Research Focus for Clinicians

A systematic review of 44 clinical studies published between January 1980 and April 2011 examined the comparative effectiveness, benefits, and adverse effects of interventions for adults and adolescents with major depressive disorder (MDD) who have an unsatisfactory response to treatment with a selective serotonin-reuptake inhibitor (SSRI). The review also compared recommendations from 27 Clinical Practice Guidelines (CPGs) published from January 2004 to April 2011. The findings of this review do not apply to subjects who have a primary diagnosis of bipolar disorder, schizophrenia, or anxiety disorder. This summary is provided to inform discussions of options with patients and to assist in decisionmaking along with consideration of a patient’s values and preferences and should not be construed to represent clinical recommendations or guidelines. The full report is available at www.effectivehealthcare.ahrq.gov/ssri-depression.cfm.

Background

Although patients with MDD have a 63-percent response rate during 6 to 12 weeks of treatment with second-generation antidepressants, 53 percent do not achieve remission.^1,2

Up to two-thirds of adult patients will not achieve remission with an SSRI.³ SSRIs are a frequently used class of second-generation antidepressants.

Clinicians are faced with a number of treatment options (see Table 1) after an inadequate response to an SSRI, including both monotherapy and combination therapy approaches.

Table 1

Pharmacological and Nonpharmacological Interventions Studied in the Review.

Monotherapy approaches include:

• Optimizing the dosage or duration of the current SSRI
• Switching to another SSRI or another antidepressant
• Switching to a nonpharmacological treatment (e.g., psychological therapies or exercise)

Combination therapy approaches include:

• Adding medications (e.g., augmenting agents, a different SSRI, or other antidepressants)
• Switching to another agent (e.g., a different SSRI) and adding another medication
• Adding a nonpharmacological treatment
• Combinations of these treatments

In the studies included in the systematic review, the definition of an adequate response to SSRI medications is not consistent but generally refers to a 50-percent decrease in symptom severity. Remission from depression is defined as being free or nearly free of symptoms for the current episode. The systematic review evaluated treatment options for patients who only had a partial response or who had no response to an SSRI medication.

Conclusion

Evidence remains limited to support clinical decisionmaking about the available approaches for treating patients with MDD who have an inadequate response to SSRIs. For adults with MDD, evidence is insufficient to guide decisionmaking for comparisons among monotherapies, monotherapies versus combination therapies, and comparisons among combination therapies with a few exceptions. Adding an atypical antipsychotic—risperidone or olanzapine—to ongoing SSRI treatment may slightly improve response and remission rates when compared with continuing SSRI treatment alone. Low-level evidence suggests that comparable response and remission rates are obtained from switching to a new antidepressant versus combining the new antidepressant with pharmacological or nonpharmacological treatment. For adolescents with MDD, low-level evidence suggests that combining an antidepressant and cognitive behavioral therapy (CBT) may be superior to medication alone. For adults, most reported adverse effects were consistent with those typically associated with antidepressant use. Comparative evidence is insufficient to guide decisionmaking about adverse effects both in adults and in adolescents.

Clinical Bottom Line

Strength of Evidence Scale

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High:		High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect.
Moderate:		Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate.
Low:		Low confidence that the evidence reflects the true effect. Further research is likely to change our confidence in the estimate of effect and is likely to change the estimate.
Insufficient:		Evidence is either unavailable or does not permit a conclusion.

Gaps in Knowledge

• Overall, few studies have evaluated the impact of different depressive diagnoses, disease severity, previous comorbidities, age, sex, and race on treatment outcomes.
• There is inconsistency between studies in the definition of “inadequate response” and in the distinction between response and remission.
• More studies are needed on the response and remission rates in children and adolescents to treatments subsequent to an inadequate SSRI response.
• Evidence is very limited on response and remission rates for patients with subsyndromal depression or dysthymia who have inadequate responses to an SSRI.

Additional Information

• For adults with dysthymia or subsyndromal symptoms who have an inadequate response to SSRIs, there is insufficient evidence to evaluate treatment approaches.
• There is some evidence that suggests that people with concurrent anxiety symptoms have less likelihood of achieving remission.
• There is some evidence that suggests that milder depression, less family conflict, and the absence of suicidal behavior are associated with greater likelihood of a positive treatment response in adolescents.

What To Discuss With Your Patients

• The health consequences of depression
• The rate of treatment response following treatment with SSRIs and the possibility of treatment-resistant depression
• The various interventions for treating depression after unsatisfactory response to SSRIs
• Patient preferences regarding cost, nonpharmacological treatment, medication type, and potential side effects
• What is known about nonpharmacological interventions for treating depression
• Potential drug interactions with medications
• The risk of antidepressants and other medications for pregnant or nursing women
• The possibility of severe adverse effects such as suicidality and that additional resources or help are available from the National Suicide Prevention Lifeline at www.suicidepreventionlifeline.org or 1-800-273-8255

Resource for Patients

Treatment Options When Your SSRI Antidepressant Is Not Working Well is a free companion to this clinician research summary. It covers:

• Background information about depression and unsatisfactory response to SSRIs
• Descriptions of the types of treatments, how they work, and potential side effects
• Questions to guide a discussion with you about treatment options

Ordering Information

For electronic copies of Treatment Options When Your SSRI Antidepressant Is Not Working Well, this clinician research summary, and the full systematic review, visit www.effectivehealthcare.ahrq.gov/ssri-depression.cfm. To order free print copies, call the AHRQ Publications Clearinghouse at 800-358-9295.

Source

The information in this summary is based on Treatment for Depression After Unsatisfactory Response to SSRIs, Comparative Effectiveness Review No. 62, prepared by the McMaster University Evidence-based Practice Center under Contract No. 290-2007-10060-I for the Agency for Healthcare Research and Quality, April 2012. Available at www.effectivehealthcare.ahrq.gov/ssri-depression.cfm. This summary was prepared by the John M. Eisenberg Center for Clinical Decisions and Communications Science at Baylor College of Medicine, Houston, TX.