• Users Online: 290
  • Print this page
  • Email this page


 
 
Table of Contents
REVIEW
Year : 2019  |  Volume : 33  |  Issue : 1  |  Page : 13-19

Antidepressant therapy in patients with cancer: A clinical review


1 Department of Psychiatry, Wan Fang Medical Center, Taipei, Taiwan
2 Department of Psychiatry, Wan Fang Medical Center; Department of Psychiatry, College of Medicine, Taipei Medical University, Taipei, Taiwan

Date of Submission04-Jan-2019
Date of Decision06-Jan-2019
Date of Acceptance07-Jan-2019
Date of Web Publication28-Mar-2019

Correspondence Address:
Winston W Shen
No.111, Section 3, Shing Long Road, Taipei 116
Taiwan
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/TPSY.TPSY_3_19

Rights and Permissions
  Abstract 


Background: The prevalence of major depressive disorder (MDD) by DSM criteria among cancer patients is about 14%–15% in oncological, hematological, and palliative services and the number is risen up to 20%–25% when other depressive disorders are also included. Like MDD patients in general, patients with cancer are thought to be underdiagnosed and undertreated. Untreated depression in cancer patients may lead to having distressed symptoms and signs, decreased quality of life, higher suicide risk, greater psychological burden on the family, longer hospital stays, poorer anticancer treatment compliance, as well as even increased risk for mortality. Methods: In this review, the authors reviewed published articles on the use of antidepressant use for patients with cancer, to familiarize the readers with the use of antidepressants. Results: Antidepressants have been found to be more effective than placebo in relieving depressive symptoms in patients with cancer, and the efficacy is positively associated with length of treatment. Although the rate of antidepressant prescription is increasing, still about 75% of cancer patients with depression have not yet received antidepressant treatment. Besides the use in treating mood and anxiety symptoms, antidepressants have also been found to have versatile rôles as palliative treatment for cancer-related symptoms – pain, hot flushes, nausea, anorexia/cachexia, and fatigue. Furthermore, antidepressants have been studied for their anticancer potentials. They can inhibit tumor growth through either indirectly regulating immunity by enhancing cytotoxic activity and modulating cytokine production, or directly initiating cancer cell death and arresting cancer cell proliferation. We also found important drug-drug interaction between antidepressants and tamoxifen. Conclusion: Besides treating depressive and anxiety disorders, antidepressants are effective in treating cancer-related symptoms (pain, hot flushes, nausea, anorexia/cachexia, and fatigue). Cancer patients are eager to receive more effective treatment against their cancer as well as comorbid depression, and physicians should be more aggressive in providing every beneficial regimen – including an antidepressant.

Keywords: Anorexia/cachexia, fatigue, nausea, pain


How to cite this article:
Chang SC, Shen WW. Antidepressant therapy in patients with cancer: A clinical review. Taiwan J Psychiatry 2019;33:13-9

How to cite this URL:
Chang SC, Shen WW. Antidepressant therapy in patients with cancer: A clinical review. Taiwan J Psychiatry [serial online] 2019 [cited 2019 Apr 19];33:13-9. Available from: http://www.e-tjp.org/text.asp?2019/33/1/13/255142




  Introduction Top


In a cross-country meta-analysis[1], the prevalence of major depressive disorder (MDD) by DSM criteria among cancer patients is about 14%–15% in oncological, hematological and palliative care settings, and it is risen up to 20%–25% when other depressive disorders – such as dysthymic and minor depressive disorders – are also included. A Scottish study[2] revealed that the prevalence of MDD is highest in patients with lung cancer (13.1%), followed by those with gynecological cancer (10.9%), breast cancer (9.3%), colorectal cancer (7.0%), and genitourinary cancer (5.6%).

Depression is often unrecognized partly because that clinicians tend to presume all cancer patients being “understandably depressed[3],” and that depressive symptoms defined in DSM-5 such as appetite and weight changes, fatigue, and psychomotor retardation are indistinguishable from cancer symptoms. However, Brenne et al., found that many other symptoms such as despair, anxiety, and social withdrawal are common in depressed patients with incurable cancer[4]. Chochinov et al. also suggested that simply asking a question “Are you depressed most of the time?” is proven to be a good simple tool to screen for depression in the patients with advanced cancer, showing excellent sensitivity and specificity[5].

Depressive symptoms are emerged markedly after diagnosis of cancer, which typically reaches the highest prevalence in the first 6 months, and become lesser in severity over the time after adjustment to the shock of being diagnosed with cancer and the side effects of anticancer treatments[6].

In cancer patients, depression may lead to a decreased quality of life, higher suicide risk, greater psychological burden on the family, longer hospital stays, and poorer anticancer treatment compliance[7]. The result of a meta-analysis shows that depression, defined categorically or dimensionally, is associated with increased risk for mortality in cancer patients after controlling for confounding medical variables[8].


  Antidepressants for Depression in Cancer Patients Top


A meta-analysis of 19 studies[9] shows that antidepressants – particularly selective serotonin-reuptake inhibitors (SSRIs) and mianserin – are more effective than placebo in relieving depressive symptoms in patients with cancer, and the efficacy is positively associated with length of treatment. While SSRIs and tricyclic antidepressants (TCAs) are not different from placebo in overall acceptability, the “other antidepressant” group – including bupropion, venlafaxine, and mianserin – has less dropout rate than placebo does[10].

In 2016, Sanjida et al. reviewed 38 articles and found that the prevalence of prescribing antidepressants to cancer patients is 15.6%[9]. The prescription is remarkably less common in studies from Asia (7.4%), but more common in female (22.6%) or breast cancer patients (22.6%). SSRIs are the most frequently prescribed antidepressants in that review[9].

