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Mirtazapine for Symptomatic Relief on a Psychiatric Consultation Service: A Case Series
Psychosomatics 2016:]:]]]–]]]
Published by Elsevier Inc. on behalf of The Academy of Psychosomatic Medicine.
Original Research Reports Mirtazapine for Symptomatic Relief on a Psychiatric Consultation Service: A Case Series Nicholas D. Allen, M.D., Jonathan G. Leung, Pharm.D., R.Ph., Hannah K. Betcher, M.D., Kristin L. Borreggine, D.O., Daniel K. Hosker, M.D., Blaine A. Minton, D.O., Eliza M. Sukiennik, M.D., Jacob J. Wilson, M.D., Kemuel L. Philbrick, M.D., Keith G. Rasmussen, M.D.
Background: With a complex pharmacologic profile, mirtazapine may promote sleep, stimulate appetite, improve nausea, and reduce pain. Some practitioners working on the Mayo Clinic inpatient psychiatric consultation/liaison service have recommended mirtazapine in medically ill patients with or without formal psychiatric comorbidity to target these symptoms. Objective: To assess the success of this practice, we conducted a retrospective chart review covering a 4.5year period. Methods: For patients recommended to start mirtazapine, global improvement in specific symptoms and suspected side effects were recorded. Results: During the study period, 528 medically ill patients started mirtazapine following a recommendation from the psychiatric consultation service. In total, 475 patients were provided mirtazapine to specifically target sleep, nausea, pain, or appetite. There was
documented improvement in these symptoms for 37.7%, 37.0%, 36.4%, and 23.5% of the patients, respectively. These rates of improvement are conservative for the 229 patients without documented response, i.e., 48% of the patients who were given the medication for a somatic symptom were counted as having no improvement. Commonly documented adverse effects were daytime sedation (5.3%), worsening mental status (2.3%), and nightmares (1%). Conclusions: Despite the limitations of this retrospective, qualitative study, these data confirm that mirtazapine is generally well tolerated and can provide at least short-term relief of certain symptoms in medically ill patients. Controlled trials are needed to assess these benefits more systematically, and it is not clear how long mirtazapine should be used for these symptoms. (Psychosomatics 2016; ]:]]]–]]])
INTRODUCTION
Mirtazapine acts as a histamine-1 receptor (H1) antagonist and 5-HT2C receptor antagonist, which
As mirtazapine carries a single Food and Drug Administration-approved indication for major depressive disorder, practitioners may not recognize mirtazapine's potential to provide benefit in managing somatic symptoms. Outside psychiatric use, mirtazapine has gained attention in the oncology literature as possessing beneficial properties for nausea and appetite stimulation.1 Mirtazapine possesses complex neuropharmacologic actions, which may explain its possible usage for a number of symptoms. Psychosomatics ]:], ] 2016
Received February 4, 2016; revised February 24, 2016; accepted February 26, 2016. From Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN (NDA, HKB, KLB, DKH, BAM, EAS, JJW, KLP KGR); Department of Pharmacy, Mayo Clinic, Rochester, MN (JGL). Send correspondence and reprint requests to Nicholas D. Allen, M.D., Department of Psychiatry and Psychology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905; e-mail: allen.nicholas@mayo. edu Published by Elsevier Inc. on behalf of The Academy of Psychosomatic Medicine.
www.psychosomaticsjournal.org
1
Mirtazapine for Symptomatic Relief may help improve appetite and sleep. The binding affinity to the serotonin-3 receptor (5-HT3) is similar to that of ondansetron and other medications in the same class, making a notable antiemetic.1 Action at the alpha adrenergic-2 receptor (alpha-2) plus 5-HT1A agonism has led to studies evaluating mirtazapine to attenuate pain.2 Despite the potential benefits of mirtazapine on somatic symptoms, randomized, placebo-controlled trials are lacking in the literature, with data supporting its use limited to small open-label studies or retrospective reports. Given the paucity of data, we sought to describe the use of mirtazapine as recommended by our psychiatric consultation/liaison service. Our primary goal was to assess the effectiveness of mirtazapine for symptomatic treatment of pain, nausea, low appetite, or insomnia. We did not attempt to assess its antidepressant activity as it is already approved for that purpose. METHODS This project was approved by the Mayo Clinic Institutional Review Board. Pharmacy records were obtained from the dates of January 1, 2010–June 30, 2015, to identify patients in a nonpsychiatric inpatient setting who were dispensed at least 1 dose of mirtazapine during hospitalization. We reviewed the relevant medical records for age, sex, reason for hospitalization, psychiatric diagnoses, and symptoms targeted by mirtazapine. Initial and final dose at dismissal, documented response, potential adverse effects, and concomitant psychotropics were also recorded. Patients were excluded if they had mirtazapine documented as an outpatient medication before admission, if psychiatry was not consulted, if mirtazapine was initiated before psychiatric consultation, or if mirtazapine was not administered to the patient. Given the nature of this retrospective evaluation, descriptive statistics were used to describe outcome variables as means with standard deviations or proportions where appropriate. RESULTS Pharmacy records revealed that 3954 individual patients were dispensed mirtazapine during the 4.5year study period. Screening these records yielded a total of 528 patients with a psychiatric consult specifically recommending mirtazapine. In this cohort 2
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TABLE 1.
