Evidence-Based Reviews

Treatment-resistant depression: Switch or augment? Choices that improve response rates

Current Psychiatry. 2004 March;3(3):11-19

When initial antidepressant therapy fails, an algorithmic approach to medication is more effective than treatment-as-usual.

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References

1. Depression Guideline Panel. Clinical practice guideline, number 5: depression in primary care: vol. 2. Treatment of major depression Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research. AHCPR publication no. 93-0551, 1993.

2. Rush AJ, Trivedi MH, Ibrahim HM, et al. The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psychiatry 2003;54:573-83.

3. Beck AT, Steer RA, Brown GK. Beck Depression Inventory (2nd ed. manual). San Antonio, TX: The Psychological Corporation, 1996.

4. Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561-71.

5. Kroenke K, Spitzer RL, Williams JBW. The PHQ-9. Validity of a brief depression severity measure. J Gen Intern Med 2001;16:606-13.

6. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003;289(23):3095-105.

7. Depression Guideline Panel. Clinical practice guideline, number 5: Depression in primary care, vol. 1: detection and diagnosis Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research. AHCPR publication no. 93-0550, 1993.

8. Murray CJ, Lopez AD. (eds) The global burden of disease Boston: Harvard School of Public Health, 1996.

9. Barbee JG, Jamhour NJ. Lamotrigine as an augmentation agent in treatment-resistant depression. J Clin Psychiatry 2002;63(8):737-41.

10. Sackeim HA, Rush AJ, George MS, et al. Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology 2001;25(5):713-28.

11. Koran LM, Gelenberg AJ, Kornstein SG, et al. Sertraline versus imipramine to prevent relapse in chronic depression. J Affect Disord 2001;65(1):27-36.

12. Nierenberg AA, Feighner JP, Rudolph R, et al. Venlafaxine for treatment-resistant unipolar depression. J Clin Psychopharmacol 1994;14(6):419-23.

13. Quitkin FM, Petkova E, McGrath PJ, et al. When should a trial of fluoxetine for major depression be declared failed? Am J Psychiatry 2003;160(4):734-40.

14. Fava M, Rush AJ, Trivedi MH, et al. Background and rationale for the sequenced treatment alternatives to relieve depression (STAR*D) study. Psychiatr Clin North Am 2003;26(2):457-94.

15. Fava M, Papakostas GI, Petersen T, et al. Switching to bupropion in fluoxetine-resistant major depressive disorder. Ann Clin Psychiatry 2003;15:17-22.

16. Entsuah AR, Huang H, Thase ME. Response and remission rates in different subpopulations with major depressive disorder administered venlafaxine, selective serotonin reuptake inhibitors, or placebo. J Clin Psychiatry 2001;62:869-77.

17. Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry 2001;178:234-41.

18. Montgomery SA, Huusom A, Bothmer J. Flexible dose comparison of s-citalopram and venlafaxine XR. J Eur Neuropsychopharmacol 2002;12(suppl 3):S-254.

19. Keller MB, Gelenberg AJ, Hirschfeld RM, et al. The treatment of chronic depression, part 2: a double-blind, randomized trial of sertraline and imipramine. J Clin Psychiatry 1998;59(11):598-607.

20. Thase ME, Rush AJ, Howland RH, et al. Double-blind switch study of imipramine or sertraline treatment of antidepressant-resistant chronic depression. Arch Gen Psychiatry 2002;59(3):233-9.

21. Thase ME, Rush AJ. Treatment resistant depression. In: Bloom FE, Kupfer DJ (eds). Psychopharmacology: the fourth generation of progress New York: Raven Press, 1995;1081-97.

22. Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 2001;158:131-4.

23. Keller MB, McCullough JP, Klein DN, et al. A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med 2000;342:1462-70.

24. Schatzberg AF, Rush AJ, Arnow BA, et al. Medication or psychotherapy is effective when the other is not in chronic depression: empirical support. Arch Gen Psychiatry (submitted).

25. Nemeroff CB, Heim CM, Thase ME, et al. Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma. Proc Natl Acad Sci USA 2003;100(24):14293-6.

26. Crismon ML, Trivedi M, Pigott TA, et al. The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychiatry 1999;60(3):142-56.

27. Trivedi MH, Rush AJ, Crismon ML, et al. The Texas Medication Algorithm Project (TMAP): clinical results for patients with major depressive disorder. Arch Gen Psychiatry (in press).

28. Rush AJ, Fava M, Wisniewski SR, et al. for the STAR*D Investigators Group. Sequenced Treatment Alternatives to Relieve Depression (STAR*D): rationale and design. Control Clin Trials 2004;25(1):118-41.

