Sequential multiple-assignment randomized trial design of neurobehavioral treatment for patients with metastatic malignant melanoma undergoing high-dose interferon-alpha therapy.
BACKGROUND
Interferon-alpha therapy, which is used to treat metastatic malignant melanoma, can cause patients to develop two distinct neurobehavioral symptom complexes: a mood syndrome and a neurovegetative syndrome. Interferon-alpha effects on serotonin metabolism appear to contribute to the mood and anxiety syndrome, while the neurovegetative syndrome appears to be related to interferon-alpha effects on dopamine.


OBJECTIVE
Our goal is to propose a design for utilizing a sequential, multiple assignment, randomized trial design for patients with malignant melanoma to test the relative efficacy of drugs that target serotonin versus dopamine metabolism during 4 weeks of intravenous, then 8 weeks of subcutaneous, interferon-alpha therapy.


METHODS
Patients will be offered participation in a double-blinded, randomized, controlled, 14-week trial involving two treatment phases. During the first month of intravenous interferon-alpha therapy, we will test the hypotheses that escitalopram will be more effective in reducing depressed mood, anxiety, and irritability, whereas methylphenidate will be more effective in diminishing interferon-alpha-induced neurovegetative symptoms, such as fatigue and psychomotor slowing. During the next 8 weeks of subcutaneous interferon therapy, participants whose symptoms do not improve significantly will be randomized to the alternate agent alone versus escitalopram and methylphenidate together.


RESULTS
We present a prototype for a single-center, sequential, multiple assignment, randomized trial, which seeks to determine the efficacy of sequenced and targeted treatment for the two distinct symptom complexes suffered by patients treated with interferon-alpha.


CONCLUSIONS
Because we cannot completely control for external factors, a relevant question is whether or not 'short-term' neuropsychiatric interventions can increase the number of interferon-alpha doses tolerated and improve long-term survival.


CONCLUSIONS
This sequential, multiple assignment, randomized trial proposes a framework for developing optimal treatment strategies; however, additional studies are needed to determine the best strategy for treating or preventing neurobehavioral symptoms induced by the immunotherapy interferon-alpha.
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA.
S Freda
SF
Auyeung
Qi
Q
Long
Erica Bruce
EB
Royster
Smitha
S
Murthy
Marcia D
MD
McNutt
David
D
Lawson
Andrew
A
Miller
Amita
A
Manatunga
Dominique L
DL
Musselman
D001526:Behavioral Symptoms / Q000139:chemically induced / Q000188:drug therapy*; D015283:Citalopram / Q000627:therapeutic use; D018765:Dopamine Uptake Inhibitors / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006801:Humans; D007279:Injections, Subcutaneous; D016898:Interferon-alpha / Q000009:adverse effects* / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology*; D008774:Methylphenidate / Q000627:therapeutic use; D019964:Mood Disorders / Q000139:chemically induced / Q000188:drug therapy*; D009362:Neoplasm Metastasis; D017063:Outcome Assessment, Health Care; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012702:Serotonin Antagonists / Q000627:therapeutic use; D013577:Syndrome
D018765:Dopamine Uptake Inhibitors; D016898:Interferon-alpha; D012702:Serotonin Antagonists; D015283:Citalopram; D008774:Methylphenidate