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Research
Multicentre, double-blind, randomised placebo-controlled clinical trial on the efficacy of methylphenidate on depressive symptoms in advanced cancer patients Carlos Centeno,1 Alvaro Sanz,2 Miguel Angel Cuervo,3 Daniel Ramos,4 Silvia Hernansanz,5 Jesús Gonzalez,6 Maria Jose Almaraz,7 Marcos Lama,8 Francisco Vara,9 María Nabal,10 Antonio Pascual11 1Palliative
Care Team, Clinica Universidad de Navarra, Pamplona, Spain 2Medical Oncology, Hospital Universitario del Rio Hortega, Valladolid, Spain 3Palliative Care Team, Hospital Infanta Cristina, Badajoz, Spain 4 Palliative Care Team, Hospital Provincial de Zamora, Zamora, Spain 5Palliative Care Team, Hospital Clinico Universitario de Valladolid, Valladolid, Spain 6Palliative Care Team, Institut Catala Oncologia, Hospitalet, Spain 7Palliative Care Unit, Hospital Txagorritxu, Vitoria, Alava, Spain 8Palliative Care Unit, Hospital San Juan de Dios, Pamplona, Navarra, Spain 9 Palliative Medicine Regional Centre, Hospital Universitario de Salamanca, Salamanca, Spain 10 Palliative Care Unit, Hospital Universitari Arnau de Vilanova, Lleida, Spain 11Palliative Care Unit, Hospital Santa Creu i Sant Pau, Barcelona, Spain Correspondence to Alvaro Sanz, Hospital Universitario del Rio Hortega, Medical Oncology, Valladolid E-47012, Spain; [email protected] Accepted 24 April 2012 Published Online First 8 June 2012
ABSTRACT Introduction Methylphenidate is a psychostimulant that has been used to relieve depressive symptoms in advanced cancer patients. No studies compare its efficacy against placebo in this group of patients. Objective To explore the efficacy of methylphenidate compared with placebo in the relief of depressive symptoms in advanced cancer patients. Material and methods A multicentre, doubleblind, randomised placebo-controlled clinical trial was undertaken comparing the efficacy of methylphenidate and placebo in depressive symptoms. Advanced stage cancer patients were eligible if they scored at least two points on the Two Question Screening Survey for depression. A reduction of at least two points on the Edmonton Symptom Assessment Scale for depression (0–10) was considered as a response. Results Sixty-nine patients were included (methylphenidate: n=31, placebo: n=38); median daily dose of methylphenidate was 25 mg. Fifty-eight patients (84%) who completed the first week of treatment were considered suitable for evaluation. In the intention to treat analysis, there were 14/31 (45%) responses with methylphenidate and 10/38 (26%) responses with placebo (difference: 19%; 95% CI: 4% to 39%; p=0.10). With the Hospital Anxiety and Depression Scale, 11/19 (58%) patients with methylphenidate and 10/24 (42%) with placebo improved from a score compatible with depression in the first 7 days (difference 16%; 95% CI 13% to 42%; p=0.29). The proportion of patients indicating adverse effects was similar for both cohorts (p=0.99). Conclusion Compared with the placebo, methylphenidate demonstrated a positive trend in the incidence of response for depressive symptoms in advanced cancer patients.
INTRODUCTION Approximately 25% of advanced cancer patients suffer from depression.1 However, the proportion of patients with depressive symptoms who do not satisfy the specific criteria of depression seems to be higher. 2 These cases are often associated with concepts such as adaptive disorder, dysthymia or emotional distress. In such situations, the therapeutic approach may include emotional support as counselling, or the 328
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use of psychoactive drugs as antidepressants or anxiolytics. To avoid delay in both the identification of, and treatment for, depression in patients whose lifeexpectancy is limited, there is a trend towards a simple, brief approach based on diagnostic estimation and supported by elementary screening techniques that are reinforced, wherever possible, by more complex tests. 3 Within this context, the Two Question Screening Survey (TQSS) for depression focuses on the state of mind and anhedonia and asks if the patient has been feeling low, depressed or despondent, or has felt a lack of interest or satisfaction over the previous month. The TQSS is a valid tool in the screening for depression in cancer patients,4 with high sensitivity and positive predictive value but with a somewhat limited specificity. 5 6 Once depressive symptoms are presented in a terminally ill cancer patient, palliation of these symptoms becomes an urgent objective, and this will usually involve the choice of rapidly acting treatments.7 Because of delay in the effect of classic antidepressants and because mild depressive symptoms cannot be diagnosed as classic depression, they are not considered as the best chance for these depressive symptoms, above all in patients with a very limited life expectancy. As a result, psychostimulant drugs such as methylphenidate have been considered as an appropriate therapeutic option. These psychostimulants are used to treat depressive symptoms, asthenia and opioidinduced somnolence.8 As opposed to classic antidepressants, psychostimulants start to take effect very quickly, often within hours.9 The percentage of advanced cancer patients with depressive symptoms showing response to methylphenidate ranges from 50% to 75%, with a low incidence of side effects (
