Our results demonstrate a significantly negative relationship between neuroticism—more specifically, anxiety—with subsequent response to a 4-week course of escitalopram. Although the strong correlation may be spurious, this finding persisted on a follow-up completer analysis. There is also some, albeit inconsistent, support in the literature for this finding. Contrary to our initial hypothesis, O3FA levels did not predict early antidepressant response; in fact, a trend was observed in the opposite direction in this small sample. One could alternatively hypothesize that, given the associations between DHA depletion and low serotonin levels,50
those with lower O3FA levels may be more likely to respond to treatment with escitalopram.
Studies of personality and antidepressant response have produced varied results and have had substantial methodological variation, including that related to the measurement of neuroticism. Only 2 studies have assessed neuroticism using the NEO-PI, a more comprehensive and contemporary assessment.21,28
Of these studies, Bagby et al allowed treatment with any antidepressants over 5 weeks; they found extraversion but not neuroticism to predict response, although neuroticism was correlated with depression indices at the onset and conclusion of the study, and analyses of facets as predictors were not reported.28
Tanum et al used mianserin for the treatment of functional gastrointestinal disorders, not depression, and found that those whose pain did not remit had higher baseline neuroticism raw scores. Neither study used the current revision of the NEO, the NEO-PI-R. Two studies using the abbreviated NEO Five-Factor Inventory (NEO-FFI) found no differences in neuroticism indices between responders and nonresponders.25,27
The NEO-FFI provides only information on personality domains and does not allow a more refined facet analysis, as performed in our follow-up analysis. Other studies have used clinician assessment or the Eysenck Personality Inventory, in which neuroticism is less reliably or more broadly defined.23,24,26,51
Our refined analysis demonstrated the strongest association for the anxiety facet within the domain of neuroticism. The NEO-PI-R is a self-report measure, and questions for anxiety include—though are not limited to—“I am not a worrier” (reverse scored), “I am easily frightened,” and “I often feel tense and jittery.” Anxiety as measured by the self-report NEO-PI-R is a personality trait, which may be amplified in the setting of major depression.32
The apparent focus of our finding on a more narrowly defined facet within neuroticism may explain the discrepancy on prior findings. Trait anxiety or an anxious temperament has long been suggested as a predisposing factor for depression,52,53
although it has not been studied for antidepressant response as conceptualized by the NEO-PI-R. Recent reports from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial suggest that those with a categorically defined anxious depression differ in terms of baseline characteristics and are less likely to remit on antidepressants.54,55
Based on these findings, Fava et al concluded that anxious depression may be a valid diagnostic subtype of MDD.55
Extending these categorical conclusions, our findings suggest that a dimensional measure of anxiety may further have predictive validity.
Recent studies have suggested an association between serotonin receptor binding and neuroticism,56,57
and variants of the serotonin transporter gene have been associated both with neuroticism and anxiety-related traits.58,59
The lower functioning variants of the promoter for the serotonin transporter gene, reduced to the short allele in most studies, have further been linked to reduced antidepressant response.60
Our findings may imitate such variations in serotoninergic function or, more likely, reflect even more complex genotype or gene-environment interactions. Mechanistic considerations aside, these findings, if replicated, may be clinically useful.
There are several important limitations of this study. This sample size limits statistical power, although a statistically significant finding was identified. The magnitude of the observed effect is admittedly greater than would be expected and may be exaggerated in this small sample. Our sample included patients who had not been responding to a stable dose of an antidepressant, which may select for nonresponders in the current episode. Exclusion criteria were reported in brochures and to referring sources, so our enrollment rate following screening may overestimate the true generalizability of this finding to populations with major depression. Although our trial used recommended starting doses for escitalopram, rapid titration of serotonergic antidepressants may be associated with worsening anxiety, particularly in anxiety-prone individuals. This phenomenon has been referred to as the “jitteriness syndrome”61
and could perhaps have attenuated clinical improvement. A relatively low dose of escitalopram was used in this study, and some clinicians may have titrated more quickly to higher doses, particularly for those patients not previously responding to a stable dose of an antidepressant. However, this approach does not improve response rates,62
and given the elevated risk of worsening anxiety with rapid titration of antidepressants in anxiety-prone individuals, a more aggressive titration would have been unlikely to weaken the association observed. Patients on prior antidepressants were directly transitioned to escitalopram, which could result in a discontinuation syndrome, although no such symptoms were observed. Strengths of our study include our use of a rigorous erythrocyte O3FA analysis, use of a fixed-dose of a single antidepressant over a consistent time period, and use of the comprehensive and contemporary NEO-PI-R. Our use of continuous variables in the analysis further improved statistical power and mitigated the risk of our findings simply reflecting an artifact of dichotomization.