29. Lavori PW, Rush AJ, Wisniewski SR, et al. Strengthening clinical effectiveness trials: equipoise-stratified randomization. Biol Psychiatry 2001;50:792-801.

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When depression fails to respond to initial therapy—as it commonly does—we have many options but little evidence to guide our choices. We often wonder:

Is this patient’s depression treatment-resistant?
Would switching medications or augmenting the initial drug be more likely to achieve an adequate response?
How effective is psychotherapy compared with medication for treatment-resistant depression?

This article offers insights into each question, based on available trial data, algorithmic approaches to major depressive disorder, and clinical experience. Included is a preview of an ongoing multicenter, treatment-resistant depression study that mimics clinical practice and a look at vagus nerve stimulation (VNS)—a novel somatic therapy being considered by the FDA.

Measuring treatment response

Sustained symptom remission—with normalization of function—is the aim of treating major depressive disorder. Outcomes are categorized as:

remission (virtual absence of depressive symptoms)
response with residual symptoms (>50% reduction in baseline symptom severity that does not qualify for remission)
partial response (>25% but <50% decrease in baseline symptom severity)
nonresponse (<25% reduction in baseline symptoms).

Box

Major depressive disorder: Common and disabling

Major depressive disorder (MDD) is typically recurrent or chronic and characterized by marked disability and a life expectancy shortened by suicide and increased mortality from associated medical conditions. Lifetime prevalence is 16.2%.⁶

MDD is twice as likely to affect women as men and is common among adolescents, young adults, and persons with concurrent medical conditions.

Major depression’s course is characterized by:

recurrent episodes (approximately every 5 years)
or a persistent level of waxing and waning depressive symptoms (in 20% to 35% of cases).

Dysthymic disorder often heralds major depression. Within 1 year, 5% to 20% of persons with dysthymic disorder develop major depression.⁷

Disability associated with major depression

often exceeds that of other general medical conditions. Depression is the fourth most disabling condition worldwide and is projected to rank number two by 2020 because of its chronic and recurrent nature, high prevalence, and life-shortening effects.⁸

Consequences of unremitting depression include:

poor day-to-day function (work, family)
increased likelihood of recurrence
psychiatric or medical complications, including substance abuse
high use of mental health and general medical resources
worsened prognosis of medical conditions
high family burden.

In 8-week acute-phase trials, 7% to 15% of patients do not tolerate the initial medication, 25% show no response, 15% show partial response, 10% to 20% exhibit response with residual symptoms, and 30% to 40% achieve remission. Complicated depressions that may not respond as well include those concurrent with Axis I conditions—such as panic disorder or substance abuse—or Axis II or III conditions.¹

Time-limited psychotherapies targeted at depressive symptoms (such as cognitive, interpersonal, and behavioral therapies) also typically achieve a 50% response rate in uncomplicated depression that is not treatment-resistant.

Recommendation. When treating depression, assess response at least every 4 weeks (preferably at each visit), using a self-report or clinician rating such as:

Quick Inventory of Depressive Symptomatology² (see Related resources)
Beck Depression Inventory^3,4
Patient Health Questionnaire.⁵

Defining treatment resistance

A patient may not achieve remission for a variety of reasons, including poor adherence, inadequate medication trial or dosing, occult substance abuse, undiagnosed medical conditions (Box),^6-8 concurrent Axis I or II disorders, or treatment resistance.

The general consensus is to consider depression “treatment-resistant” when at least two adequately delivered treatments do not achieve at least a response. A stricter definition—failure to achieve sustained remission with two or more treatments—has also been suggested.

Several schemes have proposed treatment resistance levels, such as the five stages identified in the Table. Recent studies^9,10 suggest that increasing treatment resistance is associated with decreasing response or remission rates.

Therefore, when a patient’s treatment resistance is high, two appropriate strategies are to:

persist with and use maximally tolerated dosages of the treatment you select
aim for response because high resistance lowers the likelihood of remission.

Predicting response. A major clinical issue is determining whether remission will occur during an acute treatment trial. It is important to not declare treatment resistance unless there has been:

adequate exposure (dosing and duration) to the treatment
and adequate adherence.

Patients often have apparent but not actual resistance, meaning that the agent was not used long enough (at least 6 weeks) or at high enough doses. Remission typically follows response by several weeks or even 1 to 2 months for more-chronic depressions.¹¹ Thus, treatment trials should continue at least 12 weeks to determine whether remission will occur.

On the other hand, not obtaining at least a signal of minimal benefit (at least a 20% reduction in baseline symptom severity) in 4 to 6 weeks often portends a low likelihood of response in the long run.^12,13 Thus, continue a treatment at least 6 weeks before you decide that it will not achieve a response.