Pharmacology Consult

Effective pharmacological management of depression ‘imperative’ for patients with cancer

Major depression is a significant comorbidity in cancer, with prevalence estimated at 15% to 20%.

Depression has been associated with prolonged hospital stays, increased physical distress, lack of treatment compliance, impaired quality of life and increased mortality risk.

A clinical practice guideline issued last year suggested patients with cancer who have depression benefit from psychological or pharmacological interventions, without evidence for the superiority of one therapy vs. another. The guideline authors also contended a multidisciplinary “mental health care restructuring” may be required for optimal management of depression.

Depression and cancer survival

Several studies have examined the comorbidity of depression with cancer, and some propose that depression may be associated with disease progression or survival.

Jai N. Patel, PharmD, BCOP
Jai N. Patel

Giese-Davis and colleagues found that women with metastatic breast cancer whose depression scores decreased over 1 year achieved an overall median survival of 53.6 months, more than double the median 25.1 months for women whose scores increased during that time.

Suppli and colleagues conducted a nationwide cohort study in Denmark that showed patients with breast cancer treated with antidepressants before diagnosis appeared significantly more likely to receive nonguideline treatment (OR = 1.14; 95% CI, 1.03-1.27). They also achieved significantly shorter OS (HR = 1.21; 95% CI, 1.14-1.28) and breast cancer–specific survival (HR = 1.11; 95% CI, 1.03-1.2).

Sullivan and colleagues investigated longitudinal changes in depression symptoms among patients with lung cancer. More than one-third (38%) had depression symptoms at baseline, and 14% developed new-onset depression during treatment.

Researchers observed increased mortality risk — regardless of disease stage — among those with new-onset depression (HR = 1.5; 95% CI, 1.12-2.01) and persistent depression symptoms (HR = 1.42; 95% CI, 1.15-1.75) compared with those who never had depression symptoms.

Similar findings have been reported for patients with other cancer types, suggesting the presence of depressive symptoms can significantly diminish response to anticancer therapy and affect survival.

Biological influence

A study by Cohen and colleagues revealed an association between depression symptoms and increased risk for death among patients with late-stage renal cell carcinoma. The researchers also identified a significant association between cortisol slope and shorter survival.

Cortisol — produced by the adrenal gland in response to stress — helps regulate the inflammatory response in the body. Patients with sustained cortisol levels throughout the day demonstrated increased risk for mortality. These data suggest that emotional factors can have an impact on biology, which — in turn — can influence cancer outcomes.

In the same study, functional genomic analyses linked depressive symptoms to increased expression of pro-inflammatory and pro-metastatic genes in circulating leukocytes.

Wu and colleagues conducted a study that included patients with stage III or stage IV small cell lung cancer. They found that presence of depression severely decreased patient tolerance to chemotherapy, reducing PFS and OS.

Investigators also found that patients with severe depression displayed a downregulated level of serum brain derived neurotrophic factor (BDNF), which appeared highly correlated with survival. Further, cotreatment with BDNF enhanced the chemosensitivity of tumor cells to cisplatin, suggesting depression may directly antagonize chemotherapy effects.

Chronic psychological stress also has been proposed to influence inflammatory response. After a prolonged period of chronic stress, body tissues become desensitized to cortisol, thus reducing its effects in regulating inflammation. Chronic inflammation ultimately can promote the development and progression of many illnesses, including depression, cancer and heart disease.

Elevations in interleukin-1, interleukin-6, interferon alpha and tumor necrosis factor alpha levels also have been observed in patients with cancer and depression. Monitoring for mood changes — coupled with more objective measurements, such as cortisol or pro-inflammatory cytokines — may be beneficial as an additional screening tool to identify high-risk patients.

Pharmacological considerations

There are two primary classes of antidepressant medications. One is tricyclic antidepressants (TCAs); the other includes selective serotonin reuptake inhibitors (SSRIs) and selective serotonin norepinephrine reuptake inhibitors.

These medications are thought to cause adaptive changes in the brain and, over time, increase serotonin neurotransmission, leading to improvement in mood.

