism and the age of onset of depression as well as the cognitive outcome of ECT was studied. In the whole population, no association was found between APOE polymorphism and response to ECT. However, in nonpsychotic patients, the e2 allele tended to be more frequent in responders than nonresponders. Earlier onset of depression was observed in the patients with e4 allele in late-life depression. There was no association between the APOE genotype and the cognitive change caused by ECT in the population as a whole. In women, however, e2 allele may play a protective and e4 allele a deleterious role in cognition during ECT.

20. Leinonen E, Anttila S, Kampman O, Illi A. Voiko vastetta psyykenlääkkeeseen ennustaa? Duodecim 2005;121:45-52.

Yksilön vastetta psyykenlääkkeisiin ei voida varmasti etukäteen ennustaa kuten ei vastetta muuhunkaan lääkehoitoon. Tietyt potilaaseen ja toisaalta lääkitykseen liittyvät seikat lisäävät kuitenkin lääkehoidon onnistumisen todennäköisyyttä. Potilaan hoitomyöntyvyys on keskeinen onnistumisen edellytys. Tiettyjen psyykenlääkkeiden kuten mielialaa tasoittavien lääkkeiden ja eräiden masennuslääkkeiden tehoa voidaan parantaa lääkeaineiden pitoisuuksia määrittämällä. Hoitovasteeseen vaikuttavaa perinnöllistä vaihtelua tutkitaan intensiivisesti. Lääkehoidon osuvuus paranee, kun hoitovasteeseen vaikuttavat geneettiset polymorfismit saadaan selville.

The aims of the present study were to compare the allele frequencies of a common single nucleotide polymorphism located upstream of the regulator of G-protein signaling 4 (RGS4) gene (T > G, Rs 951436) in 219 Finnish patients with schizophrenia and in 389 control subjects, to analyze corresponding frequencies between two different subtypes of 93 schizophrenia patients according to their medication response, and to study the effect of this SNP on age at onset in schizophrenia.The RGS4 (T > G, Rs 951436) genotype was not associated with incidence or age at onset in schizophrenia. Neither was the RGS4 genotype associated with medication response with two different subpopulations with schizophrenia.

The aim of this study was to investigate the relationship between the functional C957T single-nucleotide polymorphism of the dopamine D2 receptor (DRD2) gene and the risk for schizophrenia. We therefore conducted a case-control association study of 188 Finnish schizophrenia patients meeting the DSM-IV criteria and 384 healthy controls. The 5' nuclease assay (TaqMan) was used to determine genotypes. A greater proportion of patients with schizophrenia than healthy controls were C-allele carriers (odds ratio 1.5, 95% confidence interval (CI) 1.0-2.3, P=0.05). Our results are in agreement with an earlier association study suggesting that the C957T C-allele plays a role in the genetic vulnerability for schizophrenia and support the involvement of the DRD2 gene in schizophrenia pathogenesis.

There is evidence to suggest that dysfunction of dopaminergic neurotransmission in the central nervous system (CNS) plays a role in the etiopathology of schizophrenia. Epidermal growth factor (EGF) gene polymorphism has an impact on EGF production in mononuclear cells, and EGF seems to affect the development of midbrain dopaminergic neurons. The few studies concerning EGF gene polymorphism and schizophrenia have yielded contradictory results. Our aim was to investigate whether EGF gene A61G polymorphism predisposes to schizophrenia, and this polymorphism was therefore studied in 149 schizophrenic patients and in 94 healthy controls using 5' nucleotidase assay (TaqMan). As far as EGF A61G polymorphism was concerned, we detected no significant differences in the allele and genotype frequencies between the patients and the controls. However, the G/G genotype was significantly associated with an earlier age of onset of schizophrenic psychosis in male subjects (P=0.005) as well as in the entire population, but not in female patients (P=0.008 and 0.46, respectively). The average age (+/-SD) of onset of schizophrenia was 20.1+/-3.9 years in male EGF A61G G/G homozygotes and 23.7+/-6.6 (P=0.02) years in other genotypes. In conclusion, EGF gene polymorphism was not associated with the risk of schizophrenia. However, the EGF G/G genotype, which has been suggested to involve abundant production of EGF, was associated with early onset of schizophrenia in male patients.

The aim of the present study was to examine an association of brain-derived neurotrophic factor (BDNF) polymorphisms G196A and C270T and the response to electroconvulsive therapy (ECT) in major depressive disorder (MDD). The study group consisted of 119 patients consecutively admitted for ECT in the Department of Psychiatry, Tampere University Hospital. All patients fulfilled the diagnostic criteria of DSM-IV for MDD. ECT was administered three times a week with a brief pulse constant current device. The Montgomery and Åsberg Depression Rating Scale (MADRS) was used as an outcome measure of depression. Genotyping was performed using fluorescent allele-specific TaqMan probes. No association between either G196A or C270T and the response to ECT was found in the whole population. There were no significant differences in responses between men and women or between psychotic and non-psychotic patients. However, within subgroups such as in psychotic and in late-onset depression CC genotype of C270T may predict good response. BDNF may not be associated with response to ECT in general, but some association in subgroups may exist.

