Ng, C.G., Boks, M.P., Roes, K.C., Zainal, N.Z., Sulaiman, A.H., Tan, S.B., & de Wit, N.J. (2014). Rapid response to methylphenidate as an add-on therapy to mirtazapine in the treatment of major depressive disorder in terminally ill cancer patients: A four-week, randomized, double-blinded, placebo-controlled study. European Neuropsychopharmacology, 24, 491–498. 

DOI Link

Study Purpose

To test the effectiveness of major depression treatment using add-on therapy methylphenidate to mirtazapine compared with the addition of placebo to mirtazapine in terminally ill patients with cancer (prognosis of living less than three months)

Intervention Characteristics/Basic Study Process

Patients with a confirmed diagnosis of major depression were randomly assigned to one of two groups and were treated with mirtazapine and methylphenidate or with mirtazapine and placebo. The study treatment medication and placebo handed out by the pharmacists were the same color, size, and shape. The protocol required the mirtazapine to remain at a fixed dose of 30 mg nightly at 10 p.m. and allowed one dosage increase of the add-on medication, methylphenidate or placebo, after the third day of treatment as decided by the treating physician. Depression severity of illness measures were taken at baseline and on days 3, 6, 9, 14, 21, and 28.

Sample Characteristics

  • N = 88   
  • AGE RANGE = 44.39–70.82 years, no significant difference between groups
  • MALES: 10 males (23%) in one group and 20 males (46%) in one group, FEMALES: Not reported
  • CURRENT TREATMENT: Not applicable
  • KEY DISEASE CHARACTERISTICS: The study excluded patients who were already being treated with antidepressants and who had existing psychiatric comorbidities. Cancer diseases were not significantly different between groups, and the study included patients with breast, upper gastrointestinal, colorectal, renal, pancreatic, bone, urinary tract, prostate, uterine-cervical-ovarian (grouped), and other cancers.
  • OTHER KEY SAMPLE CHARACTERISTICS: Breast cancer occurrence was the only significant difference between groups.

Setting

  • SITE: Single site   
  • SETTING TYPE: Multiple settings    
  • LOCATION: University of Malaya Medical Centre in Kuala Lumpur, Malaysia

Phase of Care and Clinical Applications

  • PHASE OF CARE: End-of-life care
  • APPLICATIONS: Palliative care

Study Design

Four-week, randomized, double-blind, placebo-controlled trial

Measurement Instruments/Methods

  • Montgomery-Åsberg Depression Rating Scale (MADRS): 10-item measure of appearance of depression symptoms. One item is by self-report, and nine items are rated by clinicians.
  • Clinical Global Impression-Severity (CGI-S): single-item measure of clinicians' impression of illness severity

Results

No significant differences existed between groups except for breast cancer, which had a significant gender difference (p = 0.04). The study completion for groups was relatively equal at 41% and 42% (p = 0.52). The MADRS outcome measures showed significantly decreased depression scores from baseline to day 3 and at day 28. Baseline to day 3 linear regression analysis revealed an estimated mean difference of 4.14 (95% confidence interval [CI] [1.83, 6.45]). Day 28 liner regression analysis revealed significant differences (p < 0.01, 95% CI [–2.04, –7.70]) in the add-on treatment group over the add-on placebo group. The CGI-S outcome measures showed significant changes starting day 14 (p = 0.006) and continuing through day 28 (p = 0.027). Significantly different (p value not reported) effect size was 0.45 in the treatment group compared to 0.13 in the placebo group. Adverse events were reported in 34.1% of patients receiving methylphenidate, and included psychosis, agitation, insomnia, tremors, and seizures, and 11% discontinued participation because of these events. Causes of discontinuation were death (n = 23, 26.1%) (no significant between groups difference) and neuropsychiatric symptoms (n = 9) (no significant difference).

Conclusions

Symptom relief by day 3 was noted among patients with the add-on therapy. Scores on the depression scale and severity of illness were improved by day 3 and day 14, respectively.

Limitations

  • Small sample (< 100)
  • Measurement validity/reliability questionable
  • Subject withdrawals ≥ 10%
  • Discontinuation rate above 26% because of death and 11% because of adverse events

Nursing Implications

Early patient screening for depression among patients in palliative care is highlighted. Improved depression scores were noted by day 3 and improved the severity of illness by day 14. Consider add-on therapy with a fixed dose of mirtazapine and adding methylphenidate as described for patients with cancer with major depressive disorders in palliative care. Whether or not the rapid antidepressant effect of methylphenidate outweighs the potential for significant adverse effects needs to be individually determined for each patient.