Research report
Neuroticism as a mediator of treatment response to SSRIs in major depressive disorder

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Abstract

Background

Serotonin function has been implicated in both major depressive disorder and neuroticism. In the current investigation, we examined the hypothesis that any change in depression severity is mediated through the reduction of neuroticism, but only for those compounds which target serotonin receptors.

Methods

Ninety-three outpatients in the midst of a major depressive episode received one of three antidepressant medications, classified into two broad types: selective serotonin reuptake inhibitors (SSRIs) and non-SSRIs (i.e. reversible monoamine oxidase inhibitors [RIMAs] and noradrenergic and dopaminergic reuptake blockers [NDMs]). Patients completed the Hamilton Rating Scale for Depression, Beck Depression Inventory II and Revised NEO Personality Inventory prior to and following approximately 16 weeks of treatment. Structural equation modeling was used to test two models: a mediation model, in which neuroticism change is the mechanism by which SSRIs exert a therapeutic effect upon depressive symptoms, and a complication model, in which neuroticism change is a mere epiphenomenon of depression reduction in response to SSRIs.

Results

The mediation model provided a good fit to the data; the complication model did not. Patients treated with SSRIs demonstrated greater neuroticism change than those treated with non-SSRIs, and greater neuroticism change was associated with greater depressive symptom change. These effects held for both self-reported and clinician-rated depressive symptom severity.

Limitations

Replication within a randomized control trial with multiple assessment periods is required.

Conclusion

Neuroticism mediates changes in depression in response to treatment with SSRIs, such that any treatment effect of SSRIs occurs through neuroticism reduction.

Introduction

Serotonin receptor systems have been implicated in major depressive disorder (Bhagwager et al., 2006, Meyer et al., 2003), and many of the current pharmacological treatments for this disorder are thought to specifically target the serotonergic system (American Psychiatric Association, 2000). Despite slight variations in pharmacological profile, selective serotonin reuptake inhibitors (SSRIs) have a specific and direct effect on the serotonin system via inhibition of the serotonin transporter (Meyer et al., 2004, Voineskos et al., 2007). Yet, uncertainty remains as to the mechanisms by which SSRIs exert therapeutic effects.

In very recent reports, several investigators have shown that serotonin receptors are also associated with the personality trait of neuroticism (Frokjaer et al. 2008, Takano et al., 2007). Moreover, neuroticism is associated with the short variant of the serotonin transporter gene (Gonda et al., 2006, Rihmer et al., 2007, Schmitz et al., 2007), further supporting the potential of this trait as a behavioural endophenotype and mediator of depressive symptoms. Neuroticism, as assessed by self-report measures such as the Eysenck Personality Questionnaire-Revised (EPQ-R; Eysenck and Eysenck, 1994) and Revised NEO Personality Inventory (NEO PI-R; Costa and McCrae, 1992), is the general tendency to experience negative affects such as anxiety, sadness, embarrassment, anger, guilt and disgust. Individuals high in neuroticism are emotional, insecure, impulsive, susceptible to psychological distress and vulnerable to stress. Neuroticism is strongly associated with depressive symptoms (Bagby et al., 2008), and has been long proposed to be a vulnerability factor for the development of major depressive disorder (Boyce et al., 1991, Duggan et al., 1995). This trait has further been shown to be heritable (Ebstein, 2006, Kendler et al., 2006), biologically based (Canli, 2004) and generalizable across different languages, cultures and countries (McCrae and Allik, 2002, McCrae and Terracciano, 2005).