In the United States of America, the average rate of antidepressant use among cancer patients is 18.3%, compared with 12.3% among adults without a cancer history in 1999–2012, and the prevalence of use among cancer patients was increased nearly doubled, from 10.6% in 1999–2000 to 20.8% in 2011–2012[11]. Over the same period, a smaller increase of 7.2% has been observed among adults without a cancer history[11].

In a study to analyze the use of antidepressants in depressive patients with cancer (patient group) and without cancer (control group)[12], German investigators found that after a 1-year follow-up, less patients receive antidepressants than controls (66.5% vs. 72.8%)[12]. TCAs were given less frequently to patients than to controls (31.2% vs. 38.2%); by contrast, 7.0% of patients with cancer and 4.2% of controls receive benzodiazepines[12]. However, an Australian study showed that 17.2% of cancer patients receive antidepressants and that they are 42% more likely to get antidepressant therapy than noncancer patients. Cancer patients with the comorbid disease, receiving opioids, corticosteroids, or benzodiazepines, and those death is approaching, are more likely to be treated with an antidepressant[13].


  Antidepressant for Cancer-Related Symptoms Top


Antidepressant has been lauded for its versatile use clinically[14],[15], including some distressing cancer-related symptom[10]. The symptoms listed below are some frequently seen clinical symptoms in patients with cancer which is treatable with antidepressants.

Pain

Cancer-related pain is frequent and debilitating and is reported by more than 70% of cancer patients[16]. Studies showed that around two-thirds to three quarters of pains are related to tumor itself, 10%–20% to cancer treatments, and about 10% to comorbid diseases[17]. ICD-11 has been released by the World Health Organization in 2018 (www.icd.who.int/browse11/l-m/en), listing cancer-related pain as a separate entity which includes chronic cancer pain (code: MG30.10) and chronic post-cancer treatment pain (code: MG30.11). Chronic cancer pain is a chronic pain caused by the primary cancer or metastases. However, chronic post-cancer treatment pain is caused by any treatment given to treat the primary tumor or metastases, including chemotherapy, radiotherapy, surgery, and hormone therapy.

Pain can be classified as neuropathic or nociceptive. Neuropathic pain is caused by direct injury to nerves or nerve roots, which is due to tumor infiltration or treatment such as chemotherapy and radiation therapy. Nociceptive pain is due to tissue damage with activating nociceptors secondary to tumor invasion into bone, joints, or connective tissues, or is associated with invasive procedures including lumbar puncture, biopsy and surgical intervention[18]. In a review of 19 studies comprising 11,063 cancer patients[19], Bennett et al. found that 6,569 (59.4%) have nociceptive pain, 2,102 (19%) neuropathic pain, 2,227 (20.1%) mixed-mechanism pain, and 165 (1.5%) those are classified as having unknown or other causes.

Besides nonopioids (acetaminophen and non-steroid anti-inflammatory drugs) and opioids as suggested by the WHO's three-step analgesic ladder for treating cancer pain (www.who.int/cancer/palliative/painladder/en/), adjuvant analgesics, including antidepressants and anticonvulsants which have analgesic properties, to reduce opiate doses and their adverse effects, and can be used at any step of the ladder[20]. In a randomized double-blind crossover trial in 231 patients with chemotherapy-induced neuropathy[21], Smith et al., found that 60 mg/day of duloxetine over a period of 5 weeks is effective in reducing neuropathic pain. Another randomized controlled trial in 48 patients[22] also showed that short-term treatment with venlafaxine around oxaliplatin treatment can reduce the risk of chemotherapy-induced neuropathic pain. Furthermore, Nishihara et al.[23] found that low-dose imipramine (5 mg Q12H) and mirtazapine (7.5 mg BID) combined with a pregabalin 25 mg Q8H are more effective in treating pain associated with bone metastases than pregabalin 50 mg Q8H alone.

Hot flushes

Patients with breast cancer or prostate cancer are likely to have hot flushes during or after treatment. In women, treatments such as chemotherapy, hormone therapy, or ovariectomy can cause premature menopause and develop hot flushes. In men, castration and treatment with certain hormones can also cause this symptom[24]. Although hormone replacement therapy has been a mainstay of treatment for hot flushes in healthy menopausal women, it is contraindicated for patients with breast and prostate cancer due to an increased risk of cancer recurrence[24].

Hot flushes can cause chills, night sweats, anxiety, and insomnia, hence have negative impact on patients' quality of life[25]. SSRIs and SSRIs are found to be effective in managing hot flushes, and venlafaxine (an serotonin and norepinephrine reuptake inhibitors [SNRI]) and paroxetine (an SSRI) have been studied more extensively and are more consistent in effectively reducing the frequency and severity of hot flushes in cancer patients[26]. Studies also show that duloxetine and mirtazapine are effective in improving hot flushes in breast cancer patients[27],[28].

Nausea

Nausea and vomiting are common symptoms in cancer patients. While the most common cause is the administration of chemotherapy, many complications of advanced cancer such as gastroparesis, bowel and outlet obstructions, and brain tumors may lead to nausea or vomiting as well[29].

SSRI- and SNRI-induced side effect of nausea, especially during the medication initiation, can cause patients' nonadherence, particularly if given at close range with chemotherapies. SSRI and SNRI treatments should start 10–15 days before chemotherapy to avoid the overlapping and potentiation of such side effects[7].

Mirtazapine itself blocks 5-HT3 receptor and thus is linked to an anti-nausea effect[14]. Two case reports are identified, to specifically report mirtazapine use in treating nausea in cancer patients[26].

Anorexia/cachexia

Anorexia/cachexia is prevalent in cancer patients, which is characterized by anorexia, decreased food intake, and irreversible skeletal muscle mass loss. It is possibly due to excessive systemic inflammation and hyper-catabolism and is worsened by anticancer therapy[30]. Cachexia may account for up to 20% of cancer deaths[31].

