Evidence-Based Reviews

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

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

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.

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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.

30. Marangell LB, Rush AJ, George MS, et al. Vagus nerve stimulation (VNS) for major depressive episodes: one-year outcomes. Biol Psychiatry 2002;51(4):280-7.

STAR*D trial. The ongoing National Institute of Mental Health (NIMH) Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial may offer a new algorithmic approach to treating major depression.^14,28 NIMH launched STAR*D in 1999, enrollment began in 2001, and results are expecte by May 2005 (see Related resources).

STAR*D—of which I am the study director—is a randomized, controlled, raterblinded, multisite trial of outpatients ages 18 to 75 with nonpsychotic major depression (17-item Hamilton Rating Scale for Depression score 14). The trial design includes four treatment levels and numerous antidepressant options (Figure).

The study’s aim is to enroll 4,000 patients into level 1, with 1,500 entering level 2. Patients who achieve an adequate response based on clinician judgment may continue the effective treatment for 12 months, during which their symptoms and other relevant information are monitored monthly by telephone. Patients who do not achieve an acceptable response in level 1 (or in subsequent levels) may proceed to the next level, which involves a randomized assignment.

STAR*D has an innovative design that mimics clinical practice and ensures high levels of patient participation. When patients agree to randomization, they may elect to exclude groups of treatments but may not pick a particular treatment (they must accept randomization to stay in the study).

Figure STAR*D treatment levels for major depressive disorder

For example, patient A entering level 2 may exclude switch treatments and elect to accept randomization to citalopram plus bupropion SR, citalopram plus buspirone, or citalopram and cognitive therapy. Conversely, patient B may exclude all augment options at level 2, and accept randomization to the four switch options.

Patients may exclude cognitive psychotherapy as an augment and/or switch option as long as they accept randomization to all available medication switches, or augments, or both. They may also choose cognitive therapy and exclude all medication switch and augment options. These patients must accept randomization to either cognitive therapy switch or cognitive therapy augmentation.

This so-called equipoise stratified randomized design²⁹ allows us to compare all participants randomized to the treatments being compared. To date, only 1% of subjects have accepted randomization to all seven level-2 treatments. About one-half elect only the switch options, and about one-half elect only the augment options.

STAR*D’s goal is to determine whether there is a preferred next step for varying types and degrees of treatment-resistant repression.

Vagus nerve stimulation

Somatic therapies being investigated to expand our therapeutic options for major depressive disorder include magnetic seizure therapy, repetitive transcranial magnetic stimulation, and vagus nerve stimulation (VNS).

VNS—now indicated for treatment-resistant epilepsy—is being investigated as a potential augmentation for treatment-resistant depression. An application for this supplemental indication was submitted to the FDA in October 2003.

With VNS, a device implanted in the patient’s chest provides intermittent stimulation to the left vagus nerve (typically 30 seconds on and 5 minutes off, 24 hours a day). In an open trial¹⁰ and follow-up report,³⁰ VNS was associated with a 30% to 45% response rate in 59 depressed patients with high levels of treatment resistance (inadequate response to an average of 16 treatment trials).

VNS is well tolerated, though it has not been prospectively studied in patients with diagnosed cardiovascular disease. Side effects that may occur when the stimulation is “on” include:

voice alteration in about 60% of patients (the voice becomes more hoarse when the left recurrent laryngeal nerve is activated)
paresthesias in the neck
shortness of breath on heavy exertion.

These effects are usually absent in the 5-minute “off” phase.

Related resources

National Institute of Mental Health. Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Includes the Quick Inventory of Depressive Symptomatology. www.star-d.org
HealthyPlace.Com Depression Community. Vagus nerve stimulation for treating depression. www.healthyplace.com/communities/depression/treatment/vns

Drug brand names

Bupropion • Wellbutrin, Wellbutrin SR
Buspirone • BuSpar
Citalopram • Celexa
Fluoxetine • Prozac
Imipramine • Tofranil
Mirtazapine • Remeron
Modafinil • Provigil
Nefazodone • Serzone
Nortriptyline • Pamelor, Aventyl
Olanzapine • Zyprexa
Risperidone • Risperdal
Sertraline • Zoloft
Tranylcypromine • Parnate
Venlafaxine • Effexor, Effexor XR

Disclosure

Dr. Rush receives grant/research support from the Robert Wood Johnson Foundation, National Institute of Mental Health, and The Stanley Foundation. He is a consultant to Bristol-Myers Squibb Co., Cyberonics, Eli Lilly & Co., Forest Laboratories, and GlaxoSmithKline, and a speaker for Bristol-Myers Squibb Co., Cyberonics, Eli Lilly & Co., Forest Laboratories, GlaxoSmithKline, and Wyeth Pharmaceuticals.