Research
Multicentre, double-blind, randomised placebo-controlled clinical trial on the efficacy of methylphenidate on depressive symptoms in advanced cancer patients Carlos Centeno,1 Alvaro Sanz,2 Miguel Angel Cuervo,3 Daniel Ramos,4 Silvia Hernansanz,5 Jesús Gonzalez,6 Maria Jose Almaraz,7 Marcos Lama,8 Francisco Vara,9 María Nabal,10 Antonio Pascual11 1Palliative
Care Team, Clinica Universidad de Navarra, Pamplona, Spain 2Medical Oncology, Hospital Universitario del Rio Hortega, Valladolid, Spain 3Palliative Care Team, Hospital Infanta Cristina, Badajoz, Spain 4 Palliative Care Team, Hospital Provincial de Zamora, Zamora, Spain 5Palliative Care Team, Hospital Clinico Universitario de Valladolid, Valladolid, Spain 6Palliative Care Team, Institut Catala Oncologia, Hospitalet, Spain 7Palliative Care Unit, Hospital Txagorritxu, Vitoria, Alava, Spain 8Palliative Care Unit, Hospital San Juan de Dios, Pamplona, Navarra, Spain 9 Palliative Medicine Regional Centre, Hospital Universitario de Salamanca, Salamanca, Spain 10 Palliative Care Unit, Hospital Universitari Arnau de Vilanova, Lleida, Spain 11Palliative Care Unit, Hospital Santa Creu i Sant Pau, Barcelona, Spain Correspondence to Alvaro Sanz, Hospital Universitario del Rio Hortega, Medical Oncology, Valladolid E-47012, Spain; [email protected] Accepted 24 April 2012 Published Online First 8 June 2012
ABSTRACT Introduction Methylphenidate is a psychostimulant that has been used to relieve depressive symptoms in advanced cancer patients. No studies compare its efficacy against placebo in this group of patients. Objective To explore the efficacy of methylphenidate compared with placebo in the relief of depressive symptoms in advanced cancer patients. Material and methods A multicentre, doubleblind, randomised placebo-controlled clinical trial was undertaken comparing the efficacy of methylphenidate and placebo in depressive symptoms. Advanced stage cancer patients were eligible if they scored at least two points on the Two Question Screening Survey for depression. A reduction of at least two points on the Edmonton Symptom Assessment Scale for depression (0–10) was considered as a response. Results Sixty-nine patients were included (methylphenidate: n=31, placebo: n=38); median daily dose of methylphenidate was 25 mg. Fifty-eight patients (84%) who completed the first week of treatment were considered suitable for evaluation. In the intention to treat analysis, there were 14/31 (45%) responses with methylphenidate and 10/38 (26%) responses with placebo (difference: 19%; 95% CI: 4% to 39%; p=0.10). With the Hospital Anxiety and Depression Scale, 11/19 (58%) patients with methylphenidate and 10/24 (42%) with placebo improved from a score compatible with depression in the first 7 days (difference 16%; 95% CI 13% to 42%; p=0.29). The proportion of patients indicating adverse effects was similar for both cohorts (p=0.99). Conclusion Compared with the placebo, methylphenidate demonstrated a positive trend in the incidence of response for depressive symptoms in advanced cancer patients.
INTRODUCTION Approximately 25% of advanced cancer patients suffer from depression.1 However, the proportion of patients with depressive symptoms who do not satisfy the specific criteria of depression seems to be higher. 2 These cases are often associated with concepts such as adaptive disorder, dysthymia or emotional distress. In such situations, the therapeutic approach may include emotional support as counselling, or the 328
bmjspcare-2011-000093.indd Sec1:1
use of psychoactive drugs as antidepressants or anxiolytics. To avoid delay in both the identification of, and treatment for, depression in patients whose lifeexpectancy is limited, there is a trend towards a simple, brief approach based on diagnostic estimation and supported by elementary screening techniques that are reinforced, wherever possible, by more complex tests. 3 Within this context, the Two Question Screening Survey (TQSS) for depression focuses on the state of mind and anhedonia and asks if the patient has been feeling low, depressed or despondent, or has felt a lack of interest or satisfaction over the previous month. The TQSS is a valid tool in the screening for depression in cancer patients,4 with high sensitivity and positive predictive value but with a somewhat limited specificity. 5 6 Once depressive symptoms are presented in a terminally ill cancer patient, palliation of these symptoms becomes an urgent objective, and this will usually involve the choice of rapidly acting treatments.7 Because of delay in the effect of classic antidepressants and because mild depressive symptoms cannot be diagnosed as classic depression, they are not considered as the best chance for these depressive symptoms, above all in patients with a very limited life expectancy. As a result, psychostimulant drugs such as methylphenidate have been considered as an appropriate therapeutic option. These psychostimulants are used to treat depressive symptoms, asthenia and opioidinduced somnolence.8 As opposed to classic antidepressants, psychostimulants start to take effect very quickly, often within hours.9 The percentage of advanced cancer patients with depressive symptoms showing response to methylphenidate ranges from 50% to 75%, with a low incidence of side effects (