Primary Service Type (n ¼ 528).
Service Type
N ¼ (%)
BMT/Transplant Cardiac Critical Care Gastroenterology Hematology/Oncology Medical Neurology PMR Surgical
63 (11.9) 34 (6.5) 27 (5.1) 15 (2.8) 29 (5.5) 148 (28) 23 (4.4) 21 (4) 168 (31.8)
of patients, the mean age (þ standard deviation [SD]) was 60.8 þ 17.3 years and 54% of them were male. Mirtazapine was initiated at a mean dose of 9.6 þ 3.5 mg and titrated to a mean maximal dose of 12.3 þ 6.2 mg. Patients treated on a wide variety of medical services (Table 1) received mirtazapine for 1 of 3 documented reasons: (1) solely for mood or anxiety (n ¼ 53), (2) mood or anxiety plus one or more somatic symptoms (i.e., sleep, appetite, nausea, and pain) (n ¼ 340), or (3) one or more somatic symptoms without a diagnosis of comorbid depression or anxiety (n ¼ 135). Thus, 475 patients received mirtazapine to target at least 1 somatic symptom. The 475 patients were often started on mirtazapine for multiple proposed benefits. The most common target symptom documented was insomnia, for which 432 (90.1%) patients received mirtazapine. The other documented rationales for mirtazapine included appetite stimulation, nausea, and pain in 251 (52.8%), 46 (9.7%), and 46 (4.6%) patients, respectively. Supplementary rationales included the smaller effect on the corrected QT interval compared with another prescribed antidepressant, favorable use in the setting of hyponatremia compared with selective serotonin reuptake inhibitors, less risk of sexual side effects, selection over a selective serotonin reuptake inhibitor or tricyclic in the setting of gastrointestinal bleeding, availability as an orally-disintegrating tablet, minimal drug-drug interactions, cost, rapid onset of action, anxiolytic effects, and low abuse potential. It was difficult to characterize the response to mirtazapine for a specific target symptom due to poor documentation in many cases. Any improvement of a somatic symptom or a lack of benefit related to mirtazapine was documented in only 246 of 475 patients. Of the 432 patients given mirtazapine for sleep, 163 (37.7%) patients had documented improvement. Nausea reduction was reported in 17 (37.0%) of 46 patients, and improved Psychosomatics ]:], ] 2016
Allen et al. TABLE 2.
Documented Side Effects (n ¼ 528).
