Introduction
Major depressive disorder (MDD) is a common complication in patients diagnosed with cancer, being more frequent than in the general population (Walker et al., Reference Walker, Hansen, Martin, Symeonides, Ramessur, Murray and Sharpe2014). Its prevalence has been estimated to be 16.5%, and it is associated with greater disability, worsened quality of life and functionality, higher and more intense physical symptoms, less adherence to treatment, and lower survival rates (Arrieta et al., Reference Arrieta, Angulo, Núñez-Valencia, Dorantes-Gallareta, Macedo, Martínez-López, Alvarado, Corona-Cruz and Oñate-Ocaña2013; Kroenke et al., Reference Kroenke, Theobald, Wu, Loza, Carpenter and Tu2010; Wilson et al., Reference Wilson, Chochinov, Skirko, Allard, Chary, Gagnon, Macmillan, De Luca, O'Shea, Kuhl, Fainsinger and Clinch2007). It is also the principal factor for suicidal ideation and requests for assisted death in this population (Ballard et al., Reference Ballard, Pao, Henderson, Lee, Bostwick and Rosenstein2008; Zhong et al., Reference Zhong, Li, Lv, Tian, Liu, Li, Zhuang, Tao, Zhang and Zhuo2017).
Treatment with antidepressants has proven to be effective in most studies. However, patients diagnosed with advanced cancer may not tolerate oral medication and present with uncommon side effects and pharmacological interactions. Antidepressants’ latency to therapeutic effect (Harmer, Duman, & Cowen, Reference Harmer, Duman and Cowen2017) represents a major difficulty in depressed cancer patients. Therefore, patients at the end of life have limited options to improve affective symptoms and associated quality of life.
Ketamine, a dissociative anesthetic, has shown rapid efficacy in treating MDD and diminishing suicidal ideation (Bartoli et al., Reference Bartoli, Riboldi, Crocamo, Di Brita, Clerici and Carra2017; Wilkinson et al., Reference Wilkinson, Ballard, Bloch, Mathew, Murrough, Feder, Sos, Wang, Zarate and Sanacora2018). Ketamine's antidepressant mechanism of action has been linked to N-methyl-D-aspartate receptor (NMDAR) antagonism, with the subsequent action of glutamate on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and downstream signaling pathways leading to neuroplasticity (regulated mostly by Brain-Derived Neurotrophic Factor through rapid activation of the mammalian target of rapamycin) (Zanos & Gould, Reference Zanos and Gould2018).
Antidepressant effects of ketamine in patients with cancer have been previously reported, showing rapid action and safety (Iglewicz et al., Reference Iglewicz, Morrison, Nelesen, Zhan, Iglewicz, Fairman, Hirst and Irwin2015). Moreover, it has a direct benefit on diminishing suicidal ideation in newly diagnosed cancer patients (Fan et al., Reference Fan, Yang, Sun, Zhang, Li, Zheng and Liu2017). This promising therapeutic approach may provide relief for patients with cancer and affective comorbidities.
Case report
A 39-year-old woman with no prior physical illness presented to the Emergency Department. She was hospitalized due to uncontrollable pain in her right leg. She was diagnosed with epidermoid carcinoma of the cervix, stage IVB (liver and locally advanced) one year earlier and was previously treated with three cycles of paclitaxel and gemcitabine. As the disease progressed, she presented multiple complications that required frequent emergency care (obstructive kidney failure, septic shock, and pain), requiring constant medical and surgical treatment. On the first day of hospitalization, she was referred to the Palliative Care (PC) team and assessed by the Edmonton Symptom Assessment System (ESAS) (Bruera, Kuehn, Miller, Selmser, & Macmillan, Reference Bruera, Kuehn, Miller, Selmser and Macmillan1991), which showed the presence of pain, depression, anxiety, drowsiness, tiredness, and nausea mainly (scores of 9, 8, 7, 7, 3, and 3 respectively). The clinical prediction of survival was determined by the Palliative Prognosis Index in A (>6 weeks). She was treated with opioids (150 mg morphine equivalent dose), presenting a poor response, so epidural blockade was performed to treat the pain. Upon evaluation, she reported a previous depressive episode and presented suicide attempt the day before by hanging and was therefore assessed for the first time by the palliative care psychiatrist, diagnosing the patient with MDD. The patient had a depressed mood and irritability, anhedonia, feelings of worthlessness and hopelessness, diminished ability to concentrate, insomnia, and thoughts of death with suicidal ideation with specific plans, dating 10 months back. A diagnosis of severe MDD with active suicidal ideation was made, and a previous suicide attempt was documented. She had a score of 18 as assessed by the Brief Edinburgh Depression Scale (BEDS) (Rodriguez-Mayoral et al., Reference Rodriguez-Mayoral, Rodriguez-Ortiz, Ascencio-Huertas, Pena-Nieves, Verastegui, Allende-Perez and Lloyd-Williams2018).