Randomized trials have shown treatment with antidepressants, such as SSRIs, significantly improve quality of life and mitigate depressive symptoms; however, data are inconsistent.

A review by Ostuzzi and colleagues revealed available studies were few and provided very low–quality evidence of the effects of these drugs compared with placebo.

Regardless, guidelines recommend to screen early and treat with psychological or pharmacological interventions. A meta-analysis by Laoutidis and Mathiak offered no recommendation for one antidepressant type over another in cancer due to a lack of research.

TCAs are associated with more adverse effects and higher risk for overdose compared with SSRIs. However, SSRIs must be considered carefully for patients who receive chemotherapy or radiotherapy. These medications can work in opposition to serotonin antagonists — such as ondansetron — which may worsen emesis and nausea. The anticholinergic effects of TCAs may worsen delirium associated with chemotherapy.

Some antidepressants — particularly fluoxetine and paroxetine, prescribed concurrently in approximately 25% of patients with breast cancer for the treatment of depression or hot flashes — may reduce the efficacy of tamoxifen, thus increasing breast cancer recurrence, by inhibiting the hepatic enzyme CYP2D6 and metabolism to its active metabolite, endoxifen. This interaction has been studied clinically and pharmacokinetically.

A large cohort study of more than 16,000 breast cancer survivors treated with tamoxifen demonstrated no apparent increased risk for breast cancer recurrence among those who concurrently used strong CYP2D6 inhibitors, such as paroxetine. However, experts suggest these medications should be avoided given the availability of multiple antidepressants with lower potential for interaction.

Citalopram, escitalopram, venlafaxine and desvenlafaxine are weaker CYP2D6 inhibitors and are not expected to significantly interact with tamoxifen metabolism.

Additionally, SSRIs and herbal preparations that contain hypercium perforatum (St John’s Wort) may induce the CYP3A4 enzyme, which may increase the metabolism of cancer drugs inactivated by CYP3A4, such as tyrosine kinase inhibitors.

Lal and colleagues studied 297 patients with cancer who received at least three prescriptions for antidepressants for a continuous 6-month period; 49% of them took a drug combination that could have caused a major interaction, such as bleeding or serotonin syndrome.

Multivariate analysis showed the presence of a potential major drug interaction with antidepressants appeared associated with increased hospital and ED visits, underscoring the need to screen for potential drug interactions with antidepressants.

Despite multiple therapy options, up to half of all patients with depression do not respond to initial treatment. As few as a third of patients treated with SSRIs achieve remission, or absence of symptoms.

Genetic polymorphisms resulting in variations in the metabolism of antidepressant medications may contribute to this low rate of remission, as well as incidence of adverse drug reactions.

CYP2C19, CYP2D6 and CYP3A4 account for nearly 75% of the total metabolism of all antidepressants, and CYP2D6 alone is responsible for more than one-quarter of the metabolism of psychopharmacological drugs. Genetic variations in CYP2C19 and CYP2D6 can significantly effect drug exposure, altering clinical activity.

The Clinical Pharmacogenetics Implementation Consortium guidelines provide prescribing decisions based on CYP2D6 or CYP2C19 for amitriptyline, citalopram, clomipramine, desipramine, doxepin, escitalopram, imipramine, nortriptyline, paroxetine, sertraline and trimipramine.

In some studies, patients found to be CYP2D6 or CYP2C19 rapid metabolizers demonstrated an increased risk for ongoing depression and suicidal ideation. Poor metabolizers demonstrated increased risk for side effects, including serotonin syndrome and QT prolongation.

Research suggests application of pre-emptive pharmacogenetic testing and genotype-guided drug selection improves clinical response to antidepressants and allows for more rapid symptom relief.

Future implications

Understanding the mechanism by which depression influences cancer survival may allow for improved screening methods and potentially innovative treatments.

A multidisciplinary approach that involves psychological and pharmacological interventions is required to mitigate depressive symptoms.

Although there are no robust randomized trials that demonstrate the administration of antidepressants and reduced symptom bur den improves OS or cancer-specific survival, it is imperative that clinicians screen patients early, monitor them closely — ideally with a psycho-oncology expert as part of a multidisciplinary palliative care team — and treat as appropriate.

