Effect of paroxetine on depression and insomnia in 547 fatigued cancer patients undergoing chemotherapy

Reviewer: Christine Hill, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 2, 2008

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Presenter: O.G. Palesh
Presenter's Affiliation: University of Rochester Cancer Center, Rochester, NY
Type of Session: Scientific

Background

  • Sleep disruption as a vegetative symptom is a cardinal symptom of psychiatric illness, and often co-occurs with depression, chronic pain, and fatigue.
  • Insomnia is a sleep disorder defined by difficulty falling asleep, difficulty staying asleep, and/ or unplanned early awakening, occurring at least three days per week, and lasting for at least 30 minutes.
  • Acute insomnia is defined as that present for one month or less, while chronic insomnia persists for over a month.
  • Little is known about insomnia in cancer patients; however, insomnia in the general population is recognized to be precipitated by acute stress and stressful life events.
  • Also, in the general population, insomnia may be a symptom of depression and/ or anxiety. For this reason, medical treatment of depression may result in improvement in insomnia.
  • Selective serotonin re-uptake inhibitors (SSRIs) are a class of medications commonly used to treat depression and major depressive disorder. Since their conception, these medications have gained popularity among healthcare providers, and are now used quite commonly for treatment of depression and anxiety.
    • The SSRI class of medication includes fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil).
  • Depression, anxiety, and insomnia are relatively common complaints of cancer patients
    • Approximately half of patients undergoing treatment for breast cancer report clinical symptoms of distress, and approximately 10% meet criteria for major depressive disorder (Hegel, 2006).
    • Bothersome insomnia has been documented to occur in approximately 30% of cancer patients, and cancer patients are about 2.5 times as likely to experience insomnia as members of the general population (Davidson, 2002)
    • Cancer patients have been demonstrated to have decreased sleep efficiency (ratio of time spent sleeping versus time spent in bed) (Owen, 1999); decreased quantity and quality of sleep; and difficulty maintaining sleep and wake states (Parker, 2008).
  • Since sleep disturbance is a known symptom of depression, insomnia in cancer patients who also note depression is often attributed to the depression itself. This may lead clinicians to attempt to treat insomnia through treatment of depression, often with SSRIs. Given documentation of sleep differences in cancer patients, however, the possibility must be considered that insomnia and depression in cancer patients may be separate issues that may not respond to a single treatment.
  • This study was carried out in order to determine the effectiveness of paroxetine in treatment of both depression and insomnia in patients undergoing treatment for cancer.

Materials and Methods

  • This study was a randomized, controlled trial investigating the use of paroxetine as treatment for depression and insomnia in cancer patients.
  • Patients were enrolled prior to beginning cancer treatment, and patient depression, insomnia, and fatigue levels were assessed at the time of each of the first four chemotherapy sessions.
    • Insomnia was assessed via the Hamilton Depression Inventory
    • Depression was assessed via the Center for Epidemiologic Studies Depression Scale.
    • Fatigue was assessed via the Multidimensional Assessment of Fatigue instrument.
  • Following the second cycle of chemotherapy, patients reporting cancer-related fatigue were randomized to receive paroxetine, 20 mg orally daily, versus placebo.