Side Effect
N ¼ (%)
Oversedation Worsening mental status Nightmares Other (agitation, akathisia, diarrhea, hypertension, and nausea)
28 (5.3) 12 (2.3) 5 (1) 6 (1.1)
pain was documented in 8 (36.4%) of 22 patients receiving mirtazapine for this purpose. A total of 251 patients were given mirtazapine to stimulate appetite and 59 (23.5%) had documented benefit. These rates of improvement are conservative as there was a lack of any documentation in 229 patients who were counted as having no improvement. Only 40 patients had documentation that mirtazapine provided no benefit for the targeted symptom. Mirtazapine was discontinued in 86 patients for reasons both related and unrelated to the effects of mirtazapine. Documentation of a suspected adverse event (Table 2) associated with mirtazapine occurred in 51 patients, with the most common side effects being daytime sedation (n ¼ 28), worsening mental status (n ¼ 10), and nightmares (n ¼ 5). DISCUSSION Mirtazapine is a tetracyclic antidepressant that exhibits its main antidepressant action via alpha-2 adrenergic receptor antagonism, as well as inhibiting alpha-2 heteroreceptors in serotonergic nerve terminals. The resulting effects are the synaptic increase of both norepinephrine and serotonin. As mirtazapine inhibits 5-HT2 and 5-HT3 receptors, the primary serotonergicmediated neurotransmission is via 5-HT1A receptors.3 Mirtazapine also has a high affinity for H1 receptors. Mirtazapine is rapidly absorbed and peaks within 1–2 hours, whereas the antidepressant effects may take several weeks to begin, and other pharmacologic effects can be seen after the administration of a single dose.4 With potent H1 receptor antagonism, mirtazapine can produce significant sedation. Additionally, 5HT2A antagonism has been reported to increase the slow wave sleep, thereby deepening sleep.5 In a large meta-analysis, the incidence of reported drowsiness was 23.4%, when compared to 14.2% with placebo (p o 0.05), but it has been reported to be as high as 53.3% Psychosomatics ]:], ] 2016
across US clinical trials.6 Although this property has been exploited to specifically enhance sleep in patients, sedation is seen less prominently at higher doses. Therefore, clinicians should be mindful to use a lower dosing range of mirtazapine if specifically targeting sleep.7 Studies have evaluated the sleep benefits of mirtazapine in different patient populations, including healthy volunteers and patients with cancer, obstructive sleep apnea, neuropathic pain, or depression with varying results.5,8,9 A small study suggested the advantage of mirtazapine over imipramine for initial, middle, and terminal insomnia in patients with cancer.10 Another prospective, open-label study of orallydisintegrating mirtazapine showed improvement in ease of sleep initiation, duration, and quality of sleep in depressed patients with cancer.11 Another metaanalysis reported the sleep-promoting effects of mirtazapine in patients with major depressive disorder to be significantly greater than placebo and similar to tricyclic antidepressants.12 In our sample, mirtazapine was prescribed to improve sleep in 90.1% of patients. These data parallel the recently reported rise of lowdose mirtazapine prescriptions in the Netherlands for sleep enhancement.13 In our cohort, the most common adverse effect with mirtazapine was related to the sedative properties of the drug, i.e., causing a documented oversedation or next-day somnolence. Finally, despite the sedative benefits to promote sleep restoration, a number of case reports suggest possible disruption of sleep exhibited by sleep-related eating disorder, periodic leg movements, REM sleep behavior disorder, restless leg syndrome, and nightmares; all with different suggested mechanisms.14–18 Interestingly, we did note that 5 patients in our cohort had mirtazapine discontinued for nightmares. Given the potential for mirtazapine to disrupt sleep, careful ongoing monitoring for these adverse events must be conducted. Histamine-1 receptor antagonism also affects appetite, and in combination with 5-HT2C receptor antagonism, mirtazapine may lead to weight gain.19,20 In the literature, a meta-analysis describes weight gain of about 1.5 kg associated with the use of mirtazapine.21 Mirtazapine-related weight gain has been reported in cancer-related cachexia and weight loss.22,23 Less convincing evidence has been published regarding mirtazapine's use for weight gain in elderly patients with unintentional weight loss.24,25 Related to appetite are additional benefits of mirtazapine in www.psychosomaticsjournal.org
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Mirtazapine for Symptomatic Relief preventing or treating nausea and vomiting. These effects in part may also be mediated by H1 antagonism, but mirtazapine is a 5-HT3 antagonist as well, similar to other anti-emetics with this mechanism of action (e.g., ondansetron).1 Mirtazapine is reported to relieve nausea and vomiting in a wide variety of clinical scenarios. This includes patients receiving cancer chemotherapy or bariatric patients following surgical intervention, as well as those with hyperemesis gravidarum during pregnancy, functional vomiting, and cyclic vomiting syndrome.26–30 Additional noted benefits of mirtazapine as an anti-emetic include the availability of an orally-disintegrating tablet with an increased half-life and decreased cost when compared with “setron” medications.1 With mirtazapine available as generic, the estimated cost is between $2–5/day, compared with other antinausea medicines, which can cost upward of $140/day.1 Mirtazapine was only used in approximately 10% of our patients to target nausea and vomiting with documentation of benefit or lack thereof in only one-third of these patients. Compared to use for other somatic symptoms, evidence to support mirtazapine as an analgesic is less established in the literature, and this correlates with the low frequency in which mirtazapine was suggested for pain in our sample. Proposed analgesic mechanisms of mirtazapine include alpha adrenergic-2 receptor (alpha-2) and 5-HT1A agonism. There are case studies indicating that it may be useful for chronic and neuropathic pain syndromes.2,31 In addition, 1 randomized placebo-controlled pilot study suggested that the drug may be useful in treating patients with fibromyalgia.32 Finally, a small, doubled-blinded crossover study demonstrated mirtazapine’s ability to increase pain tolerance in healthy participants compared with placebo.33 Although the pharmacologic profile and certain side effects of mirtazapine may be exploited to target somatic symptoms, other rare adverse effects may result in discontinuation or therapy modification. Based on premarketing trials, agranulocytosis is estimated to occur at an incidence of approximately 1.1 per 1000 patients exposed to mirtazapine; this has
implications when used in medically ill patients with a pre-existing or predisposition to neutropenia from disease processes or other medication exposures.19,34 In the setting of baseline liver dysfunction, mirtazapine clearance may be decreased by up to 30%. In kidney dysfunction, mirtazapine clearance may be decreased by 30% and 50% in patients with moderate and severe renal disease, respectively.34 Baseline kidney and liver function should be assessed before starting mirtazapine. In both kidney and hepatic impairment, there is no clear guidance for dose adjustments, but clinically, lower doses may be required. Unfortunately, we did not assess baseline liver or kidney function in this cohort to assess if any dose adjustments were made. There were no documented mirtazapine discontinuations due to agranulocytosis/neutropenia, induced liver dysfunction, or suspicion of drug accumulation secondary to organ disfunction.
