Study of Methylphenidate as Add on Therapy in Depressed Cancer Patients

Study Overview
=================
Brief Summary
-----------------
Primary Objective To determine the efficacy of Methylphenidate as add on therapy to mirtazapine in the treatment of depression in cancer patients under palliative care Hypothesis Methyphenidate add on to mirtazapine treated subjects will show significant early reduction in (Montgomery Asberg Depression Rating Scale) MADRS between baseline and Day 3. Secondary Objective To determine the efficacy of Methylphenidate as add on therapy to mirtazapine in the treatment of anxiety in cancer patients under palliative care. Hypothesis Methyphenidate add on to mirtazapine treated subjects will show significant early reduction in anxiety score of HADS than Mirtazepine alone treated subjects between baseline and Day 3. To determine the efficacy of Methylphenidate as add on therapy to mirtazapine in reducing distress in cancer patients under palliative care. Hypothesis Methyphenidate add on to mirtazapine treated subjects will show significant early reduction in distress score of distress thermometer than Mirtazepine alone treated subjects between baseline and Day 3. To determine the efficacy of Methylphenidate as add on therapy to mirtazapine in improving function in cancer patients under palliative care. Hypothesis Methyphenidate add on to mirtazapine treated subjects will show increase in the (Eastern Cooperation Group performance status) ECOG score than Mirtazepine alone treated subjects between baseline and Day 3 To determine the efficacy of Methylphenidate as add on therapy to mirtazapine in reducing somatic complaints in cancer patients under palliative care. Hypothesis Methyphenidate add on to mirtazapine treated subjects will show significant early reduction in the score of Numeric Rating Scale (NRS) for Pain and Visual Analogue Scale (VAS) for Fatigue than Mirtazapine alone treated subjects between baseline and Day 3.

