Neuregulin genotype and medication response in Finnish patients with schizophrenia

Kampman, Olli; Anttila, Sami; Illi, Ari; Saarela, Marika; Rontu, Riikka; Mattila, Kari M.; Leìnonen, Esa; Lehtimäki, Terho

doi:10.1097/00001756-200411150-00017

Cited by 47 publications

(29 citation statements)

References 25 publications

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“…It is therefore interesting to note that Green et al 24 showed that subgroups of the two disorders, bipolar disorder with predominantly mood-incongruent psychotic features and schizophrenic cases who had experienced mania, showed a stronger association in their sample. Similarly, Bakker et al 48 reported that, while schizophrenia was not associated with the two Hap ICE markers examined, a subgroup of nondeficit schizophrenia was associated, and Kampman et al 49 reported association of the single Hap ICE SNP tested in only schizophrenic individuals who do not respond to conventional antipsychotics (P = 0.013). These results may indicate that subgroups of schizophrenia and bipolar disorder are associated with NRG1, and further that some regions of the gene may confer risk to both bipolar and schizophrenia and others to only one of the diagnoses.…”

Section: Discussionmentioning

confidence: 93%

Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population

et al. 2006

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Neuregulin 1 (NRG1) is a strong candidate for involvement in the aetiology of schizophrenia. A haplotype, initially identified as showing association in the Icelandic and Scottish populations, has shown a consistent effect size in multiple European populations. Additionally, NRG1 has been implicated in susceptibility to bipolar disorder. In this first study to select markers systematically on the basis of linkage disequilibrium across the entire NRG1 gene, we used haplotype-tagging single-nucleotide polymorphisms to identify single markers and haplotypes associated with schizophrenia and bipolar disorder in an independently ascertained Scottish population. Haplotypes in two regions met an experiment-wide significance threshold of P = 0.0016 (Nyholt's SpD) and were permuted to correct for multiple testing. Region A overlaps with the Icelandic haplotype and shows nominal association with schizophrenia (P = 0.00032), bipolar disorder (P = 0.0011), and the combined case group (P = 0.0017). This region includes the 5 0 exon of the NRG1 GGF2 isoform and overlaps the expressed sequence tag (EST) cluster Hs.97362. However, no haplotype in Region A remains significant after permutation analysis (P > 0.05). Region B contains a haplotype associated with both schizophrenia (P = 0.00014), and the combined case group (P = 0.000062), although it does not meet Nyholt's threshold in bipolar disorder alone (P = 0.0022). This haplotype remained significant after permutation analysis in both the schizophrenia and combined case groups (P = 0.024 and P = 0.016, respectively). It spans a B136 kb region that includes the coding sequence of the sensory and motor neuron derived factor (SMDF) isoform and 3 0 exons of all other known NRG1 isoforms. Our study identifies a new of NRG1 region involved in schizophrenia and bipolar disorder in the Scottish population.

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Section: Discussionmentioning

confidence: 93%

Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population

et al. 2006

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“…However, it has been suggested that NRG1 may play a role in clinical outcome via regulation of glutamate, GABA and acetylcholine receptors, a hypothesis supported by a positive finding of association between a NRG1 polymorphism and treatment response. 154 The brain-derived neurotrophic factor (BDNF) is involved in the development, survival and functional maintenance of neurons, and plays a role in the regulation of expression of dopamine-related systems. BDNF variants have been related to schizophrenia, but only marginal association or negative significance has been described in relation to treatment response.…”

Section: Developmental and Regulatory Genesmentioning

confidence: 99%

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

2007

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The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients' metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic. Alternatively, CYP2D6 ultrarapid matabolizers (UMs) will need increased drug dosage to obtain therapeutic response. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. In particular, there is important evidence suggesting association between dopamine 2 receptor (D2) polymorphisms (Taq I and À141-C Ins/Del) and a dopamine 3 receptor (D3) polymorphism (Ser9Gly) with antipsychotic response and drug-induced tardive dyskinesia. Additionally, there is accumulating evidence indicating the influence of a 5-HT2C polymorphism (À759ÀT/C) in antipsychotic-induced weight gain. Application of this knowledge to clinical practice is slowly gathering pace, with pretreatment determination of individual's drug metabolic rates, via CYP genotyping, leading the field. Genetic determination of patients' metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions. Genetic tests for the pretreatment prediction of antipsychotic response, although still in its infancy, have obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered as successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research in psychiatric clinical practice are far from being realized. Further development of genetic tests is required before the concept of tailored treatment can be applied to psychopharmatherapy. This review aims to summarize the key findings from the last decade of research in the field. Current knowledge on genetic prediction of drug metabolic status, general response and drug-induced side effects will be reviewed and future pharmacogenomic and epigenetic research will be discussed.