Pharmacological considerations — such as screening for potential drug–drug and even drug–gene interactions — are important to optimize therapy selection for patients with cancer.

References:

Andersen R, et al. Pharmacogenomics. 2016;doi:10.2217/pgs.15.178.

MK. CA Cancer J Clin. 2011;doi:10.3322/caac.20127.

Cohen L, et al. PLoS One. 2012;doi:10.1371/journal.pone.0042324.

Fisch MJ, et al. J Clin Oncol. 2003;21:1937-1943.

Giese-Davis J, et al. J Clin Oncol. 2011;doi:10.1200.JCO.2010.28.4455.

Hall-Flavin DK, et al. Pharmacogenet Genomics. 2013;doi:10.1097/FPC.0b013e3283649b9a.

Lal LS, et al. Support Care Cancer. 2011;doi:10.1007/s00520-011-1170-4.

Laoutidis ZG, Mathiak K. BMC Pyschiatry. 2013;doi:10.1186/1471-244X-13-140.

Li M, et al. J Oncol Pract. 2016;doi:10.1200/JOP.2016.011072.

Ostuzzi G, et al. Cochrane Database Syst Rev. 2015;doi:10.1002/14651858.CD011006.pub2.

Suppli NP, et al. J Clin Oncol. 2017;doi:10.1200/JCO.2016.68.8358.

Sullivan DR, et al. J Clin Oncol. 2016;34:3984-3991.

Wu Y, et al. Oncotarget. 2016;doi:10.18632/oncotarget.13291.

For more information:

Jai N. Patel, PharmD, BCOP, is chief of pharmacology research and phase 1 trials at Levine Cancer Institute at Carolinas HealthCare System, as well as adjunct assistant professor at UNC Eshelman School of Pharmacy. He also is a HemOnc Today Editorial Board member. He can be reached at jai.patel@carolinashealthcare.org.

Disclosure: Patel reports no relevant financial disclosures.

Major depression is a significant comorbidity in cancer, with prevalence estimated at 15% to 20%.

Depression has been associated with prolonged hospital stays, increased physical distress, lack of treatment compliance, impaired quality of life and increased mortality risk.

A clinical practice guideline issued last year suggested patients with cancer who have depression benefit from psychological or pharmacological interventions, without evidence for the superiority of one therapy vs. another. The guideline authors also contended a multidisciplinary “mental health care restructuring” may be required for optimal management of depression.

Depression and cancer survival

Several studies have examined the comorbidity of depression with cancer, and some propose that depression may be associated with disease progression or survival.

Jai N. Patel, PharmD, BCOP
Jai N. Patel

Giese-Davis and colleagues found that women with metastatic breast cancer whose depression scores decreased over 1 year achieved an overall median survival of 53.6 months, more than double the median 25.1 months for women whose scores increased during that time.

Suppli and colleagues conducted a nationwide cohort study in Denmark that showed patients with breast cancer treated with antidepressants before diagnosis appeared significantly more likely to receive nonguideline treatment (OR = 1.14; 95% CI, 1.03-1.27). They also achieved significantly shorter OS (HR = 1.21; 95% CI, 1.14-1.28) and breast cancer–specific survival (HR = 1.11; 95% CI, 1.03-1.2).

Sullivan and colleagues investigated longitudinal changes in depression symptoms among patients with lung cancer. More than one-third (38%) had depression symptoms at baseline, and 14% developed new-onset depression during treatment.

Researchers observed increased mortality risk — regardless of disease stage — among those with new-onset depression (HR = 1.5; 95% CI, 1.12-2.01) and persistent depression symptoms (HR = 1.42; 95% CI, 1.15-1.75) compared with those who never had depression symptoms.

Similar findings have been reported for patients with other cancer types, suggesting the presence of depressive symptoms can significantly diminish response to anticancer therapy and affect survival.

Biological influence

A study by Cohen and colleagues revealed an association between depression symptoms and increased risk for death among patients with late-stage renal cell carcinoma. The researchers also identified a significant association between cortisol slope and shorter survival.