The relevant anti-histaminergic activity and the blockage of 5-HT2C receptor of mirtazapine can help increase food intake, results in having considerable weight gain[14], improving cancer cachexia in cancer patients. An open-label trial of mirtazapine for 8 weeks in nondepressed patients with cancer-related cachexia/anorexia showed that mirtazapine helps improve appetite and health-related quality of life, although the high attrition rate due to poor clinical condition, death, or study contamination (start of highly emetogenic chemotherapy or steroid use)[32].

Fatigue

Cancer-related fatigue is defined as a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning[33]. Cancer-related fatigue is found in around 50%–90% of the cancer patients[34]. Bupropion has a dual effect on norepinephrine (NE) and dopamine neurotransmitter systems, and thus shares actions with psychostimulants[14]. A 4-week open-label study of the effects of bupropion sustained release on 21 cancer patients with and without depression showed that improvement has been found for symptoms of fatigue and depression. When dividing the patients into two groups, – depressed and non-depressed based on a cutoff score of 17 on the Hamilton Depression Rating Scale – the investigator found that both groups show improvement in fatigue and depressive symptoms, but only non-depressed group shows improved quality of life[35].


  Actions of Mechanism of Antidepressants for Treating Cancer-Related Symptoms Top


The therapeutic rationale for choosing antidepressants is basically based on their clinical classification of transmissions of three monoamines (serotonin, NE, and dopamine) in the brain[14],[15],[36]. Dealing with the side effects of antidepressant is also based on the same concept of those three monoamines.

As shown in [Table 1], pain – even all kinds of pain – can be improved with the SNRIs and mirtazapine[14],[15]. Although not shown in clinical review in cancer patient here, monoamine oxidase inhibitor (MAOI) (such as moclobemide) is also expected to improve pain because the use of an MAOI can improve 5-HT and NE transmission too[15],[36]. Anecdotally, SNRIs (venlafaxine or duloxetine) in continuous daily use can improve periodic severely abdominal cramping in cancer patients after gastrointestinal operations.
Table 1: Common cancer-related symptoms and suggested antidepressants for treatment

Click here to view


The neuronal fibers of transmitting 5-HT and NE from Raphé neuclus and locus coeruleus, respectively, to regulate mood and anxiety symptoms ascendingly and to improve pain symptom descendingly[14]. The patients with depressive/anxiety disorder and pain have low levels of brain-derived neurotrophic factors[14],[15]. The use of SNRIs, mirtazapine, and MAOIs can improve the brain level of BDNF, resulting in improving the pain in cancer patients with pain. Due to unbearable and dangerous side effects (such as dry mouth and cardiotoxicity), TCAs are not drugs of choice in modern psychopharmacology. Usually, SNRIs can be used substituting TCAs to give their comparable therapeutic benefit without those unwanted (strong anticholinergic and antihistaminergic) side effects[14].

5-HT and NE also play a decisive rôle in stabilizing the thermoneutral zone. As sex hormone levels decline, NE levels rise, causing an elevation in core body temperature. Furthermore, diminished sex hormone levels are also associated with low 5-HT levels, leading to an upregulation of 5-HT receptors in the hypothalamus and reset of the natural thermostat[37]. While many clinical trials have demonstrated the effectiveness of SSRIs and SNRIs in treating hot flushes, the authors would like to recommend to use a dual action antidepressant, i.e. an SNRI instead of an SSRI for a broader ranges of benefits. The uses of mirtazapine to mitigate anorexia/cachexia and nausea are based on mirtazapine's own direct pharmacological blockage of 5-HT2C and 5-HT3 receptors, respectively.

Not shown in the clinic review [Table 1], a preliminary study suggested that agomelatine can be a novel treatment of chronic fatigue syndrome[38]. Agomelatine, sharing similar pharmacological function with bupropion through improving both DA and NE transmissions[36], is anticipated to be used in improving cancer-related fatigue as well. However, newer serotonergic antidepressants (such as vilazodone and vortioxetine)[15] are not expected to have more additional benefits besides those from SSRIs in patients with cancer besides their better tolerability.


  Immunomodulatory Effects of Antidepressant Drugs Top


Animal studies show that fluoxetine and mirtazapine administration increase CD8 + cytotoxic cells[39],[40]. Human studies also reveal that SSRIs – including fluvoxamine, escitalopram, and fluoxetine – give cytotoxic effects through increasing natural killer cells counts or activity[41],[42],[43]. Besides their cytotoxic effect, growing evidence indicates that antidepressants modulate the cytokine production[44]. For example, studies show that antidepressants with different mechanisms, such as TCAs (imipramine), SSRIs (fluoxetine), and SNRI (venlafaxine) consistently reduce the IFN-γ/IL-10 ratio[45].

In addition to the direct effect mediated through lymphocytes, Hernández et al.[46] also found that after a 52-week fluoxetine use, cortisol levels are found to be decreased by 30% compared to baseline. Antidepressants also down-regulate glucocorticoid receptor sensitivity[47], restore negative feedback by cortisol on the hypothalamic-pituitary-adrenal (HPA) axis[14],[48], and normalize HPA hyperactivity.

In 1863, German physician Virchow first made a connection between inflammation and cancer[49]. Recent work confirmed that immunity protects against cancer development and shape the character of emerging tumors through the process of immunoediting[50]. The antidepressant drugs can regulate the immune system and hence modulate tumor progression. For example, Fang et al. found that mirtazapine-treated mice have higher IL-12 and interferon-γ levels, more infiltrating CD4+/CD8+ T cells, less tumor necrosis factor-α, as well as produce tumor growth inhibition, compared with those never received mirtazapine[40].


