Serotonin-Norepinephrine Reuptake Inhibitors for the Prevention and Treatment of Pain, Depression, and Anxiety in Patients With Head & Neck Cancer
Phase: PHASE4
Conditions: Depressive Disorder, Head and Neck Cancer
Sponsor: University of Alabama at Birmingham

 
 
Protocol Title: Serotonin-Neuroepinephrine Reuptake Inhibitors for the Prevention and Treatment of Pain, 
Depression, and Anxiety in Patients with Head & Neck Cancer 
Principal Investigator: Harishanker Jeyarajan 
 
I. 
Background and Significance/Preliminary Studies 
 
The incidence of major depressive disorder (MDD) in head and neck cancer (HNC) patients is 
estimated to be anywhere from 15-50% compared to the 15-25% seen in patients with other types of 
cancer. Around 25% of HNC patients have depression prior to treatment. It has been suggested that 
physical disfigurement and loss of the ability to speak or swallow are contributing factors. Around 15-40% 
of head and neck cancer survivors report chronic pain. Patients with chronic pain are more likely to have 
depressive symptoms. Depression can also lead to lower quality of life, non-compliance, apathy about 
treatment, and suicide. A systematic review by Barber et al from Alberta, Canada showed worse overall 
survival in H&N cancer patients with depressive symptoms although the exact mechanism of this is 
unclear. Pharmacologic treatment is first-line therapy for depression. 
  
In 2008, Lydiatt et al. conducted the first randomized, placebo-controlled trial for the prevention of 
depression during treatment for cancer patients. Thirty-six patients with newly diagnosed HNC were 
enrolled in this pilot study. Patients were initially screened using the Mini-International Neuropsychiatric 
Interview (MINI) depression module. Patients were randomized to receive either citalopram or placebo for 
12 weeks. Patients were evaluated every 4 weeks for a total of 16 weeks. The Hamilton Rating Scale for 
Depression was used to determine whether or not patients developed depression. The Clinical Global 
Impression Severity Scale was used to determine severity of depression. The Washington Quality of Life 
scale was used to determine quality of life. These tests were administered at all 5 visits. By the end of the 
study, the patients on citalopram had a lower incidence of depression than the placebo group (17% vs 
50%). The placebo group also had worse severity of depression and worse quality of life. Additionally, 
during a retrospective analysis of patients enrolled in this study, the authors found that patients who 
developed depression at any point during the study had worse overall survival than those patients who did 
not develop depression. 
  
Lydiatt et al. then conducted a larger randomized, placebo-controlled trial in which non-depressed patients 
about to begin treatment for HNC were randomized to receive escitalopram or placebo. Patients were again 
initially screened using the Mini-International Neuropsychiatric Interview (MINI) depression module. The 
Quick Inventory of Depressive Symptomatology (QIDS) scales was administered at baseline and at weeks 
2, 4, 6, 8, 10, 12, 16, 20, 24, and 28. Significantly fewer patients receiving escitalopram developed 
depression (24.6% in the placebo group vs 10.0% in the escitalopram group; stratified log-rank test, P = 
.04). The study concluded that in nondepressed patients undergoing treatment for head and neck cancer, 
prophylactic escitalopram reduced the risk of developing depression by more than 50%. This is the only 
RCT that has been performed to evaluate the use of an anti-depressant to reduce rates of depression in HNC 
patients. 
  
Since incidence of both depression and pain is high in patients with HNC, a medication that stabilizes mood 
and improves pain could be beneficial. SNRIs have been shown to treat both depression and neuropathic 
pain. Smith et al used a Randomized, double-blind, placebo-controlled crossover trial at 8 National Cancer 
Institute (NCI)-funded cooperative research networks to study the effectiveness of duloxetine at reducing 
chemotherapy-induced neuropathy. Patients were randomized to receive either duloxetine or placebo over a 
5-week period then the study groups were crossed over. There was a two-week washout period between. 
Patients were assessed weekly with the Brief Pain Inventory Short Form. The duloxetine-first group 
reported greater decreased in pain (59% vs 38%). 
  
There has been no previous study examining the role of SNRIs in the prevention and treatment of 

 
 
depression, anxiety, and pain control in patients undergoing HNC treatment. 
 
 
II. 
Study Aims 
The purpose of this research study is to initiate a pharmacotherapy protocol for at-risk patients with  
newly diagnosed head and neck cancer in order to decrease the incidence of anxiety, depression, and  
uncontrolled pain during cancer treatment. 
III. 
Administrative Organization  
 
The investigators will screen their clinics for potential patients and pass this information to the study     
coordinator, who will reach out to the participants about the study and enrolling. Ideally, the study 
coordinator will be able to call the patient prior to their clinic visit to discuss the study; however, even if 
they are initially approached in clinic, all participants will be given at least 24 hours to consider whether or 
not they wish to enroll in the study, and will reminded that they may withdraw at any point, for any reason, 
if they so choose, without any changes to the care they are receiving for their disorder. 
 
 
IV. 
Study Design 
Participants will be randomized into either the Treatment Group or the Control Group via a 
computer-based algorithm. Those who are randomized to the Treatment Group will begin the study  
drug at that visit. They will have telephone visits with a study coordinator over the next 3 weeks as  
the dose of the study drug is titrated per its package insert to the desired level of 300 mg/day  
(taken as 150 mg/day). Those participants with kidney or liver impairment will be dosed accordingly, 
 as per the package insert instructions. Participants will be asked to complete a daily medication  
diary. 
 
All participants will have study visits at Week 6, Month 6, Month 9, and Month 12. These research  
visits will be scheduled to coincide with their standard of care visits - we will not ask them to come  
for research-only visits. They will complete the study procedures as outlined in Section 8.1 of the  
study protocol. All participants will have adverse events and concomitant medications reviewed, and  
will complete the study questionnaires, and those in the Treatment Group will have their medication  
diary reviewed and will have a pill count of the study drug for medication reconciliation. 
Study questionnaires will be given to participants via paper forms, which they will complete and give  
back to the study coordinator. 
 
 
V. 
Study Procedures 
Participants will be enrolled for 12 months. Baseline visit will take approximately 75 minutes. Visits 
at Week 6, Month 6, Month 9, Month 12 will take approximately 45 minutes each. Those who are 
randomized into the Treatment Group will have telephone visits at Weeks 2, 3, and 4, which will take 
approximately 15 minutes. 
 
 
VI. 
Risks and Benefits 
Common side effects from previous clinical studies include: nausea (30.0%), somnolence (15.3%), 
dry mouth (14.8%), sweating (11.4%), abnormal ejaculation (9.9%), anorexia (9.8%), constipation 
(9.3%), impotence (5.3%) and decreased libido (5.1%). 
A major potential benefit of the study is optimizing management of mood disorders in patients who 
are at-risk for developing moderate or severe depression and anxiety. By initiating medication to 

 
 
patients who are not yet meeting criteria for moderate or severe depression, our goal is to prevent 
major depression and anxiety during treatment. Another benefit of this study is the increase in 
knowledge we will obtain from initiating pharmacotherapy to patients who are already showing signs 
of moderate to severe depression. Since we will recommend initiation of pharmacotherapy and 
referral to counseling for all patients who demonstrate moderate or severe depression, we will better 
understand our ability to intervene and the effects of that intervention. This is the first study, to our 
knowledge, that will utilize a serotonin-norepinephrine reuptake inhibitor to assess its efficacy in 
preventing depression and pain in patients undergoing treatment for head and neck cancer. The 
knowledge we gain from this study will add to the growing understanding of mood disorders in 
patients with head and neck cancer in order to appropriately and effectively provide quality and 
effective care.