Treatment response was measured using the BEDS before and after the intervention. The depressive symptoms decreased by 17% on day 1, 39% on day 3 and 72% on day 17 (Figure 1). Suicidal ideation disappeared and pain was reduced, and she was discharged. She continued with sertraline (50 mg) and clonazepam (1 mg) upon discharge.
Figure 1. Brief Edinburgh Depression Scale (BEDS) change after intervention.
After discharge she continued her treatment as an outpatient. She reported improvement in mood, pain, and an overall better quality of life. On a follow-up visit on day 17 of the intervention, she was re-evaluated and presented a BEDS score of 5. The patient died at home seven weeks later due to medical complications of her cancer diagnosis.
Discussion
Palliative care has the objective of improving quality of life in people with severe illness and suffering by an active and transdisciplinary approach for the control of physical and mental symptoms, without disregard to the spiritual and social aspect. Providing mental health care to this population is crucial due to the frequent comorbidity with depression, which increases the risk of medical complications and suicide (Grotmol et al., Reference Grotmol, Lie, Loge, Aass, Haugen, Stone, Kaasa and Hjermstad2019).
MDD diagnosis in cancer patients is frequently underdiagnosed and undertreated (Chochinov, Reference Chochinov2001). Also, current antidepressant therapies have a long latency of therapeutic effect (Harmer et al., Reference Harmer, Duman and Cowen2017), and suicidal ideation is a medical emergency that requires fast action (Gibbons, Brown, Hur, Davis, & Mann, Reference Gibbons, Brown, Hur, Davis and Mann2012). Ketamine's effect as monotherapy fades 5–8 days after administration (Kishimoto et al., Reference Kishimoto, Chawla, Hagi, Zarate, Kane, Bauer and Correll2016). This case report shows ketamine's rapid effect on diminishing suicidal ideation and a potential benefit of fast-acting antidepressant efficacy when waiting for regular pharmacotherapy to benefit a patient with advanced cancer presenting to the Emergency Department with a previous suicide attempt. This effect is in accordance with previous reports in similar populations (Fan et al., Reference Fan, Yang, Sun, Zhang, Li, Zheng and Liu2017; Iglewicz et al., Reference Iglewicz, Morrison, Nelesen, Zhan, Iglewicz, Fairman, Hirst and Irwin2015).
Although analgesia was provided by the PC in this case, ketamine has also shown to have an analgesic effect that might provide further benefit in patients with cancer and MDD (Sexton, Atayee, & Bruner, Reference Sexton, Atayee and Bruner2018; Zanicotti, Perez, & Glue, Reference Zanicotti, Perez and Glue2012). Therefore, analgesia might have influenced the BEDS scores. No side effects were reported by the patient, although they are common when used in antidepressant doses (headache, dizziness, dissociation, increased blood pressure) but transient and spontaneously resolved (Short, Fong, Galvez, Shelker, & Loo, Reference Short, Fong, Galvez, Shelker and Loo2018).
Some authors have expressed concerns about the need to be cautious when using ketamine as an antidepressant due to insufficient safety and efficacy data for off-label use, misuse potential, long-term side effects (Singh et al., Reference Singh, Morgan, Curran, Nutt, Schlag and McShane2017), and a theoretic possibility of acceleration of tumor growth because of the mechanistic target of rapamycin (mTOR) activation (Yang, Zhou, & Yang, Reference Yang, Zhou and Yang2011). However, recently the U.S. Food and Drug Administration approved esketamine (nasal spray) for its use in treatment-resistant depression (U.S. Food and Drug Administration, 2019), and its misuse potential and long-term side effects have been only shown in repeated and chronic use (Short et al., Reference Short, Fong, Galvez, Shelker and Loo2018).
Although ketamine has shown to be efficacious in treating MDD and suicidal ideation, more studies are needed to provide further evidence of its potential use and safety in cancer patients with suicidal risk or desire for hastened death who are highly vulnerable and frequently express hopelessness (Breitbart et al., Reference Breitbart, Rosenfeld, Pessin, Kaim, Funesti-Esch, Galietta, Nelson and Brescia2000).
Acknowledgments
The authors would like to thank to Adriana Peña-Nieves MPH for her valuable contribution to this paper.
Conflicts of interest
Oscar Rodríguez-Mayoral, Rodrigo Pérez-Esparza, and Silvia Allende-Pérez are supported by the National Council of Science and Technology's (CONACyT) National System of Researchers and have no conflict of interest. Georgina Dominguez-Ocadio does not report actual or potential conflicts of interest.