  Anticancer Potentials of Antidepressant Drugs Top


Some earlier clinical studies suggested that use of antidepressants – including SSRIs and TCAs – can increase the risk of breast cancer and ovarian cancer[51],[52]. However, later epidemiological studies – including those using Taiwan's National Health Insurance Research Database – show that antidepressant prescription is not associated with risk of cancers of breast, ovary, and colorectum[53],[54],[55].

Contrariwise, increasing studies show that antidepressants may have anticancer effects. Beside their immunomodulatory effect as the aforementioned, antidepressants are found to eliminate cancer cells through modulating oxidative stress, suppressing angiogenesis, inhibiting tumor proliferation, as well as inducing apoptosis and autophagy. Details of action of the mechanism are discussed as followed:

Oxidative stress modulation

Overproduction of reactive oxygen species (ROS) has been detected in almost all cancers and is involved with their initiation, promotion, and progression of the cancer cells. Meanwhile, cancer cells also express increased antioxidant activity to detoxify from ROS, suggesting that cancer cells function under an exquisite balance of ROS levels[56]. Chemotherapy can increase intracellular ROS disproportionally, and induce cancer cell cycle arrest and apoptosis[56].

Imipramine, clomipramine, and citalopram can also increase intracellular ROS, cause the loss of mitochondrial membrane potential, activate caspase, and finally lead to the apoptosis of human myeloid leukemia cells[57],[58]. Amitriptyline has been found to increase ROS and to irreversibly damage mitochondria, and to reduce antioxidant activity, exerting anticancer potentials for lung, cervical and liver cancers[59]. Nortriptyline has been reported to increase the ROS production and induce mitochondria-mediated and death receptor-mediated apoptosis in human bladder cancer cells[60]. The cytotoxic effects of citalopram on liver cancer cells are also associated with an increased ROS formation[61].

Contrariwise, some reports also exist to show that fluoxetine acts as antioxidant, to decrease the melanoma-induced oxidative changes in mice spleen[62], and to lower the activity of superoxide dismutase levels in the brain of hepatoma-bearing mice[63].

Antiangiogenesis

The new growth of the vascular network, so-called angiogenesis, is important since an adequate supply of oxygen and nutrients is necessary for the proliferation and metastatic spread of cancer cells. Many proteins have been identified as angiogenic activators, and among them, vascular endothelial growth factor (VEGF) is receiving more attention[64]. Kannen et al. have found fluoxetine-induced reduction of VEGF expression and the antiproliferative potential of fluoxetine on colon cancer cells in vitro[65]. Contrariwise, Kubera et al.[66] have found the prometastatic effect of desipramine in young melanoma-bearing mice, which is connected with an increased VEGF and metalloproteinase-9 (MMP-9) plasma levels. MMPs degrade basement membrane and extracellular matrix components, increasing the migration, invasion, and metastasis of tumor cells[66].

Cell cycle arrest

Deregulation of the cell cycle and uncontrolled proliferation are hallmarks of the cancer cells. The cell cycle is controlled by regulating cyclin-dependent kinases (CDKs) through their activator cyclins and CDK inhibitors (also known as CKI)[67]. The p53 protein can also arrest the cell cycle at checkpoints and initiate apoptosis, hence plays an important anti-cancer rôle[68].

Stepulak et al.[69] found that fluoxetine can slow down the cell cycle progression and inhibition of proliferation of lung and colon cancer cells in vitro, which are associated with the decreased expression of cyclin A and cyclin D1, as well as the increased expression of p21 (CKI-1) and p53 genes. Fluoxetine also decreases of c-fos and c-jun expression, which are transcriptional activators to regulate the expression of genes during cell proliferation[69].

Kinjo et al. also found that desipramine decreases the expression of the proliferating cell nuclear antigengene, causes an increase in the expression of CKI p21 and p27 genes, and induces cell cycle arrest of mice skin squamous carcinoma cells[70].

Apoptosis and autophagy

Apoptosis and autophagy are two pivotal mechanisms in mediating cell survival and death. Apoptosis – or programmed cell death – is the result of a cascade of caspase activation which is initiated by extrinsic (death receptor-mediated) or intrinsic (mitochondrial-mediated) stimuli[71]. The apoptotic signaling pathway is impaired or perverted during the formation of cancer, and restoring apoptosis as a therapeutic strategy to cancer treatment has been intensively studied[72]. On the other hand, autophagy maintains cellular homeostasis through degrading and recycling damaged intracellular proteins and organelles in lysosomes and provides substrates for energy generation and biosynthesis in stress. As a result, autophagy is regarded as a double-edged sword that in some cases can induce cancer cell death, and in others provides cancer cells nutrient and promotes their survival[72].

Levkovitz et al. found that paroxetine, fluoxetine, and clomipramine cause apoptosis in glioma and neuroblastoma cell lines, which is preceded through rapid increase in activated c-jun levels, cytochrome c release from mitochondria, and increased caspase-3-like activity[73]. A study also showed that fluoxetine induces apoptosis in neuroblastoma through mitogen-activated protein kinase pathways and histone hyperacetylation[74].

Studies showed that fluoxetine induces autophagy in the chemoresistant Burkitt's lymphoma and triple negative breast cancer, resulting in having a novel therapeutic implications in cancer therapy[75],[76]. Contrariwise, autophagy inhibition may also be beneficial for the therapy of some advanced tumors[77].


