Clinical correlates of the worsening or emergence of suicidal ideation during SSRI treatment of depression: An examination of citalopram in the STAR⁎D study

Abstract

Background

Untreated major depressive disorder (MDD) is a major risk factor for suicide, but some data suggest antidepressants may be associated with increased suicidal ideation (SI) in some depressed patients. The purpose of this study was to determine whether, and in whom, treatment of MDD is associated with increased or emergent SI.

Methods

Patients were treated with Citalopram, 10–60 mg/day for 12–14 weeks. A score > 0 on Item 12 of the Quick Inventory of Depressive Symptomatology — Self-Report indicated the presence of SI. Worsening was defined by a ≥ 1 point increase. Emergent SI was defined by an increase from 0 at baseline to ≥ 1 during treatment.

Results

Of the 1909 participants with baseline SI, 57% experienced improvement in SI by their first post-baseline visit and 5% worsened. By the final visit, 74% experienced improvement and 4% worsened. Of 1721 participants without baseline SI, 7% experienced emergence by the first postbaseline visit. Of these, 63% had no SI at their final visit. Major risk factors for treatment-emergent SI at the first treatment visit were drug abuse, severe depression and melancholic features.

Limitations

Main limitations are lack of a comparison group to help pinpoint whether citalopram treatment added risk or protection, a placebo group to determine whether changes in SI were related to illness factors, medication effects or other factors, and more detailed and validated measures of SI.

Conclusions

SI and behaviors, core features of MDD, wax and wane in intensity before, during, and perhaps after treatment. It is clinically important to understand risk factors, maintain careful surveillance and treat as vigorously as necessary to attain remission.

Introduction

Suicide, the 11th leading cause of death among adults in the United States (Centers for Disease Control and Prevention, 2008) ends the life of more than one in 10,000 Americans every year (Hoyert et al., 2006). Suicide takes an enormous toll in terms of family and survivor suffering, and it causes a staggering economic burden that includes $11.8 billion/year in lost income (Goldsmith et al., 2002). Psychiatric illnesses, especially major depressive disorder (MDD), are closely linked to suicide.

There are many effective treatments for MDD (Leon et al., 2003) but some treatments may at least transiently be associated with an increase in suicidal ideation (thoughts of suicide), particularly in youths and younger adults (Laughren, 2006). This information, combined with the high prevalence of depression-related suicidal ideation, behavior and intent, and the potential role of antidepressant medication in preventing suicide makes it imperative to clarify the influence of antidepressants on suicidal risk (Moller, 2006). Clinical studies have reported that antidepressants a) may increase suicidal ideation and/or behaviors, (Fergusson et al., 2005, Juurlink et al., 2006, Teicher et al., 1990) b) have no effect on suicide risk, c) decrease risk, (Gibbons et al., 2007, Moller, 2006, Moller, 2003, Montgomery et al., 1995, Simon and Savarino, 2007) and d) protect against suicidal behaviors over the long term (Yerevanian et al., 2004). These mixed findings suggest either a very weak relationship or that the risks or benefits differ depending on patient subgroups. Ultimately, the most important question may not be whether antidepressants increase or decrease suicide risk, but rather which ones, for whom, when, and under what circumstances.

Risk factors for antidepressant-induced suicidal ideation and behaviors are not well established. Studies have reported all of the following: all antidepressants are about equally likely to increase suicide (Khan et al., 2003), selective serotonin reuptake inhibitors (SSRIs) are more likely to be associated with suicidal behaviors than tricyclic antidepressants (Juurlink et al., 2006), SSRIs are more likely to reduce suicide risk than placebo and possibly other antidepressants (Moller, 2003, Isacsson et al., 2005), venlafaxine (a serotonin and norepinephrine reuptake inhibitor) is more likely to be related to suicide than SSRIs (Rubino et al., 2007), and the SSRI sertraline may be less likely to be associated with suicide ideation than either placebo or other antidepressants (Laughren, 2006). Patients with MDD may be more vulnerable to antidepressant related suicidal ideation than patients with other psychiatric diagnoses, younger adults more susceptible than older adults, and non-responders more likely to exhibit treatment-emergent suicidal ideation than responders (Laughren, 2006, Szanto et al., 2007). Finally, the risk of treatment-emergent suicidal behaviors appears to be most pronounced within the first few weeks after treatment initiation or dose increase (Juurlink et al., 2006).

This report is based on secondary data analyses from the Sequenced Treatment Alternatives to Relieve Depression (STAR⁎D) study (Fava et al., 2003, Rush et al., 2004). The study's large sample of outpatients with nonpsychotic MDD allowed us to address the following questions:

• In patients with MDD and suicidal ideation prior to the initiation of treatment, is treatment with citalopram associated with increases or decreases in suicidal ideation?

• In patients with MDD who have no suicidal ideation at treatment initiation, is treatment with citalopram associated with emergent suicidal ideation, and if so, when?

• Which patients are most at risk for worsening with treatment or emergence of suicidal ideation?