Cortisol — produced by the adrenal gland in response to stress — helps regulate the inflammatory response in the body. Patients with sustained cortisol levels throughout the day demonstrated increased risk for mortality. These data suggest that emotional factors can have an impact on biology, which — in turn — can influence cancer outcomes.

In the same study, functional genomic analyses linked depressive symptoms to increased expression of pro-inflammatory and pro-metastatic genes in circulating leukocytes.

PAGE BREAK

Wu and colleagues conducted a study that included patients with stage III or stage IV small cell lung cancer. They found that presence of depression severely decreased patient tolerance to chemotherapy, reducing PFS and OS.

Investigators also found that patients with severe depression displayed a downregulated level of serum brain derived neurotrophic factor (BDNF), which appeared highly correlated with survival. Further, cotreatment with BDNF enhanced the chemosensitivity of tumor cells to cisplatin, suggesting depression may directly antagonize chemotherapy effects.

Chronic psychological stress also has been proposed to influence inflammatory response. After a prolonged period of chronic stress, body tissues become desensitized to cortisol, thus reducing its effects in regulating inflammation. Chronic inflammation ultimately can promote the development and progression of many illnesses, including depression, cancer and heart disease.

Elevations in interleukin-1, interleukin-6, interferon alpha and tumor necrosis factor alpha levels also have been observed in patients with cancer and depression. Monitoring for mood changes — coupled with more objective measurements, such as cortisol or pro-inflammatory cytokines — may be beneficial as an additional screening tool to identify high-risk patients.

Pharmacological considerations

There are two primary classes of antidepressant medications. One is tricyclic antidepressants (TCAs); the other includes selective serotonin reuptake inhibitors (SSRIs) and selective serotonin norepinephrine reuptake inhibitors.

These medications are thought to cause adaptive changes in the brain and, over time, increase serotonin neurotransmission, leading to improvement in mood.

Randomized trials have shown treatment with antidepressants, such as SSRIs, significantly improve quality of life and mitigate depressive symptoms; however, data are inconsistent.

A review by Ostuzzi and colleagues revealed available studies were few and provided very low–quality evidence of the effects of these drugs compared with placebo.

Regardless, guidelines recommend to screen early and treat with psychological or pharmacological interventions. A meta-analysis by Laoutidis and Mathiak offered no recommendation for one antidepressant type over another in cancer due to a lack of research.

TCAs are associated with more adverse effects and higher risk for overdose compared with SSRIs. However, SSRIs must be considered carefully for patients who receive chemotherapy or radiotherapy. These medications can work in opposition to serotonin antagonists — such as ondansetron — which may worsen emesis and nausea. The anticholinergic effects of TCAs may worsen delirium associated with chemotherapy.

Some antidepressants — particularly fluoxetine and paroxetine, prescribed concurrently in approximately 25% of patients with breast cancer for the treatment of depression or hot flashes — may reduce the efficacy of tamoxifen, thus increasing breast cancer recurrence, by inhibiting the hepatic enzyme CYP2D6 and metabolism to its active metabolite, endoxifen. This interaction has been studied clinically and pharmacokinetically.

PAGE BREAK

A large cohort study of more than 16,000 breast cancer survivors treated with tamoxifen demonstrated no apparent increased risk for breast cancer recurrence among those who concurrently used strong CYP2D6 inhibitors, such as paroxetine. However, experts suggest these medications should be avoided given the availability of multiple antidepressants with lower potential for interaction.

Citalopram, escitalopram, venlafaxine and desvenlafaxine are weaker CYP2D6 inhibitors and are not expected to significantly interact with tamoxifen metabolism.

Additionally, SSRIs and herbal preparations that contain hypercium perforatum (St John’s Wort) may induce the CYP3A4 enzyme, which may increase the metabolism of cancer drugs inactivated by CYP3A4, such as tyrosine kinase inhibitors.

Lal and colleagues studied 297 patients with cancer who received at least three prescriptions for antidepressants for a continuous 6-month period; 49% of them took a drug combination that could have caused a major interaction, such as bleeding or serotonin syndrome.

