Targeting Neuroticism May Help Predict Long-Term Outcomes in Major Depression
By Caroline Cassels
Medscape Medical News
December 23, 2009 — The selective serotonin reuptake inhibitor (SSRI) paroxetine (Paxil, GlaxoSmithKline) appears to have a positive effect on personality that is separate and distinct from its antidepressant effects — a finding researchers say may assist in the prediction of long-term outcomes in patients with major depression.
A large placebo-controlled trial led by Tony Z. Tang, PhD, Northwestern University, Evanston, Illinois, showed patients with major depressive disorder (MDD) taking paroxetine underwent greater personality change than those taking placebo, including a significant reduction in neuroticism and a marked increase in extraversion, even after controlling for depression improvement.
Investigators found patients taking paroextine reported 6.8 times as much change on neuroticism and 3.5 times as much change on extraversion as placebo patients matched for depression improvement.
"People on paroxetine had a reduction in neuroticism and an increase in extraversion, but probably more important than that is if you look at the difference between the paroxetine group and the placebo group, the difference on those 2 personality dimensions are much bigger than on their difference of depression severity," Dr. Tang told Medscape Psychiatry.
If replicated, these results may lay waste to the so-called "state effect" hypothesis, which asserts that any personality changes that occur during SSRI treatment are the direct result of improvement in depressive symptoms.
The study is published in the December issue of the Archives of General Psychiatry.
Greater Personality Change
According to the investigators, high neuroticism is a personality risk factor that reflects much of the genetic vulnerability to MDD, and low extraversion may increase risk as well. Both personality traits have been linked to the serotonin system, the key therapeutic target for SSRIs.
To explore the potential effect of SSRI treatment on neuroticism and extraversion, the investigators randomly assigned 240 MDD patients aged 18 to 70 years to receive paroxetine (n = 120), placebo (n = 60), or cognitive therapy (n = 60).
The study's main outcome measure was change in the NEO Five-Factor Inventory (NEO-FFI), a widely used self-report measure used in personality research, and the Hamilton Rating Scale for Depression.
Following an acute treatment phase, responders to cognitive therapy and paroxetine entered a 12-month continuation phase. Paroxetine responders were randomly assigned to 2 subgroups — 34 continued taking the medication at the same dose, and 35 were withdrawn from the active drug and given the placebo. The 35 participants who responded to cognitive therapy were allowed up to 3 booster sessions scheduled 1 month apart.
The investigators found that patients who received paroxetine reported greater personality change than placebo patients, even after controlling for depression improvement (P < .001; extraversion, P = .002).
Further, Dr. Tang pointed out the advantage of paroxetine over placebo in terms of its antidepressant effect was no longer significant after controlling for change in neuroticism (P = .46) or extraversion (P = .14).
In addition, the authors report that although placebo patients exhibited substantial depression improvement, they experienced little change in neuroticism or extraversion.
Patients in the cognitive therapy group experienced a greater personality change than placebo (P ? .01), but its effect on neuroticism was no longer significant after controlling for depression.
Lower Relapse Rates
Importantly, said Dr. Tang, neuroticism reduction during treatment predicted lower relapse rates among paroxetine responders (P = .003) but not among cognitive therapy responders (P = .86).
"We were surprised by quite a few of the findings — one of the biggest surprises was how well neuroticism improvement predicted long-term outcomes," said Dr. Tang.
The biggest challenge in treating depression is achieving good long-term outcomes. "Initial response and recovery comes fairly easily, but relapse rates are high so that within a year, a large proportion of patients end up back in the clinic," he said.
However, he added, this study suggests the chances of relapse in patients who experience a large improvement in neuroticism are much, much lower than those who recover but who do not show much neuroticism improvement.
"This finding is very surprising partly because physicians don't generally expect any type of long-lasting impact from [SSRIs] but these data seem to suggest there might be an enduring effect and that this could be very important to long-term outcomes," said Dr. Tang.
"Our data show that 84% of patients who showed the least amount of neuroticism improvement relapsed. If these findings can be replicated, it suggests that you could predict which patients are at high risk of relapse and direct the appropriate resources towards them to prevent it from occurring," he added.
No Clinical Implications Yet
Asked by Medscape Psychiatry to comment on the study findings, Michelle Riba, MD, from the University of Michigan in Ann Arbor, and a past president of the American Psychiatric Association, said the study makes an important contribution to the depression literature.
However, she pointed out, physicians probably should not be targeting neuroticism as a clinical outcome just yet.
"Although this study is interesting clinically, we don't tend to look at neuroticism and extraversion in everyday clinical practice, and so I don't think these findings will, or should, change anyone's clinical practice today," she said.
She added that it was unclear why the investigators chose paroxetine as the study drug, as it is not as widely used as other SSRIs because of its propensity to interfere with other medications.
Dr. Riba noted that the NEO-FFI is largely a research tool and not in wide use in clinical practice. Furthermore, she noted the wide age range of subjects (18 - 70 years) and the fact that excluding individuals with antisocial, borderline, and/or schizotypal disorders from the study may affect the generalizability of the findings.
"This is a well-done study, but clinicians already understand that personality is important in depression. When a patient is not getting better with standard antidepressant treatment, we often go back to the drawing board and look at the personality issues that may be affecting the depression," said Dr. Riba.
The authors have disclosed no relevant financial relationships.