  Drug-Drug Interaction in Cancer Patients Using Antidepressants Top


Most antidepressants are metabolized through the cytochrome P450 (CYP) enzyme system, and many drug interactions are a result of induction or inhibition of CYP enzymes. Tamoxifen, a hormone therapy drug for estrogen receptor-positive breast cancer, is mainly metabolized through the CYP2D6 to endoxifen, which is 30-100 times stronger than tamoxifen and is responsible for most of the clinical effects[78]. Antidepressants that inhibit CYP2D6 enzymes can hinder tamoxifen's anticancer effect and increase risk for cancer recurrence, adversely affecting well-being and survival. Accumulating data have shown that fluoxetine, bupropion, and particularly paroxetine, are strong inhibitors of CYP2D6, and should, therefore, be better avoided in patients treated with tamoxifen, especially those with poor metabolizer phenotype of CYP2D6[79].

One population-based cohort study showed that paroxetine use during tamoxifen treatment is associated with an increased risk of death from breast cancer[80]. However, Haque et al. examined nearly 16,900 early stage breast cancer survivors who took tamoxifen for an average of 3 years[81]. Among them, about a half also took antidepressants. During the 14-year follow-up, more than 17% of the survivors developed subsequent breast cancer. Recurrence rates are similar in those who took paroxetine and those who did not, and there is no such association for other antidepressants either[81].

Due to the paradoxical finding on some antidepressants use in tamoxifen-treated patients, clinicians must carefully weigh the benefits against risks of concurrent use of tamoxifen and antidepressants with potent CYP2D6 inhibition profile. Pragmatism suggests preferential avoidance of antidepressants known to inhibit CYP2D6, and those imparting less inhibition, such as sertraline, citalopram, and escitalopram are reasonable alternatives[82].

Analgesic drugs such as tramadol, codeine, hydrocodone, oxycodone, and fentanyl, as well as antiemetics of 5-HT3 antagonists, such as ondansetron, granisetron, and metoclopramide, are often used in cancer patients as palliative treatment. But they may act synergistically with serotonergic antidepressants and increase the risk of serotonin syndrome[79]. Among those medications, tramadol is metabolized by CYP2D6 to the active metabolite, hence CYP2D6-inhibiting antidepressants can decrease the analgesic activity of tramadol[83].


  Conclusion Top


The use of antidepressants in cancer patients is indicated when depression interferes with the patient's quality of life or with adherence to anti-cancer treatment. Moreover, antidepressants have been shown to be effective in treating other distressing cancer-related symptoms, such as pain, hot flushes, nausea, cachexia, and fatigue.

Although the research showed the rate of antidepressant prescription is increasing, depression is still overlooked in most of the cancer patients, hence those who might benefit from antidepressants are often left untreated. Walker et al. found that among 1,538 cancer patients with MDD, about 370 (24%) are taking antidepressants[2]. Park et al.[84] designed a placebo-controlled antidepressant clinical trial in oncology patients, yet no one was enrolled for the trial. One of the recruitment difficulties is that patients were reluctant to be enrolled in any placebo-controlled studies[84].

We suggest that cancer patients are keen to receive more effective treatment for their cancer as well as comorbid depression and that physicians should be more aggressive in providing every beneficial regimen – including an antidepressant. After reading this review, we hope that you will think of the use of an antidepressant when you get a chance to see a cancer patient – regardless in consultation, outpatient, or inpatient psychiatric services.


  Acknowledgment Top


Some off-label indications are mentioned in this review. The readers are advised to read the package insert carefully before prescribing antidepressants to the patients.


  Financial Support and Sponsorship Top


Nil.


  Conflicts of Interest Top


There are no conflicts of interest.



 
  References Top

1.
Mitchell AJ, Chan M, Bhatti H, et al.: Prevalence of depression, anxiety, and adjustment disorder in oncological, haematological, and palliative-care settings: a meta-analysis of 94 interview-based studies. Lancet Oncol 2011; 12: 160-74.  Back to cited text no. 1
    
2.
Walker J, Hansen CH, Martin P, et al.: Prevalence, associations, and adequacy of treatment of major depression in patients with cancer: a cross-sectional analysis of routinely collected clinical data. Lancet Psychiatry 2014; 1: 343-50.  Back to cited text no. 2
    
3.
Chochinov HM: Depression in cancer patients. Lancet Oncol 2001; 2: 499-505.  Back to cited text no. 3
    
4.
Brenne E, Loge JH, Kaasa S, et al.: Depressed patients with incurable cancer: which depressive symptoms do they experience? Palliat Support Care 2013; 11: 491-501.  Back to cited text no. 4
    
5.
Chochinov HM, Wilson KG, Enns M, et al.: “Are you depressed?” screening for depression in the terminally ill. Am J Psychiatry 1997; 154: 674-6.  Back to cited text no. 5
    
6.
Schag CA, Ganz PA, Polinsky ML, et al.: Characteristics of women at risk for psychosocial distress in the year after breast cancer. J Clin Oncol 1993; 11: 783-93.  Back to cited text no. 6
    
7.
Torta RG, Ieraci V: Pharmacological management of depression in patients with cancer: practical considerations. Drugs 2013; 73: 1131-45.  Back to cited text no. 7
    
8.
Pinquart M, Duberstein PR: Depression and cancer mortality: a meta-analysis. Psychol Med 2010; 40: 1797-810.  Back to cited text no. 8
    
9.
Sanjida S, Janda M, Kissane D, et al.: A systematic review and meta-analysis of prescribing practices of antidepressants in cancer patients. Psychooncology 2016; 25: 1002-16.  Back to cited text no. 9
    
10.
Ostuzzi G, Benda L, Costa E, et al.: Efficacy and acceptability of antidepressants on the continuum of depressive experiences in patients with cancer: systematic review and meta-analysis. Cancer Treat Rev 2015; 41: 714-24.  Back to cited text no. 10
    
11.
Xiang X, An R, Gehlert S: Trends in antidepressant use among U.S. Cancer survivors, 1999-2012. Psychiatr Serv 2015; 66: 564.  Back to cited text no. 11
    