Multivariate analysis showed the presence of a potential major drug interaction with antidepressants appeared associated with increased hospital and ED visits, underscoring the need to screen for potential drug interactions with antidepressants.

Despite multiple therapy options, up to half of all patients with depression do not respond to initial treatment. As few as a third of patients treated with SSRIs achieve remission, or absence of symptoms.

Genetic polymorphisms resulting in variations in the metabolism of antidepressant medications may contribute to this low rate of remission, as well as incidence of adverse drug reactions.

CYP2C19, CYP2D6 and CYP3A4 account for nearly 75% of the total metabolism of all antidepressants, and CYP2D6 alone is responsible for more than one-quarter of the metabolism of psychopharmacological drugs. Genetic variations in CYP2C19 and CYP2D6 can significantly effect drug exposure, altering clinical activity.

The Clinical Pharmacogenetics Implementation Consortium guidelines provide prescribing decisions based on CYP2D6 or CYP2C19 for amitriptyline, citalopram, clomipramine, desipramine, doxepin, escitalopram, imipramine, nortriptyline, paroxetine, sertraline and trimipramine.

In some studies, patients found to be CYP2D6 or CYP2C19 rapid metabolizers demonstrated an increased risk for ongoing depression and suicidal ideation. Poor metabolizers demonstrated increased risk for side effects, including serotonin syndrome and QT prolongation.

Research suggests application of pre-emptive pharmacogenetic testing and genotype-guided drug selection improves clinical response to antidepressants and allows for more rapid symptom relief.

Future implications

Understanding the mechanism by which depression influences cancer survival may allow for improved screening methods and potentially innovative treatments.

A multidisciplinary approach that involves psychological and pharmacological interventions is required to mitigate depressive symptoms.

Although there are no robust randomized trials that demonstrate the administration of antidepressants and reduced symptom bur den improves OS or cancer-specific survival, it is imperative that clinicians screen patients early, monitor them closely — ideally with a psycho-oncology expert as part of a multidisciplinary palliative care team — and treat as appropriate.

PAGE BREAK

Pharmacological considerations — such as screening for potential drug–drug and even drug–gene interactions — are important to optimize therapy selection for patients with cancer.

References:

Andersen R, et al. Pharmacogenomics. 2016;doi:10.2217/pgs.15.178.

MK. CA Cancer J Clin. 2011;doi:10.3322/caac.20127.

Cohen L, et al. PLoS One. 2012;doi:10.1371/journal.pone.0042324.

Fisch MJ, et al. J Clin Oncol. 2003;21:1937-1943.

Giese-Davis J, et al. J Clin Oncol. 2011;doi:10.1200.JCO.2010.28.4455.

Hall-Flavin DK, et al. Pharmacogenet Genomics. 2013;doi:10.1097/FPC.0b013e3283649b9a.

Lal LS, et al. Support Care Cancer. 2011;doi:10.1007/s00520-011-1170-4.

Laoutidis ZG, Mathiak K. BMC Pyschiatry. 2013;doi:10.1186/1471-244X-13-140.

Li M, et al. J Oncol Pract. 2016;doi:10.1200/JOP.2016.011072.

Ostuzzi G, et al. Cochrane Database Syst Rev. 2015;doi:10.1002/14651858.CD011006.pub2.

Suppli NP, et al. J Clin Oncol. 2017;doi:10.1200/JCO.2016.68.8358.

Sullivan DR, et al. J Clin Oncol. 2016;34:3984-3991.

Wu Y, et al. Oncotarget. 2016;doi:10.18632/oncotarget.13291.

For more information:

Jai N. Patel, PharmD, BCOP, is chief of pharmacology research and phase 1 trials at Levine Cancer Institute at Carolinas HealthCare System, as well as adjunct assistant professor at UNC Eshelman School of Pharmacy. He also is a HemOnc Today Editorial Board member. He can be reached at jai.patel@carolinashealthcare.org.

Disclosure: Patel reports no relevant financial disclosures.