CONCLUSION Though the sample size is robust, we acknowledge the limitations inherent in a descriptive, retrospective study. Specifically, the lack of standardized questionnaires and complete quantitative data leaves us with incomplete qualitative data. More deliberate monitoring and documentation of the effect on specific somatic symptoms would improve our assessment of mirtazapine's clinical use. Concomitant psychotropics abounded in this heterogenous population, but this gives a truer reflection of real world clinical practice. Regardless, many of our patients reported global improvement with relatively few and mostly innocuous adverse events. Controlled trials are needed to assess these benefits more systematically, and it is not clear how long mirtazapine should be used for these symptoms. Disclosure: The authors disclosed no proprietary or commercial interest in any product mentioned or concept discussed in this article.
References 1. Kast RE, Foley KF: Cancer chemotherapy and cachexia: mirtazapine and olanzapine are 5-HT3 antagonists with
4
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good antinausea effects. Eur J Cancer Care (Engl) 2007; 16 (4):351–354
Psychosomatics ]:], ] 2016
Allen et al. 2. Brannon GE, Stone KD: The use of mirtazapine in a patient with chronic pain. J Pain Symptom Manage 1999; 18(5): 382–385 3. Anttila SA, Leinonen EV: A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev 2001; 7 (3):249–264 4. Timmer CJ, Sitsen JM, Delbressine LP: Clinical pharmacokinetics of mirtazapine. Clin Pharmacokinet 2000; 38 (6):461–474 5. Aslan S, Isik E, Cosar B: The effects of mirtazapine on sleep: a placebo controlled, double-blind study in young healthy volunteers. Sleep 2002; 25(6):677–679 6. Alam A, Voronovich Z, Carley JA: A review of therapeutic uses of mirtazapine in psychiatric and medical conditions. Prim Care Companion CNS Disord 2013; 15:5 7. Savarese M, Carnicelli M, Cardinali V, Mogavero MP, Federico F: Subjective hypnotic efficacy of Trazodone and Mirtazapine in patients with chronic insomnia: a retrospective, comparative study. Arch Ital Biol 2015; 153(2-3): 243–250 8. Carley DW, Olopade C, Ruigt GS, Radulovacki M: Efficacy of mirtazapine in obstructive sleep apnea syndrome. Sleep 2007; 30(1):35–41 9. Enomoto T, Yamashita A, Torigoe K, et al: Effects of mirtazapine on sleep disturbance under neuropathic painlike state. Synapse 2012; 66(6):483–488 10. Cankurtaran ES, Ozalp E, Soygur H, Akbiyik DI, Turhan L, Alkis N: Mirtazapine improves sleep and lowers anxiety and depression in cancer patients: superiority over imipramine. Support Care Cancer 2008; 16(11):1291–1298 11. Otte JL, Carpenter JS, Manchanda S, et al: Systematic review of sleep disorders in cancer patients: can the prevalence of sleep disorders be ascertained? Cancer Med 2015; 4(2):183–200 12. Dolder CR, Nelson MH, Iler CA: The effects of mirtazapine on sleep in patients with major depressive disorder. Ann Clin Psychiatry 2012; 24(3):215–224 13. Kamphuis J, Taxis K, Schuiling-Veninga CC, Bruggeman R, Lancel M: Off-label prescriptions of low-dose quetiapine and mirtazapine for insomnia in The Netherlands. J Clin Psychopharmacol 2015; 35(4):468–470 14. Jeong JH, Bahk WM: Sleep-related eating disorder associated with mirtazapine. J Clin Psychopharmacol 2014; 34 (6):752–753 