Dysbindin (DTNBP1) – A role in psychotic depression?

Abstract

Previous studies yielded evidence for dysbindin (DTNBP1) to impact the pathogenesis of schizophrenia on the one hand and affective disorders such as bipolar or major depressive disorder (MDD) on the other. Thus, in the present study we investigated whether DTNBP1 variation was associated with psychotic depression as a severe clinical manifestation of MDD possibly constituting an overlapping phenotype between affective disorders and schizophrenia.

A sample of 243 Caucasian inpatients with MDD (SCID-I) was genotyped for 12 SNPs spanning 92% of the DTNBP1 gene region. Differences in DTNBP1 genotype distributions across diagnostic subgroups of psychotic (N = 131) vs. non-psychotic depression were estimated by Pearson Chi² test and logistic regression analyses adjusted for age, gender, Beck Depression Inventory (BDI) and the Global Assessment of Functioning Scale (GAF).

Overall, patients with psychotic depression presented with higher BDI and lower GAF scores expressing a higher severity of the illness as compared to depressed patients without psychotic features. Four DTNBP1 SNPs, particularly rs1997679 and rs9370822, and the corresponding haplotypes, respectively, were found to be significantly associated with the risk of psychotic depression in an allele-dose fashion.

In summary, the present results provide preliminary support for dysbindin (DTNBP1) gene variation, particularly SNPs rs1997679 and rs9370822, to be associated with the clinical phenotype of psychotic depression suggesting a possible neurobiological mechanism for an intermediate trait on the continuum between affective disorders and schizophrenia.

Introduction

Psychotic major depression (PMD) is conceptualized as a severe clinical subphenotype of major depressive disorder (MDD) presenting with psychotic features such as feelings of worthlessness or guilt, delusions or hallucinations (APA, 2004, Coryell et al., 1984, Glassman and Roose, 1981, Lykouras et al., 1986, Thakur et al., 1999). PMD is diagnosed in 19–25% of depressed patients (Coryell et al., 1984, Ohayon and Schatzberg, 2002). Psychotic depression is associated with greater illness severity, higher rates of illness chronicity, relapse, more frequent hospitalizations and a higher risk of suicide (for review see Gaudiano et al., 2008) as well as higher levels of dopamine (Schatzberg and Rothschild, 1992). By some authors PMD has thus been suggested to possibly constitute a distinct clinical entity (e.g., Glassman and Roose, 1981, Schatzberg and Rothschild, 1992). Given a number of clinical and biological characteristics apparently being specific for psychotic depression, one might assume a particular genetic risk profile predisposing to the development of major depression with psychotic features (cf. Serretti et al., 1999). Identification of risk genes of psychotic depression could contribute to a better understanding of the underlying pathomechanism of this particular subtype of depression and consequently possibly also to the development of more targeted treatment options for PMD (cf. Schatzberg, 2003).

In the context of psychotic symptoms, dysbindin is a promising candidate molecule: dysbindin binds to alpha- and beta-dystrobrevin as components of the dystrophin-associated protein complex (DPC) (Benson et al., 2001). Dysbindin is involved in glutamatergic neurotransmission by influencing exocytotic glutamate release (Numakawa et al., 2004, Straub et al., 2002) with high levels of dysbindin in cells of the intrinsic glutamatergic pathways of the hippocampus as well as an inverse correlation with vesicular glutamate transporter-1 (Talbot et al., 2004). Glutamatergic neurotransmission as partly driven by dysbindin has been shown to mediate noradrenergic and serotonergic drug effects in antidepressant response (Yagasaki et al., 2006, Yoshimizu et al., 2006) and in addition to play a major role in the pathogenesis of schizophrenia as well as in the mediation of neuroleptic treatment (for review see: Goff and Coyle, 2001, Numakawa et al., 2004, Heresco-Levy, 2005). This renders dysbindin a prime candidate in the investigation of the overlapping phenotype of psychotic major depression.

The gene coding for dysbindin (dystrobrevin-binding protein 1; DTNBP1) is located on chromosome 6p22.3, a consistently replicated susceptibility region in schizophrenia as well as affective disorders (cf. Lewis et al., 2003, Park et al., 2004). Besides converging evidence for a major role of DTNBP1 gene variants in the pathogenesis of schizophrenia (Straub et al., 2002, Schwab et al., 2003; van den Bogaert et al., 2003; van den Oord et al., 2003, Funke et al., 2004, Kirov et al., 2004, Bray et al., 2005, Pae et al., 2008, Pae et al., 2009), DTNBP1 gene variation has also been implicated in psychotic features associated with bipolar disorder (Raybould et al., 2005) as well as in the aetiology of major depression (Kim et al., 2008). Additionally, in a sample of patients with schizophrenia some evidence for association between DTNBP1 gene variants and anxiety/depression symptoms was observed (Wirgenes et al., 2009). These findings underline a potential role of DTNBP1 in the well-known shared genetic susceptibility to psychotic and affective disorders (for review see Maier, 2008, Van Den Bogaert et al., 2006, Wildenauer et al., 1999) as possibly captured by the phenotype of psychotic depression comprising both affective and psychotic symptoms.

Thus, in the present study the role of dysbindin in the pathogenesis of psychotic depression was further investigated by analyzing a representative number of DTNBP1 polymorphisms for association with the clinical phenotype of psychotic depression.