Detailed Description
-----------------
Background Cancer remains one of the most feared illnesses and the diagnosis of cancer has huge psychological impact on the patients and their care-takers (Knobf, 2007). Depression is one the most common psychiatric sequella (Derogatis et al., 1983)2 and affects the quality of life, compliance to treatment, disease advancement, tolerability to pain and fatigue in cancer patients (Bennett et al., 2004; Sommerset, 2004; Green et al., 2009). However, it is likely that depression is under-recognized and under-treated in cancer patients (Kadan-Lottick et al., 2005). Depressed feelings manifest in a spectrum ranging from normal sadness to a variety of mood disturbances and clinical presentations. It is challenging to differentiate clinical depression from normal emotional distress in cancer patients and the somatic symptoms such as fatigue, loss of appetite or weight, sleep difficulties, poor memory and concentration may mirror the physiological symptoms caused by cancer or its treatment (McDaniel and Musselman, 1995; Masie and Popkin, 1998; Cochinov, 2001; Jesse et al., 2008). This complicates the diagnosis of depression in cancer patients (McDaniel and Musselman, 1995; Masie and Popkin, 1998; Cochinov, 2001; Pasquini and Biond, 2007; Jesse et al., 2008). Many studies have investigated the prevalence of depression in cancer in the past decades. A previous review by Mc Daniel et al, reported a prevalence of major depression ranging from 4.8% to 9.2% based on studies using standardized diagnostic interviews on cancer outpatients. Prevalence rates were higher in the admitted cancer patients (8% for Major Depression and 15% to 36% for all depressive disorders)(McDaniel and Musselman, 1995). A preliminary systematic review on the prevalence of depression in cancer patients was conducted by the investigator of this study. It showed that major depressive disorder was as high as 10.8% in cancer patients based on structured clinical interview. In addition to the high prevalence, uncertainty exists with respect to the optimal treatment of depression in cancer. Although a huge number of studies investigated the efficacy of pharmacotherapy for depression in general population, the number of randomized, controlled trials of antidepressants on depression in cancer patient conducted is limited(Challman and Lipsky, 2000; Raison and Miller, 2003). A comprehensive systematic review looking into the effectiveness and tolerability of antidepressant treatment in depressed cancer patients was performed and published by Rodin et al in 2007. Although 7 trials were identified, the authors commented that the number of positive randomized trials was limited and there is a need for more rigorous studies on other newer agents or alternative treatment option (Raison and Miller, 2003). The preliminary systematic review conducted by the investigator of this study also came to the same conclusion. Psychostimulants such as methylphenidate have been proposed for the treatment of depressed patients because of their rapid onset of action (Masand and Tesar, 1995; Challman and Lipsky, 2000; Rozans et al., 2002; Kaminski and Sjogren, 2007). They may have antidepressant effects and may be advantageous due to the rapid onset of action (Candy et al., 2008). Some studies suggest they provide a safe and effective treatment of depression in cancer patients (Masand and Tesar, 1995) and alleviates opioid induced somnolence, improve cognitive function and ameliorate pain in cancer patients. Another potential advantage of the use of psychostimulant in the cancer patients is the ability to improve multiple somatic symptoms irrespective of the etiology (Vigano et al., 1995). However, the number of studies looking into the efficacy of psychostimulant in improving depressive mood in cancer is limited. Five studies were identified from the review conducted by the investigator of this study. Although they showed positive result on the use of methylphenidate in depressed cancer patients, they were open-label and without control group. There is only one double blind, randomised placebo controlled study on the use of methylphenidate in cancer patients which was published in French language (Laval, 2008).Considering the lack of randomized controlled trial on the topic, the need of study on the efficacy and tolerability of psychostimulant such as methylphenidate as an add on therapy of depression in cancer patients is inevitably needed. Primary Objective To determine the efficacy of Methylphenidate as add on therapy to mirtazapine in the treatment of depression in cancer patients Secondary Objective To determine the efficacy of Methylphenidate as add on therapy to mirtazapine in the treatment of anxiety in cancer patients. To determine the efficacy of Methylphenidate as add on therapy to mirtazapine in reducing distress in cancer patients. To determine the efficacy of Methylphenidate as add on therapy to mirtazapine in improving function in cancer patients. To determine the efficacy of Methylphenidate as add on therapy to mirtazapine in reducing somatic complaints in cancer patients. Study Design Design An open label, parallel group, placebo controlled study on methylphenidate as add on therapy to mirtazapine. Procedure Subjects will be male or female with current diagnosis of cancer of any types and DSM-IV diagnoses of major depressive disorder. They are identified from the oncology, surgical and palliative clinics and wards. Depressive symptoms will be measured at screening with the MADRS. Sixty (120) subjects will be recruited and started on the mirtazapine 30mg at night. They will be then randomized to one of two groups (60 subjects per group): Methylphenidate or Placebo as add on therapy. All treatment will be initiated after screening and continued for 28 days of outpatient or inpatient treatment. Efficacy evaluation will be take place at baseline, day 3, day 6, 9, 14, 21 and day 28. At the end of the 28 days, the continuation of treatment will be depends on the investigator's clinical judgment and End of Medication Evaluation will be perform. Every effort will be made to continue to evaluate all subjects who are randomized even if they decide to discontinue the medication. Project Timetable The project will take 2 years. The plan is to randomize 2 subjects per week, taking about 15 month to acquire 120 subjects. All subjects will have completed study drug treatments before 18 months have elapsed. Follow-up evaluations will be completed 2 year from the start of the project. Primary Study Endpoints The primary endpoints to be measured in this study are: - MADRS at the baseline, Day 3, 6, 9, 14, 21 and 28. Secondary Study Endpoints The secondary endpoints to be measured are: Anxiety with HADS at baseline, Day 3, 6, 9, 14, 21 and 28 Distress score with distress thermometer at baseline, Day 3, 6, 9, 14, 21 and 28 Karnofsky Scale at the baseline, Day 3, 6, 9, 14, 21 and 28 Numeric Rating Scale (NRS) for Pain at the baseline, Day 3, 6, 9, 14, 21 and 28 Visual Analogue Scale (VAS) for Fatigue at the baseline, Day 3, 6, 9, 14, 21 and 28 Primary Safety Endpoints The primary safety endpoint will be measurement and collection of any serious adverse event that occurs from initial study treatment through and including 14 days after cessation of study treatment.

Official Title
-----------------
A Parallel-group, Double-blind, Placebo-controlled Study of Methylphenidate as an Add on Therapy for Mirtazapine in the Treatment of Major Depressive Disorder in Cancer Patients Under Palliative Care

Conditions
-----------------
Depression

Intervention / Treatment
-----------------
* Drug: Methylphenidate
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female, aged >18 years. Current DSM IV diagnosis of Major Depressive Disorder. Under palliative care. Confirmed diagnosis of cancer. Not on any antidepressants Exclusion Criteria: Clinical significant abnormal laboratory values. Clinically significant abnormal ECG. Documented history of other psychiatric diagnosis (schizophrenia, bipolar disorder, organic brain disorder, dementia etc.)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methylphenidate add on to Mirtazapine<br>Methylphenidate add on to the usual treatment (Mirtazapine) | Drug: Methylphenidate<br>* Methylphenidate started at 5mg on morning (0800) and noon (1200) on day 1. Dose increased to 10mg on morning (0800) and noon (1200) on day 3; 15mg on morning and noon on day 6 depending on the clinical response. Similarly, the dose can be reduced to 5mg/day if patients are not able to tolerate a higher dose. The treatment continues until day 28.<br>* Other names: Ritalin;|
| Placebo Comparator: Placebo add on to Mirtazapine<br>Non active compund add on to the usual treatment (Mirtazapine) | Drug: Placebo<br>* Placebo given on morning (0800) and noon (1200)daily<br>* Other names: Non active compound;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| depressive symptoms | measured with Montgomery-Åsberg Depression Rating Scale | 3 to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distress level | Measured with distress thermometer | 3 to 28 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Depression, cancer, methylphenidate, pharmacotherapy