15. Fulda S, Kloiber S, Dose T, et al: Mirtazapine provokes periodic leg movements during sleep in young healthy men. Sleep 2013; 36(5):661–669 16. Mattoo SK, Mahajan S, Sarkar S, Nebhinani N: PLMDlike nocturnal movements with mirtazapine. Gen Hosp Psychiatry 2013; 35(5): 576.e7-576.e8 17. Nash JR, Wilson SJ, Potokar JP, Nutt DJ: Mirtazapine induces REM sleep behavior disorder (RBD) in parkinsonism. Neurology 2003; 61(8):1161 [author reply] 18. Dang A, Garg G, Rataboli PV: Mirtazapine induced nightmares in an adult male. Br J Clin Pharmacol 2009; 67(1):135–136
Psychosomatics ]:], ] 2016
19. Fawcett J, Barkin RL: Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression. J Affect Disord 1998; 51(3):267–285 20. Nutt DJ: Tolerability and safety aspects of mirtazapine. Hum Psychopharmacol 2002; 17(1 suppl):S37–S41 21. Domecq JP, Prutsky G, Leppin A, et al: Clinical review: drugs commonly associated with weight change: a systematic review and meta-analysis. J Clin Endocrinol Metab 2015; 100(2):363–370 22. Riechelmann RP, Burman D, Tannock IF, Rodin G, Zimmermann C: Phase II trial of mirtazapine for cancerrelated cachexia and anorexia. Am J Hosp Palliat Care 2010; 27(2):106–110 23. Theobald DE, Kirsh KL, Holtsclaw E, Donaghy K, Passik SD: An open-label, crossover trial of mirtazapine (15 and 30 mg) in cancer patients with pain and other distressing symptoms. J Pain Symptom Manage 2002; 23(5):442–447 24. Mihara IQ, McCombs JS, Williams BR: The impact of mirtazapine compared with non-TCA antidepressants on weight change in nursing facility residents. Consult Pharm 2005; 20(3):217–223 25. Goldberg RJ: Weight change in depressed nursing home patients on mirtazapine. J Am Geriatr Soc 2002; 50(8):1461 26. Bondade S, Basavaraju V, Singh N: Use of mirtazapine in functional vomiting. Aust N Z J Psychiatry 2016; 50(1): 102–103 27. Teixeira FV, Novaretti TM, Pilon B, Pereira PG, Breda MF: Mirtazapine (Remeron) as treatment for nonmechanical vomiting after gastric bypass. Obes Surg 2005; 15(5):707–709 28. Bae SM, Kang SG, Lee YJ, Cho SJ, Seo CM: Rapid response to mirtazapine in cyclic vomiting syndrome refractory to conventional prokinetics. Psychosomatics 2014; 55(3):311–312 29. Huerta S, Siddiqui A: Intractable nausea and vomiting following Roux-en-Y gastric bypass: role of mirtazapine. Obes Surg 2006; 16(10):1399 30. Guclu S, Gol M, Dogan E, Saygili U: Mirtazapine use in resistant hyperemesis gravidarum: report of three cases and review of the literature. Arch Gynecol Obstet 2005; 272 (4):298–300 31. Mattia C, Paoletti F, Coluzzi F, Boanelli A: New antidepressants in the treatment of neuropathic pain. A review. Minerva Anestesiol 2002; 68(3):105–114 32. Yeephu S, Suthisisang C, Suttiruksa S, Prateepavanich P, Limampai P, Russell IJ: Efficacy and safety of mirtazapine in fibromyalgia syndrome patients: a randomized placebocontrolled pilot study. Ann Pharmacother 2013; 47(7-8): 921–932 33. Arnold P, Vuadens P, Kuntzer T, Gobelet C, Deriaz O: Mirtazapine decreases the pain feeling in healthy participants. Clin J Pain 2008; 24(2):116–119 34. insert M.p. Mirtazapine [package insert]. Mylan Pharmaceuticals, Inc., Morgantown, WV; Revised October 2014.
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Published by Elsevier Inc. on behalf of The Academy of Psychosomatic Medicine.