The relation between serotonergic neurotransmission, major depressive disorder and neuroticism can be understood in at least two principal ways and can be statistically modeled: (1) serotonin transmitter function influences neuroticism, which in turn influences depressive symptoms; or (2) serotonin transmitter function influences depressive symptoms, which in turn influence neuroticism. In the first model, neuroticism is posited to mediate the impact of serotonergic function change on depressive symptomatology; that is, all changes in depressive symptoms in response to SSRI treatment are causally preceded by changes in neuroticism, and presumably the alteration of the receptors associated with it. In the second model, neuroticism is posited to be a mere epiphenomenon of depression severity; that is, all changes in neuroticism over the course of SSRI treatment are viewed as a by-product state effect or mere proxy measure of depressive symptom change (Hirschfeld et al., 1983). In this study, we examine the specific mediating role of neuroticism in the treatment of depression with SSRIs. We utilize structural equation modeling (SEM), a powerful statistical procedure in which these competing models can be tested (Kline, 2005, Shrout and Bolger, 2002).

In the current investigation, we examined the relation between neuroticism, depression and treatment outcome in two studies involving distinct classes of antidepressant medication. As indicated earlier, SSRIs modulate serotonergic neurotransmission through selective targeting of the serotonin receptors. In contrast, reversible monoamine oxidase inhibitors (RIMAs) such as moclobemide, and noradrenergic and dopaminergic reuptake inhibitors (NDMs) such as buproprion are not believed to directly influence serotonergic transmission (Nutt and Kennedy, 2004). These different classes of antidepressant medication provide an ideal contrast with which to test the specificity of the mediational role of neuroticism in the treatment of major depressive disorder. We propose that change in neuroticism is the mediator for change in depression severity, but only for SSRIs.

To clarify the mediational role of neuroticism in the treatment of depression with SSRIs, we tested two models using SEM: the “mediation” model (i.e. SSRI → Neuroticism Change → Depression Change) and the “complication” model (i.e. SSRI → Depression Change → Neuroticism Change). To this end, we performed a series of SEM analyses in which separate models were designed to test the adequacy of the mediation model vs. the complication model. For these analyses, fit indices specify which of these two models is the best representation of the relation between depression and neuroticism, and parameter estimates indicate whether significant mediation is present. We hypothesized that the mediation model would provide a good fit to the data, whereas the complication model would not. We also hypothesized that the following effects would characterize the causal pathways of the mediation model: (1) SSRIs will lead to greater reduction in neuroticism compared to NDMs/RIMAs, and (2) greater reduction in neuroticism will lead to greater reduction in depressive symptoms.

Section snippets

Participants

To maximize statistical power, we combined data from a naturalistic, clinic-based study and a RCT treatment study. In both studies, the medications administered included SSRIs, NDMs and RIMAs. Participants were 62 male and 89 female outpatients at the Centre for Addiction and Mental Health, a large psychiatric centre in Toronto, Ontario.

Patients from both studies were required to meet DSM-IV criteria for current major depressive disorder, assessed using the Structured Interview for DSM-IV, Axis

Patient characteristics

Demographic characteristics for the two medication groups are displayed in Table 1. There were no significant differences between the SSRI and the NDM/RIMA treatment groups for age (t = .52, p = .60), sex (χ2 = .01, p = .94), SES (t = .52, p = .60), or marital status (χ2 = 1.22, p = .87). Pre-treatment and post-treatment depression severity and neuroticism scores for the two medication groups are also displayed in Table 1. There were no significant differences between the SSRI and the NDM/RIMA groups for

Discussion

The results are consistent with previous research across clinical and non-clinical populations that decreases in neuroticism during treatment co-occur with reductions in depressive symptoms (Bagby et al., 1999, Du et al., 2002, Knutson et al., 1998). These results are also consistent with previous research that has demonstrated that such changes in neuroticism are not completely accounted for, or redundant with, changes in depression (e.g., Costa et al., 2005, De Fruyt et al., 2006).

Conclusions

Results from the present study implicate the personality dimension neuroticism as a mediator of treatment response during treatment with a selective serotonin reuptake inhibitor. These findings provide insight into the personality factors underlying treatment response in individuals with depression, and enable a more precise characterization of the interrelations between personality and major depressive disorder.

Role of funding source

Nothing declared.

Conflict of interest

No conflict declared.

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