We studied the association between tryptophan hydroxylase 1 (TPH1) A218C and G-protein beta-3 subunit (GNB3) C825T polymorphisms and treatment response in electroconvulsive therapy (ECT). The sample consisted of 119 patients with major depressive disorder (MDD) and 398 controls. Neither TPH1 nor GNB3 polymorphisms are associated with treatment response. However, subjects carrying TPH1 CC genotype are more likely to belong to the patient sample than to the controls. In female subjects, T-allele of GNB3 polymorphism increases the risk of being a treatment-resistant patient with MDD. Moreover, in females the combination of TPH1 CC and GNB3 CT + TT genotype is associated with an increased risk of belonging to the patient group.

Several studies have linked 5-HT1A C1019G and BDNF G196A (Val66Met) gene polymorphisms to major depressive disorder (MDD) and the actions of antidepressants. We attempt to show that the interaction between 5-HT1A and BDNF polymorphism predicts the risk of treatment-resistant depression. The sample consists of 119 patients with treatment-resistant MDD and 392 controls. 5-HT1A C1019G and BDNF G196A (Val66Met) polymorphisms were studied. The combination of 5-HT1A GG and BDNF GA + AA genotypes is associated with an increased risk of depression.

Catechol-O-methyltransferase (COMT) gene has been investigated as a possible candidate gene in schizophrenia. The most studied polymorphism has been the functional val108/158met polymorphism of this COMT gene. There is also some evidence that this polymorphism could be related to drug response to antipsychotics in schizophrenia. COMT enzyme inactivates dopamine and noradrenaline. Based mainly on the original dopamine theory of schizophrenia, our primary hypothesis was that the maintenance dose of antipsychotics would be higher in patients with the low activity COMT genotype. In this study we evaluated the current daily dosage of antipsychotics in 180 patients with schizophrenia in connection with the COMT genotype. We could not demonstrate any clearly significant effect of this particular COMT genotype in relation to the daily maintenance dosages of antipsychotics in patients with schizophrenia.

Background: Schizophrenia is a common psychiatric disease affecting about 1% of population. One major problem in the treatment is finding the right the drug for the right patients. However, pharmacogenetic results in psychiatry can seldom be replicated.

Methods: We selected three candidate genes associated with serotonergic neurotransmission for the study: serotonin 2A (5-HT2A) receptor gene, tryptophan hydroxylase 1 (TPH1) gene, and G-protein beta-3 subunit (GNB3) gene. We recruited 94 schizophrenia patients representing extremes in treatment response to typical neuroleptics: 43 were good responders and 51 were poor responders. The control group consisted of 392 healthy blood donors.

Results: We do, in part, replicate the association between 5-HT2A T102C polymorphism and response to typical neuroleptics. In female patients, C/C genotype was significantly more common in non-responders than in responders [OR=6.04 (95% Cl 1.67-21.93), p=0.005] or in the control population [OR=4.16 (95% CI 1.46-11.84), p=0.005]. TPH1 A779C C/A genotype was inversely associated with good treatment response when compared with non-responders [OR=0.59 (95% Cl 0.36-0.98), p=0.030] or with the controls [OR=0.44 (95% CI 0.23-0.86, p=0.016], and GNB3 C825T C/T genotype showed a trend-like positive association among the male patients with a good response compared with non-responders [OR=3.48 (95% Cl 0.92-13.25), p=0.061], and a clearer association when compared with the controls [OR=4.95 (95% CI 1.56-15.70), p=0.004].

Conclusions: More findings on the consequences of functional polymorphisms for the role of serotonin in the development of brain and serotonergic neurotransmission are needed before more detailed hypotheses regarding susceptibility and outcome in schizophrenia can be formulated. The present results may highlight some of the biological mechanisms in different courses of schizophrenia between men and women.

Several lines of evidence suggest that catechol-O-methyltransferase (COMT) may be associated with treatment response in depression. We conducted a study on 119 patients with treatment-refractory depression admitted consecutively for electroconvulsive therapy (ECT). The COMT high/high genotype leads to a higher enzyme activity and thus lowers dopaminergic activity in the prefrontal cortex. In the present sample, those homozygous to high-active allele of COMT responded significantly more frequently to ECT.

We studied the association between RGS4 (rs951436) polymorphism and treatment response in electroconvulsive therapy (ECT) as well as risk of treatment-resistant depression. The study sample consisted of 119 patients with major depressive disorder (MDD) and 384 healthy control subjects. RGS4 polymorphism was not associated with treatment response in ECT or risk of MDD. According to the present data, the impact of RGS4 genotype is not decisive in major depressive disorder. The results provide preliminary data on the impact of RGS4 polymorphism in treatment response in ECT.

