Study of Methylphenidate as Add on Therapy in Depressed Cancer Patients
Study of Methylphenidate as Add on Therapy in Depressed Cancer Patients
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

 1. 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.

 2. 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.

 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

 4. 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.
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

 1. To determine the efficacy of Methylphenidate as add on therapy to mirtazapine in the
 treatment of anxiety in cancer patients.

 2. To determine the efficacy of Methylphenidate as add on therapy to mirtazapine in
 reducing distress in cancer patients.

 3. To determine the efficacy of Methylphenidate as add on therapy to mirtazapine in
 improving function in cancer patients.

 4. 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.
Inclusion Criteria:

 1. Male or female, aged >18 years.

 2. Current DSM IV diagnosis of Major Depressive Disorder.

 3. Under palliative care.

 4. Confirmed diagnosis of cancer.

 5. Not on any antidepressants

 Exclusion Criteria:

 1. Clinical significant abnormal laboratory values.

 2. Clinically significant abnormal ECG.

 3. Documented history of other psychiatric diagnosis (schizophrenia, bipolar disorder,
 organic brain disorder, dementia etc.)