12.
Jacob L, Kostev K, Kalder M: Treatment of depression in cancer and non-cancer patients in German neuropsychiatric practices. Psychooncology 2016; 25: 1324-8.  Back to cited text no. 12
    
13.
Pearson SA, Abrahamowicz M, Srasuebkul P, et al.: Antidepressant therapy in cancer patients: initiation and factors associated with treatment. Pharmacoepidemiol Drug Saf 2015; 24: 600-9.  Back to cited text no. 13
    
14.
Shen WW: Clinical Psychopharmacology for The 21 st Century. 3rd ed. Taipei: Hochi Publishing Company, 2011.  Back to cited text no. 14
    
15.
Shen WW: Antidepressant therapy. Aino Journal (Osaka) 2016; 15: 1-13.  Back to cited text no. 15
    
16.
Neufeld NJ, Elnahal SM, Alvarez RH: Cancer pain: a review of epidemiology, clinical quality and value impact. Future Oncol 2017; 13: 833-41.  Back to cited text no. 16
    
17.
Bennett MI: Mechanism-based cancer-pain therapy. Pain 2017; 158 Suppl 1: S74-8.  Back to cited text no. 17
    
18.
Portenoy RK, Lesage P: Management of cancer pain. Lancet 1999; 353: 1695-700.  Back to cited text no. 18
    
19.
Bennett MI, Rayment C, Hjermstad M, et al.: Prevalence and aetiology of neuropathic pain in cancer patients: a systematic review. Pain 2012; 153: 359-65.  Back to cited text no. 19
    
20.
Jara C, Del Barco S, Grávalos C, et al.: SEOM clinical guideline for treatment of cancer pain (2017). Clin Transl Oncol 2018; 20: 97-107.  Back to cited text no. 20
    
21.
Smith EM, Pang H, Cirrincione C, et al.: Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA 2013; 309: 1359-67.  Back to cited text no. 21
    
22.
Durand JP, Deplanque G, Montheil V, et al.: Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial. Ann Oncol 2012; 23: 200-5.  Back to cited text no. 22
    
23.
Nishihara M, Arai YC, Yamamoto Y, et al.: Combinations of low-dose antidepressants and low-dose pregabalin as useful adjuvants to opioids for intractable, painful bone metastases. Pain Physician 2013; 16: E547-52.  Back to cited text no. 23
    
24.
Adelson KB, Loprinzi CL, Hershman DL: Treatment of hot flushes in breast and prostate cancer. Expert Opin Pharmacother 2005; 6: 1095-106.  Back to cited text no. 24
    
25.
Hutton B, Yazdi F, Bordeleau L, et al.: Comparison of physical interventions, behavioral interventions, natural health products, and pharmacologics to manage hot flashes in patients with breast or prostate cancer: protocol for a systematic review incorporating network meta-analyses. Syst Rev 2015; 4: 114.  Back to cited text no. 25
    
26.
Zaini S, Guan NC, Sulaiman AH, et al.: The use of antidepressants for physical and psychological symptoms in cancer. Curr Drug Targets 2018; 19: 1431-55.  Back to cited text no. 26
    
27.
Biglia N, Bounous VE, Susini T, et al.: Duloxetine and escitalopram for hot flushes: efficacy and compliance in breast cancer survivors. Eur J Cancer Care (Engl) 2018; 27: e12484.  Back to cited text no. 27
    
28.
Biglia N, Kubatzki F, Sgandurra P, et al.: Mirtazapine for the treatment of hot flushes in breast cancer survivors: a prospective pilot trial. Breast J 2007; 13: 490-5.  Back to cited text no. 28
    
29.
Gordon P, LeGrand SB, Walsh D: Nausea and vomiting in advanced cancer. Eur J Pharmacol 2014; 722: 187-91.  Back to cited text no. 29
    
30.
Ming-Hua C, Bao-Hua Z, Lei Y: Mechanisms of anorexia cancer cachexia syndrome and potential benefits of traditional medicine and natural herbs. Curr Pharm Biotechnol 2016; 17: 1147-52.  Back to cited text no. 30
    
31.
Argilés JM, Busquets S, Stemmler B, et al.: Cancer cachexia: understanding the molecular basis. Nat Rev Cancer 2014; 14: 754-62.  Back to cited text no. 31
    
32.
Riechelmann RP, Burman D, Tannock IF, et al.: Phase II trial of mirtazapine for cancer-related cachexia and anorexia. Am J Hosp Palliat Care 2010; 27: 106-10.  Back to cited text no. 32
    
33.
Berger AM, Mooney K, Alvarez-Perez A, et al.: Cancer-related fatigue, version 2.2015. J Natl Compr Canc Netw 2015; 13: 1012-39.  Back to cited text no. 33
    
34.
Mohandas H, Jaganathan SK, Mani MP, et al.: Cancer-related fatigue treatment: an overview. J Cancer Res Ther 2017; 13: 916-29.  Back to cited text no. 34
    
35.
Moss EL, Simpson JS, Pelletier G, et al.: An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners. Psychooncology 2006; 15: 259-67.  Back to cited text no. 35
    
36.
Chen CY, Chiu YH, Shen WW: Drug augmentation for treatment-refractory major depressive disorder. Taiwan J Psychiatry 2018; 32: 188-99.  Back to cited text no. 36
    
37.
Rossmanith WG, Ruebberdt W: What causes hot flushes? the neuroendocrine origin of vasomotor symptoms in the menopause. Gynecol Endocrinol 2009; 25: 303-14.  Back to cited text no. 37
    
38.
Pardini M, Cordano C, Benassi F, et al.: Agomelatine but not melatonin improves fatigue perception: a longitudinal proof-of-concept study. Eur Neuropsychopharmacol 2014; 24: 939-44.  Back to cited text no. 38
    