Alterations in dopamine levels and dopamine receptors in brain are suggested to be associated with treatment response in electroconvulsive therapy (ECT). Dopamine 2 receptor gene (DRD2) polymorphism C957T (rs6277) and cathechol-o-methyltransferase (COMT) polymorphism Val158Met (rs4680) interaction was studied in 118 patients suffering from major depressive disorder (MDD) treated with ECT and 383 healthy controls. It was found that the combination of COMT Met allele and DRD2 T allele predicted more severe depression in those already affected but did not predict the risk of depression when compared to normal population. The genotype modified the response to ECT. The patients with TT genotype of D2 receptor gene C957T polymorphism combined with COMT gene polymorphism Met/Met genotype did not achieve remission as often as those with CC genotype of DRD2 C957T combined with COMT Val/Val genotype. Thus the interaction of these polymorphisms may be associated with response to ECT.

32. 32. Stewart J, Kampman O, Huuhka M, Anttila S, Huuhka K, Lehtimäki T, Leinonen E. ACE polymorphism and response to electroconvulsive therapy in major depression. Neurosci Lett 2009 458:122-125.

The angiotensin I-converting enzyme gene (ACE) has been repeatedly suggested as a major gene affecting affective disorders and their treatment, but the study results have been ambiguous so far. The primary purpose of this study was to compare the effects of the ACE genotype distributions and treatment response to electroconvulsive therapy (ECT) in patients with major depressive disorder (MDD). The association in ACE genotypes and the age at onset of depression was also analyzed and these gene distributions were also compared between patients and healthy controls. The study included 119 treatment-resistant MDD patients who were referred to ECT treatment, and 392 voluntary blood donors as controls. All participants were tested for their ACE genotype, and all study patients were evaluated both before and after treatment. The Montgomery-Asberg Depression Scale (MADRS) was used as a primary efficacy evaluating method. The ACE genotype was not associated in treatment results for MDD. However, younger onset age of primary depression was associated with the I/D genotype in the whole patient group. The finding was partly gender dependent; in male patients the I allele carried a higher risk of earlier depression onset age, while in female patients the higher risk was seen only in the heterozygous I/D allele carriers. Distributions of these genotypes or alleles did not differ between patients and controls. The studied ACE genotype was not associated with ECT results but may be associated with age of onset of the illness in patients with MDD.

The association of two tryptophan hydroxylase 2 (TPH2) polymorphisms and treatment response in electroconvulsive therapy (ECT) and the risk of depression was studied. The patient sample consisted of 119 subjects with treatment-resistant major depressive disorder who were treated with ECT. Treatment response was assessed by the Montgomery and Asberg Depression Rating Scale (MADRS) scores. Patients who had <8 scores in post-treatment MADRS were considered remitters; scores >15 indicated non-response. The polymorphisms studied (rs1386494 and rs1843809) were not associated with treatment response to ECT. However, TPH2 rs1386494 A/A genotype carrying patients had significantly higher MADRS scores before ECT than A/G+G/G genotype carriers (p<0.001). A/A genotype carriers also had a greater decline in MADRS scores than A/G+G/G genotype carriers during the course of ECT treatment (p=0.03). This polymorphism may be associated with the severity of treatment-resistant depression. ECT may able to counteract a putative genetically driven worse depressive phenotype.

The association between the tryptophan hydroxylase 1 (TPH1) 218A/C polymorphism and (1) severity of major depressive disorder (MDD) and (2) response to treatment was studied. There were three study populations, the first consisting of 119 treatment-resistant MDD inpatients treated with electro-convulsive therapy (ECT), and the second of 98 MDD open care patients treated with selective serotonin reuptake inhibitors (SSRI). In addition, there was a control population of 395 healthy blood donors. The first aim of the study was to compare the genotypes of the patient with those of the healthy controls and between patient populations. The second aim was to compare the genotypes of MDD patients achieving remission with basic SSRI treatment (MADRS<8) with the genotypes of non-responders to ECT (defined as MADRS>15). TPH1 218A/C polymorphism was associated with the risk of MDD. CC genotype was significantly more common in patients (including both ECT and SSRI treated patients) than in controls (38.2% and 26.8% respectively; p=0.008), and its frequency was significantly higher in more severe forms of depression, i.e. in ECT treated patients compared with SSRI treated patients (42.0% and 33.7%, p=0.026). CC genotype was also associated with lower probability of achieving remission. It was significantly more frequent among ECT non-responders than among SSRI remitters (53.1% and 23.3%, p=0.049). In this Finnish population TPH1 218A/C polymorphism was associated with the risk of MDD and treatment response; CC genotype was associated with the increased risk of MDD and lower probability of responding treatment. Further studies with larger samples will be required to confirm the results.

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