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“…In view of the relationships between NRG1-ErbB4 function and the pathophysiology of schizophrenia, and between antipsychotic treatment and schizophrenia symptoms, the key questions are whether antipsychotic drugs regulate the NRG1-ErbB4 signalling, and how this regulation contributes to their efficacy in controlling schizophrenia symptoms? It is very interesting that schizophrenia patients with different NRG1 genotypes have been reported to respond differently to typical antipsychotics (Kampman et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Antipsychotic treatment and neuregulin 1–ErbB4 signalling in schizophrenia

Pan

Huang

Deng

2011

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Evidence from genetic, transgenic and post-mortem studies has strongly supported the critical role that neuregulin 1 (NRG1) and its ErbB4 receptor plays in the pathophysiology of schizophrenia. This article aims to review current evidence regarding the effects of antipsychotic treatment on NRG1-ErbB4 signalling. NRG1 and ErbB4 knockout mice display abnormal behaviours relevant to certain features of schizophrenia, which could be improved by antipsychotic (clozapine/haloperidol) treatment. In contrast to most NRG1/ ErbB4 knockout mice with a decreased NRG1-ErbB4 signalling, the majority post-mortem studies showed an increased NRG1-ErbB4 signalling in schizophrenic patients. These differences could be due to degrees of alteration in risk genes (subtle variations in patients vs pronounced alteration in mutant mice) or the duration of the modification on NRG1 signalling. Various antipsychotics have different effects on NRG1 and ErbB4 expression and signalling that are dependent on treatment duration. Current evidence suggests that a chronic (12 weeks) antipsychotic treatment, at least in animal models, could downregulate NRG1-ErbB4 signalling, although an upregulation is seen for a short-term treatment. These effects may be due to multiple binding profiles with various G-coupled protein receptors (e.g. dopamine, and serotonin receptors) of antipsychotics. Studies are needed to investigate the interactions between NRG1-ErbB4 and the other signalling pathways (such as glutamatergic, GABAergic and dopaminergic). Furthermore, the interactions between NRG1/ErbB4 and other schizophrenia suspensibility genes under antipsychotic treatment also require investigation. and ErbB4 knockout mice display some schizophrenia-like behavioural abnormalities, which could be improved by antipsychotic (clozapine/haloperidol) treatment. In contrast to NRG1/ErbB4 knockout mice with a decreased NRG1-ErbB4 signalling, the majority post-mortem studies showed an increased NRG1-ErbB4 signalling in schizophrenia patients. These differences could be due to degrees of alteration in risk genes (subtle variations in patients vs pronounced alteration in mutant mice) or the duration of the modification on NRG1 signalling. Various antipsychotics have different effects on NRG1 and ErbB4 expression and signalling dependent on treatment duration. Current evidence suggests that a chronic (12 weeks) antipsychotic treatment, at least in animal models, downregulates NRG1-ErbB4 signalling, although an upregulation is seen for a short term treatment. Therefore, the dysfunctional NRG1-ErbB4 signalling observed in schizophrenia is unlikely to be due to antipsychotic therapy. Furthermore, multiple-receptor binding profiles (e.g. dopamine, and 5-HT receptors) of antipsychotics may also contribute to their different influences on NRG1-ErbB4 signalling. Studies are also needed to investigate the interactions between NRG1-ErbB4 and the other signalling pathways (such as glutamatergic, GABAergic and dopaminergic).

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Neuregulin genotype and medication response in Finnish patients with schizophrenia

Cited by 47 publications

References 25 publications

Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population

Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

Antipsychotic treatment and neuregulin 1–ErbB4 signalling in schizophrenia

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