39.
Frick LR, Rapanelli M, Arcos ML, et al.: Oral administration of fluoxetine alters the proliferation/apoptosis balance of lymphoma cells and up-regulates T cell immunity in tumor-bearing mice. Eur J Pharmacol 2011; 659: 265-72.  Back to cited text no. 39
    
40.
Fang CK, Chen HW, Chiang IT, et al.: Mirtazapine inhibits tumor growth via immune response and serotonergic system. PLoS One 2012; 7: e38886.  Back to cited text no. 40
    
41.
Ballin A, Gershon V, Tanay A, et al.: The antidepressant fluvoxamine increases natural killer cell counts in cancer patients. Isr J Med Sci 1997; 33: 720-3.  Back to cited text no. 41
    
42.
Park EJ, Lee JH, Jeong DC, et al.: Natural killer cell activity in patients with major depressive disorder treated with escitalopram. Int Immunopharmacol 2015; 28: 409-13.  Back to cited text no. 42
    
43.
Dai J, Liao N, Shi J, et al.: Study of prevalence and influencing factors of depression in tumor patients and the therapeutic effects of fluoxetine. Eur Rev Med Pharmacol Sci 2017; 21: 4966-74.  Back to cited text no. 43
    
44.
Martino M, Rocchi G, Escelsior A, et al.: Immunomodulation mechanism of antidepressants: interactions between serotonin/norepinephrine balance and Th1/Th2 balance. Curr Neuropharmacol 2012; 10: 97-123.  Back to cited text no. 44
    
45.
Kubera M, Lin AH, Kenis G, et al.: Anti-inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio. J Clin Psychopharmacol 2001; 21: 199-206.  Back to cited text no. 45
    
46.
Hernández ME, Mendieta D, Martínez-Fong D, et al.: Variations in circulating cytokine levels during 52 week course of treatment with SSRI for major depressive disorder. Eur Neuropsychopharmacol 2008; 18: 917-24.  Back to cited text no. 46
    
47.
Okuyama-Tamura M, Mikuni M, Kojima I: Modulation of the human glucocorticoid receptor function by antidepressive compounds. Neurosci Lett 2003; 342: 206-10.  Back to cited text no. 47
    
48.
Antonijevic IA: Depressive disorders – Is it time to endorse different pathophysiologies? Psychoneuroendocrinology 2006; 31: 1-5.  Back to cited text no. 48
    
49.
Balkwill F, Mantovani A: Inflammation and cancer: back to Virchow? Lancet 2001; 357: 539-45.  Back to cited text no. 49
    
50.
Mittal D, Gubin MM, Schreiber RD, et al.: New insights into cancer immunoediting and its three component phases – Elimination, equilibrium and escape. Curr Opin Immunol 2014; 27: 16-25.  Back to cited text no. 50
    
51.
Cotterchio M, Kreiger N, Darlington G, et al.: Antidepressant medication use and breast cancer risk. Am J Epidemiol 2000; 151: 951-7.  Back to cited text no. 51
    
52.
Harlow BL, Cramer DW: Self-reported use of antidepressants or benzodiazepine tranquilizers and risk of epithelial ovarian cancer: evidence from two combined case-control studies (Massachusetts, United States). Cancer Causes Control 1995;6:130-4.  Back to cited text no. 52
    
53.
Chen VC, Liao YT, Yeh DC, et al.: Relationship between antidepressant prescription and breast cancer: a population based study in Taiwan. Psychooncology 2016; 25: 803-7.  Back to cited text no. 53
    
54.
Wu CS, Lu ML, Liao YT, et al.: Ovarian cancer and antidepressants. Psychooncology 2015; 24: 579-84.  Back to cited text no. 54
    
55.
Lee HC, Chiu WC, Wang TN, et al.: Antidepressants and colorectal cancer: a population-based nested case-control study. J Affect Disord 2017; 207: 353-8.  Back to cited text no. 55
    
56.
Liou GY, Storz P: Reactive oxygen species in cancer. Free Radic Res 2010; 44: 479-96.  Back to cited text no. 56
    
57.
Xia Z, Bergstrand A, DePierre JW, et al.: The antidepressants imipramine, clomipramine, and citalopram induce apoptosis in human acute myeloid leukemia HL-60 cells via caspase-3 activation. J Biochem Mol Toxicol 1999; 13: 338-47.  Back to cited text no. 57
    
58.
Xia Z, Lundgren B, Bergstrand A, et al.: Changes in the generation of reactive oxygen species and in mitochondrial membrane potential during apoptosis induced by the antidepressants imipramine, clomipramine, and citalopram and the effects on these changes by Bcl-2 and Bcl-X (L). Biochem Pharmacol 1999; 57: 1199-208.  Back to cited text no. 58
    
59.
Cordero MD, Sánchez-Alcázar JA, Bautista-Ferrufino MR, et al.: Acute oxidant damage promoted on cancer cells by amitriptyline in comparison with some common chemotherapeutic drugs. Anticancer Drugs 2010; 21: 932-44.  Back to cited text no. 59
    
60.
Yuan SY, Cheng CL, Ho HC, et al.: Nortriptyline induces mitochondria and death receptor-mediated apoptosis in bladder cancer cells and inhibits bladder tumor growth in vivo. Eur J Pharmacol 2015; 761: 309-20.  Back to cited text no. 60
    
61.
Ahmadian E, Eftekhari A, Babaei H, et al.: Anti-cancer effects of citalopram on hepatocellular carcinoma cells occur via cytochrome C release and the activation of NF-kB. Anticancer Agents Med Chem 2017; 17: 1570-7.  Back to cited text no. 61
    
