Association of the C(− 1019)G 5-HT1A promoter polymorphism with exposure to stressors preceding hospitalization for bipolar depression

Abstract

Rationale

In animals, a higher density of 5-HT1A receptors has been associated with increased behavioral despair after stress. In humans, the G variant of the C(− 1019)G 5-HT1A receptor promoter gene polymorphism (rs6295) has been associated with higher expression of 5-HT1A receptors, increased depression, and lower stress preceding completed suicide.

Objectives

We studied the association of rs6295 with the amount of stress in early life and preceding hospitalization for a major depressive episode in course of bipolar disorder.

Materials and methods

In 74 consecutively admitted inpatients, early life and recent stressors were rated on the Social Readjustment Rating Scale and on the Risky Family Questionnaire.

Results

Homozygote carriers of the rs6295 G variant reported less stressful events before current hospitalization for bipolar depression, but not in early life. The G variant was also associated with a higher overall medication load in naturalistic settings before hospitalization.

Conclusions

This is the first study that associated 5-HT1A receptor promoter gene variants with stressors preceding the need of hospitalization for bipolar depression. Our findings support the hypothesis that genetic factors affecting serotonergic neurotransmission might contribute to shape the individual resilience to the depressogenic effects of stress in clinical settings.

Introduction

Factors affecting serotonergic function, including gene polymorphisms, could influence the relationship between depression and resilience to stress (Southwick et al., 2005). Serotonergic modulation of the acute response to stress and the adaptation to chronic stress is mediated by many molecules controlling serotonin neuron development, synthesis, packaging, actions at presynaptic and postsynaptic receptors, reuptake, and degradation (Holmes, 2008).

The 5-hydroxytryptamine 1A (5-HT1A) receptor is an inhibitory G protein-coupled receptor expressed both in serotonergic neurons, as a self-inhibitory autoreceptor, and in post-synaptic neurons in corticolimbic regions. Mice expressing higher levels of 5-HT1A autoreceptors showed a blunted physiological response to stress, increased behavioral despair, and no response to antidepressants (Richardson-Jones et al., 2010). In depressed humans, 5-HT1A inhibitors rapidly potentiate antidepressants (Celada et al., 2004).

The G variant of the C(− 1019)G 5-HT1A receptor promoter gene polymorphism (rs6295) was associated with higher expression of 5-HT1A by derepression of the promoter in presynaptic raphe neurons, thus leading to reduced serotonergic neurotransmission by increased auto-inhibition of the neurons (Lemonde et al., 2003). In patients affected by major depression the G variant was associated with worse antidepressant response (Lemonde et al., 2004, Parsey et al., 2006, Serretti et al., 2004) and with a higher risk of developing a major depressive episode and of committing suicide (Lemonde et al., 2003), although others failed to confirm this latter association (Serretti et al., 2007, Wasserman et al., 2006).

No effects were found in the general population (Chipman et al., 2010), thus suggesting that the susceptibility is only revealed in the context of disease. Brain imaging studies supported the above, by associating a higher binding for 5-HT1A with the G allele in patients affected either by unipolar (Parsey et al., 2006, Parsey et al., 2010) or bipolar depression (Sullivan et al., 2009), but not in healthy subjects (David et al., 2005).

If the G(− 1019) allele enhances the negative feedback inhibition of serotonergic neurons, thus predisposing to depression and suicide by worsening the detrimental effects of stress, a relationship between the occurrence of stressful life events and depressive psychopathology should be correlated to the presence of rs6295 different genotypic patterns.

Following this hypothesis, two studies found non-significant trends suggesting a gene–environment interaction (Chipman et al., 2010, Wasserman et al., 2006), and one study in suicide completers found the G allele to be associated with significantly less recent stressors preceding suicide, but not with adverse childhood experiences (Videtic et al., 2009). This finding indirectly confirmed a different resilience to the acute depressogenic effect of stress, depending on 5-HT1A density.

If this is true, a similar relationship between early and recent stress and rs6295 should be observed in patients referred for hospitalization for current depression. We tested this hypothesis in a homogeneous sample of patients affected by a major depressive episode in course of bipolar disorder.