Results

  • Following the second cycle of chemotherapy, 547 patients were randomized to receive either paroxetine or placebo.
    • Median patient age was 56.9 years.
    • Patients were 72.4% female, and 88.7% Caucasian.
    • The primary cancer diagnosis was breast cancer in 50% of patients.
    • Sixty-eight percent of patients had undergone prior surgery, 14.2% prior chemotherapy, and 11% prior radiotherapy.
    • Thirty-two percent of patients were undergoing chemotherapy for metastatic disease.
  • During cycle one of chemotherapy, 84.6% of patients reported insomnia, and 52.1% met diagnostic criteria for clinical insomnia. 
    • These rates were three times higher than those documented in the general population.
    • Insomnia symptoms were reported as initial (76%), middle (59%), and late (26.4%).
    • 26.4% of patients met criteria for depression.
  • Increased insomnia was noted in lung cancer patients versus patients with other cancer diagnoses (p < 0.05).
  • Increased insomnia was also noted in patients less than 50 years old when compared to insomnia in patients greater than 50 years old (p < 0.05).
  • No difference in reported insomnia was noted based on gender.
  • During chemotherapy cycles three and four, patients randomized to take paroxetine were compared to those in the control arm:
    • Patients randomized to paroxetine experienced significantly decreased rates of depression (p < 0.05) when compared to the control arm.
    • A trend towards improvement in insomnia was noted in patients randomized to paroxetine, but this was not statistically significant.
    • No impact on fatigue was seen in patients randomized to paroxetine versus those taking placebo.
  • Insomnia was associated with severely negative impact on physical and psychological well-being, and was associated with high fatigue levels, psychiatric illness, physical complaints, decreased quality of life, and cognitive impairment.

Author's Conclusions

  • The authors conclude that insomnia is three times as likely to develop in cancer patients as the general adult population.
  • They note that insomnia in cancer patients appears to persist throughout the course of chemotherapy.
  • They note that insomnia is a problem that needs to be treated and addressed separately from other symptoms, including depression. They conclude that using SSRIs to treat depression and then expecting insomnia to improve is likely to be ineffective.

Clinical/Scientific Implications

  • This study represents a well-designed, prospective, randomized, controlled clinical trial assessing the impact of paroxetine, a commonly-used SSRI, on depression and insomnia in cancer patients.
  • The results presented are very interesting, especially in light of the fact that many clinicians in oncology do in fact seem to attempt to treat depression in order to reduce insomnia.
  • Multiple groups have documented changes in sleep patterns and sleep effectiveness in cancer patients, and the etiology of these changes is largely not understood. 
    • Certainly, medications such as benzodiazepines and opiates are known to alter sleep patterns, and are frequently utilized in the treatment of cancer patients.
    • Additionally, very little information exists on the impact of antineoplastic agents themselves on sleep.
    • Interesting information does exist on SSRIs and sleep; in a population of elderly women, SSRIs were found to decrease sleep efficiency and increased sleep latency. This is particularly interesting in light of the number of cancer patients for whom SSRIs are prescribed, not only in the setting of depression, but to treat symptoms such as hot flashes and chronic pain (Ensrud, 2006).
  • In all likelihood, insomnia in cancer patients is multifactorial. In this study, insomnia in cancer patients was demonstrated to show no improvement with treatment with paroxetine. Given the known association of insomnia as a symptom of depression, however, the conclusion that treatment of patients with depression and insomnia with SSRIs will be ineffective for insomnia may be somewhat hasty. 
    • Indeed, insomnia as a symptom of depression would be expected to improve in a certain subset of patients whose insomnia was indeed a symptom of depression. As of yet, we have no way of identifying this subset; however, the trend towards improvement of insomnia with paroxetine shown in this study supports the concept that certain patients, although certainly not all, may respond to paroxetine with improvement of both insomnia and depression.
    • Additionally, SSRIs are generally not effective treatment for depression until they have been taken regularly for 4-8 weeks. As data was collected for only two chemotherapy cycles after paroxetine treatment was initiated, and the time course of each cycle was not provided, further effects of paroxetine could conceivably be seen with longer follow-up.
  • This study is a well-designed trial that raises awareness of the need to consider insomnia as a separate entity from, and not an entity caused by, depression in cancer patients.
  • This issue is certainly important for patients and clinicians alike, and further investigation into etiologies and potential treatments for insomnia in cancer patients will likely have significant impact on quality of life for patients being treated for cancer.

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News
Insomnia Prevalence High for Chemotherapy Patients

Nov 22, 2014 - In cancer patients undergoing chemotherapy, insomnia is about three times as prevalent as it is among the general population, according to a study published online Nov. 23 in the Journal of Clinical Oncology.



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