Treatment-Resistant Depression Case 3: Level 3
Nancy is a 35 yo female who presents to your clinic stating that her medications for depression are not working. She was initially started on Celexa 20mg (eventually increased to 40mg), then after still not experiencing any significant improvement started to see the clinic psychologist. However, she still wasn’t in remission so she was switched to Effexor plus continued CBT. Her PHQ-9 one month ago was 18, today it is still 18. She denies SI/HI and states she has been taking her Effexor 150mg daily and seeing her psychologist weekly. She wants to know what her other options are for her depression including over the counter options.
1. Per the STAR*D trial (or other EBM resources) how would you treat Nancy? Come up with at least 2 different options. Show your evidence!
2. When should primary care providers refer patients with treatment-resistant depression to psychiatry?
3. What is the evidence for the use of herbal/natural supplements for the treatment of depression such as St John’s wort (Hypericum perforatum) and S-adenosyl methionine (SAMe)?
1. See attached figures for assistance and/or www.star-d.org
For initial treatment of depression, the effectiveness of antidepressant medication is comparable between classes; therefore, selection of a particular antidepressant should largely be based on the side effect profile of the drug, any history of response in the patient or a family member, and cost of the medication.
Evidence regarding psychotherapy and pharmacotherapy has recently been enhanced by results from the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study, a seven-year randomized controlled trial (RCT) that evaluated medication switching and augmentation in 3,671 outpatients with unipolar depression. Citalopram (Celexa) was the initial treatment (20mg daily, titrated to 60mg daily if needed). Three additional levels of treatment were included, based on response. Each treatment level was sustained for at least 12 weeks (if the drug was tolerated) before response was determined.
The STAR*D trial found that patients who received CBT after failing to respond to citalopram (with or without continued citalopram) had similar rates of response (i.e., at least 50% improvements in symptoms compared with baseline) and remission (i.e., resolution of symptoms) as those who received other medication regimens. Patients who received CBT alone (rather than in conjunction with citalopram) achieved remission less rapidly, but they also had fewer adverse effects than those who were switched to other medications.
A systematic review identified 16 RCTs of treatment resistant depression, all of which were considered too small to detect an important clinical response. (Br J Psychiatry 2002)
The STAR*D trial significantly expanded the evidence base for pharmacotherapy of treatment-resistant unipolar major depression. Remission rates after the first level of treatment were 37%; after the second level, 31%; after the third level, 14 percent; and after the fourth level, 13 percent. The cumulative remission rate was 67%. In general, patients who required more treatment steps had higher relapse rates. Ultimately, fewer than one half of patients achieved sustained remission, even after all four treatment levels.
There were significant differences between only three treatment strategies tested in the STAR*D trial. Augmentation of citalopram with bupropion resulted in slightly improved response rates and fewer adverse effects compared with buspirone (Buspar), but no difference in remission rates. Augmentation of the level 2 treatment with T3 resulted in fewer adverse effects than augmentation with lithium, but there was no difference in effectiveness. Venlafaxine plus mirtazapine resulted in slightly improved response rates and fewer adverse effects compared with tranylcypromine (Parnate). Beyond these findings, the STAR*D trial did not find that any of the studied treatments are better than another. Other evidence suggests that augmentation of second-generation antidepressants or TCAs with pindolol, lithium, or methylphenidate (Ritalin) is not effective for treatment resistant depression.
2. Some experts advocate referral to a psychiatrist and/or psychopharmacologist, any patient who has not improved with Level 2 therapy per the STAR*D trial. Other reasons to refer include: patients with SI/HI; patients with significant psychiatric comorbidities such as bipolar disorder, PTSD, etc.; patients with psychosis; patients who require ECT; and patients who require augmentation. (Editorial: these are expert opinion only; NOT evidence based. You may refer earlier/later depending on your personal comfort, but Level 3/Level 4 patients definitely need psych involvement!)
3. St John’s wort: A total of 29 trials (5489 patients) including 18 comparisons with placebo and 17 comparisons with synthetic standard antidepressants met the inclusion criteria. Results of placebo-controlled trials showed marked heterogeneity. In nine larger trials the combined response rate ratio (RR) for hypericum extracts compared with placebo was 1.28 (95% confidence interval (CI), 1.10 to 1.49) and from nine smaller trials was 1.87 (95% CI, 1.22 to 2.87). Results of trials comparing hypericum extracts and standard antidepressants were statistically homogeneous. Compared with tri- or tetracyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs), respectively, RRs were 1.02 (95% CI, 0.90 to 1.15; 5 trials) and 1.00 (95% CI, 0.90 to 1.11; 12 trials). Both in placebo-controlled trials and in comparisons with standard antidepressants, trials from German-speaking countries reported findings more favourable to hypericum. Patients given hypericum extracts dropped out of trials due to adverse effects less frequently than those given older antidepressants (odds ratio (OR) 0.24; 95% CI, 0.13 to 0.46) or SSRIs (OR 0.53, 95% CI, 0.34-0.83). The available evidence suggests that the hypericum extracts tested in the included trials a) are superior to placebo in patients with major depression; b) are similarly effective as standard antidepressants; c) and have fewer side effects than standard antidepressants. The association of country of origin and precision with effects sizes complicates the interpretation. MUST monitor for drug interactions!!
S-adenosyl methionine (SAMe) is a naturally occurring molecule that appears to be an effective and well-tolerated treatment for depression. It is available in the US as a dietary supplement. One six-week RCT of 73 patients with unipolar major depression who failed adequate treatment with an SSRI received adjunctive SAMe (800mg bid) or placebo. Remission occurred in significantly more patients who received SAMe compared with placebo (36 vs. 12 percent). Discontinuation of treatment due to adverse side effects occurred in fewer patients who received an SSRI plus SAMe (5 vs. 9 percent). No data beyond 6 wks of therapy however.