62.
Kirkova M, Tzvetanova E, Vircheva S, et al.: Antioxidant activity of fluoxetine: studies in mice melanoma model. Cell Biochem Funct 2010; 28: 497-502.  Back to cited text no. 62
    
63.
Qi H, Ma J, Liu YM, et al.: Allostatic tumor-burden induces depression-associated changes in hepatoma-bearing mice. J Neurooncol 2009; 94: 367-72.  Back to cited text no. 63
    
64.
Nishida N, Yano H, Nishida T, et al.: Angiogenesis in cancer. Vasc Health Risk Manag 2006; 2: 213-9.  Back to cited text no. 64
    
65.
Kannen V, Hintzsche H, Zanette DL, et al.: Antiproliferative effects of fluoxetine on colon cancer cells and in a colonic carcinogen mouse model. PLoS One 2012; 7: e50043.  Back to cited text no. 65
    
66.
Kubera M, Grygier B, Arteta B, et al.: Age-dependent stimulatory effect of desipramine and fluoxetine pretreatment on metastasis formation by B16F10 melanoma in male C57BL/6 mice. Pharmacol Rep 2009; 61: 1113-26.  Back to cited text no. 66
    
67.
Bai J, Li Y, Zhang G: Cell cycle regulation and anticancer drug discovery. Cancer Biol Med 2017; 14: 348-62.  Back to cited text no. 67
    
68.
Vazquez A, Bond EE, Levine AJ, et al.: The genetics of the p53 pathway, apoptosis and cancer therapy. Nat Rev Drug Discov 2008; 7: 979-87.  Back to cited text no. 68
    
69.
Stepulak A, Rzeski W, Sifringer M, et al.: Fluoxetine inhibits the extracellular signal regulated kinase pathway and suppresses growth of cancer cells. Cancer Biol Ther 2008; 7: 1685-93.  Back to cited text no. 69
    
70.
Kinjo T, Kowalczyk P, Kowalczyk M, et al.: Effects of desipramine on the cell cycle and apoptosis in ca3/7 mouse skin squamous carcinoma cells. Int J Mol Med 2010; 25: 861-7.  Back to cited text no. 70
    
71.
Elmore S: Apoptosis: a review of programmed cell death. Toxicol Pathol 2007; 35: 495-516.  Back to cited text no. 71
    
72.
Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell 2011; 144: 646-74.  Back to cited text no. 72
    
73.
Levkovitz Y, Gil-Ad I, Zeldich E, et al.: Differential induction of apoptosis by antidepressants in glioma and neuroblastoma cell lines: evidence for p-c-Jun, cytochrome c, and caspase-3 involvement. J Mol Neurosci 2005; 27: 29-42.  Back to cited text no. 73
    
74.
Choi JH, Jeong YJ, Yu AR, et al.: Fluoxetine induces apoptosis through endoplasmic reticulum stress via mitogen-activated protein kinase activation and histone hyperacetylation in SK-N-BE(2)-M17 human neuroblastoma cells. Apoptosis 2017; 22: 1079-97.  Back to cited text no. 74
    
75.
Cloonan SM, Williams DC: The antidepressants maprotiline and fluoxetine induce type II autophagic cell death in drug-resistant Burkitt's lymphoma. Int J Cancer 2011; 128: 1712-23.  Back to cited text no. 75
    
76.
Bowie M, Pilie P, Wulfkuhle J, et al.: Fluoxetine induces cytotoxic endoplasmic reticulum stress and autophagy in triple negative breast cancer. World J Clin Oncol 2015; 6: 299-311.  Back to cited text no. 76
    
77.
Mathew R, White E: Autophagy in tumorigenesis and energy metabolism: friend by day, foe by night. Curr Opin Genet Dev 2011; 21: 113-9.  Back to cited text no. 77
    
78.
Sukasem C, Sirachainan E, Chamnanphon M, et al.: Impact of CYP2D6 polymorphisms on tamoxifen responses of women with breast cancer: a microarray-based study in Thailand. Asian Pac J Cancer Prev 2012; 13: 4549-53.  Back to cited text no. 78
    
79.
Grassi L, Nanni MG, Rodin G, et al.: The use of antidepressants in oncology: a review and practical tips for oncologists. Ann Oncol 2018; 29: 101-11.  Back to cited text no. 79
    
80.
Kelly CM, Juurlink DN, Gomes T, et al.: Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ 2010; 340: c693.  Back to cited text no. 80
    
81.
Haque R, Shi J, Schottinger JE, et al.: Tamoxifen and antidepressant drug interaction in a cohort of 16,887 breast cancer survivors. J Natl Cancer Inst 2016; 108: djv337.  Back to cited text no. 81
    
82.
Juurlink D: Revisiting the drug interaction between tamoxifen and SSRI antidepressants. BMJ 2016; 354: i5309.  Back to cited text no. 82
    
83.
Grond S, Sablotzki A: Clinical pharmacology of tramadol. Clin Pharmacokinet 2004; 43: 879-923.  Back to cited text no. 83
    
84.
Park EM, Raddin RS, Nelson KM, et al.: Conducting an antidepressant clinical trial in oncology: challenges and strategies to address them. Gen Hosp Psychiatry 2014; 36: 474-6.  Back to cited text no. 84
    



 
 
    Tables

  [Table 1]



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
   Abstract
  Introduction
   Antidepressants ...
   Antidepressant f...
   Actions of Mecha...
   Immunomodulatory...
   Anticancer Poten...
   Drug-Drug Intera...
  Conclusion
  Acknowledgment
   Financial Suppor...
   Conflicts of Int...
   References
   Article Tables

 Article Access Statistics
    Viewed200    
    Printed11    
    Emailed0    
    PDF Downloaded29    
    Comments [Add]    

Recommend this journal