How best to manage treatment-resistant depression?
Should you augment the treatment regimen with lithium, thyroxin, or an atypical antipsychotic? This review will help you decide.
• While lithium produces significant remission rates in augmentation efforts for treatment-resistant depression, it is more likely to cause side effects than many other psychotropic agents. A
• Medication and cognitive therapy are equally effective when augmenting antidepressant therapy; cognitive therapy, however, takes longer to achieve remission. B
• Since the efficacy of many agents is similar when augmenting treatment, it’s important to factor the cost of the medication, side effects, and patient preference into the decision process. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
The sobering truth about major depression is that too often it goes unrecognized or undertreated.1,2 And even when it is treated correctly, up to 34% of patients fail to respond to treatment.3 In the United States alone, the lifetime prevalence of the disease is 16.2%, and more than 6% of adults experience symptoms of major depression in any given year.2 Obviously, we need to do more for these patients.
Treatment-resistant depression has been defined as the failure to achieve remission after continuous therapy for about 6 to 12 weeks with an adequate dose of a single antidepressant.4 Remission is typically defined as a 50% reduction of scores on depression severity scales, with the 17-item Hamilton Rating Scale of Depression (HRSD17) and the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR16) being the most often used. An adequate dose is the lowest effective dose that doesn’t cause intolerable side effects.
What are our best options for treatment-resistant depression?
To answer this question, we reviewed all English language studies in PubMed or Medline that were performed among adults using the search terms “augmentation, antidepressants, major depression.” We excluded studies involving patients with comorbid anxiety, bipolar disorder, or other major mental illnesses.
Based on our review of the literature, we found support for several augmentative treatments for patients with treatment-resistant depression (TABLE). Of note, though: Most of these studies were randomized trials dating back nearly 2 decades and had limitations. Most were not blinded, nor did they have consistent placebo controls. The studies were typically small (albeit frequently still showing efficacy for the agent despite lower statistical power) and of relatively short duration (typically 6-14 weeks). There were few studies that looked at treatment approaches over longer periods or that considered indications and timelines for tapering of medications once remission had been achieved. A major exception to the rule was the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which we’ll discuss below.5
The research points to several viable options: Clinicians can switch antidepressants, augment these agents by adding others—usually nonantidepressants—or completely change the therapeutic approach. Since most of the research discusses augmentation, we’ll focus on that here. Because the decision to use electroconvulsive therapy, vagus nerve stimulators, or other nonpharmaceutical approaches is made in consultation with a psychiatrist, we will not discuss these options.
TABLE
How these agents compare for treatment-resistant depression
| Agent/approach | Remission rate | Starting dose | Titrated to… | Frequency of side effects | SOR rating |
|---|---|---|---|---|---|
| Lithium5-9 | 53%-60% | 300 mg BID-TID | Doses of 800-1500 mg and lithium level of 0.5-1 mmol/L | >25% | A |
| Thyroid supplementation10-13 | 25%-59% | 20-50 mcg | Often not titrated | 11%-25% | A |
| Aripiprazole14-17 | 25%-37% | 2-5 mg | 15-20 mg | 16%-25% | A |
| Olanzapine/fluoxetine18 | 25% | Fixed dose | Fixed dose | 10%-40% | A |
| Risperidone19-21 | 25%-71% | 0.25-1 mg | 0.5-3 mg | 6%-10% | A |
| Quetiapine22,23 | 36%-49% | 25-200 mg | 100-600 mg | >25% | B |
| Mirtazapine24 | 45% | 15 mg | 30 mg | 6%-10% | B |
| Cognitive therapy34 | 23% | NA | NA | 0%-5% | B |
| Folic acid (Leucovorin)26 | 18% | 15 mg | 30 mg | 11%-25% | C |
| SAMe27 | 43% | 800 mg | 1600 mg | 50% | C |
| NA, not applicable; SAMe, S-adenosyl-L-methionine; SOR, strength of recommendation. | |||||
Lithium: Good results, but with side effects
Lithium is one of the oldest and most well studied agents.6-9 Most studies used 900 mg divided into 3 daily doses and titrated to lithium plasma levels of 0.5 to 1 mmol/L. Unfortunately, though, lithium is more likely to cause side effects than many other psychotropic agents (>25%).5-9 And while the research has found that lithium produces significant remission rates, it’s not very effective in patients who have failed multiple antidepressant trials, with only 12.5% to 15.9% of patients in that cohort achieving remission.10,11
Thyroid hormone has only mild side effects
Low-dose thyroid supplementation has been used for decades in euthyroid patients with treatment-resistant depression; remission rates range from 25% to 59%.10-13 Most studies used a low fixed-dose therapy between 25 and 50 mcg daily; side effects were mild and occurred at rates similar to placebo.13
Atypical antipsychotics: Many pluses, but weight gain is an issue
Atypical antipsychotics are an attractive alternative to typical antipsychotics for treatment-resistant depression. They are much less likely to cause extrapyramidal symptoms, tardive dyskinesia, and other motor symptoms, but as a trade-off they often cause weight gain, abnormal glucose metabolism, dyslipidemia, and hyperprolactinemia.
Aripiprazole (Abilify) is 1 of 2 medications approved by the Food and Drug Administration (FDA) for treatment-resistant depression. Studies have shown remission rates of 25% to 37%, with side effects in 16% to 25% of patients.14-16 Akathisia, the major side effect, can be reduced by lowering the starting dose to 2.5 mg.17