Original Research Reports Mirtazapine for Symptomatic Relief on a Psychiatric Consultation Service: A Case Series Nicholas D. Allen, M.D., Jonathan G. Leung, Pharm.D., R.Ph., Hannah K. Betcher, M.D., Kristin L. Borreggine, D.O., Daniel K. Hosker, M.D., Blaine A. Minton, D.O., Eliza M. Sukiennik, M.D., Jacob J. Wilson, M.D., Kemuel L. Philbrick, M.D., Keith G. Rasmussen, M.D.
Background: With a complex pharmacologic profile, mirtazapine may promote sleep, stimulate appetite, improve nausea, and reduce pain. Some practitioners working on the Mayo Clinic inpatient psychiatric consultation/liaison service have recommended mirtazapine in medically ill patients with or without formal psychiatric comorbidity to target these symptoms. Objective: To assess the success of this practice, we conducted a retrospective chart review covering a 4.5year period. Methods: For patients recommended to start mirtazapine, global improvement in specific symptoms and suspected side effects were recorded. Results: During the study period, 528 medically ill patients started mirtazapine following a recommendation from the psychiatric consultation service. In total, 475 patients were provided mirtazapine to specifically target sleep, nausea, pain, or appetite. There was
documented improvement in these symptoms for 37.7%, 37.0%, 36.4%, and 23.5% of the patients, respectively. These rates of improvement are conservative for the 229 patients without documented response, i.e., 48% of the patients who were given the medication for a somatic symptom were counted as having no improvement. Commonly documented adverse effects were daytime sedation (5.3%), worsening mental status (2.3%), and nightmares (1%). Conclusions: Despite the limitations of this retrospective, qualitative study, these data confirm that mirtazapine is generally well tolerated and can provide at least short-term relief of certain symptoms in medically ill patients. Controlled trials are needed to assess these benefits more systematically, and it is not clear how long mirtazapine should be used for these symptoms. (Psychosomatics 2016; ]:]]]–]]])
INTRODUCTION
Mirtazapine acts as a histamine-1 receptor (H1) antagonist and 5-HT2C receptor antagonist, which
As mirtazapine carries a single Food and Drug Administration-approved indication for major depressive disorder, practitioners may not recognize mirtazapine's potential to provide benefit in managing somatic symptoms. Outside psychiatric use, mirtazapine has gained attention in the oncology literature as possessing beneficial properties for nausea and appetite stimulation.1 Mirtazapine possesses complex neuropharmacologic actions, which may explain its possible usage for a number of symptoms. Psychosomatics ]:], ] 2016
Received February 4, 2016; revised February 24, 2016; accepted February 26, 2016. From Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN (NDA, HKB, KLB, DKH, BAM, EAS, JJW, KLP KGR); Department of Pharmacy, Mayo Clinic, Rochester, MN (JGL). Send correspondence and reprint requests to Nicholas D. Allen, M.D., Department of Psychiatry and Psychology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905; e-mail: allen.nicholas@mayo. edu Published by Elsevier Inc. on behalf of The Academy of Psychosomatic Medicine.
www.psychosomaticsjournal.org
1
Mirtazapine for Symptomatic Relief may help improve appetite and sleep. The binding affinity to the serotonin-3 receptor (5-HT3) is similar to that of ondansetron and other medications in the same class, making a notable antiemetic.1 Action at the alpha adrenergic-2 receptor (alpha-2) plus 5-HT1A agonism has led to studies evaluating mirtazapine to attenuate pain.2 Despite the potential benefits of mirtazapine on somatic symptoms, randomized, placebo-controlled trials are lacking in the literature, with data supporting its use limited to small open-label studies or retrospective reports. Given the paucity of data, we sought to describe the use of mirtazapine as recommended by our psychiatric consultation/liaison service. Our primary goal was to assess the effectiveness of mirtazapine for symptomatic treatment of pain, nausea, low appetite, or insomnia. We did not attempt to assess its antidepressant activity as it is already approved for that purpose. METHODS This project was approved by the Mayo Clinic Institutional Review Board. Pharmacy records were obtained from the dates of January 1, 2010–June 30, 2015, to identify patients in a nonpsychiatric inpatient setting who were dispensed at least 1 dose of mirtazapine during hospitalization. We reviewed the relevant medical records for age, sex, reason for hospitalization, psychiatric diagnoses, and symptoms targeted by mirtazapine. Initial and final dose at dismissal, documented response, potential adverse effects, and concomitant psychotropics were also recorded. Patients were excluded if they had mirtazapine documented as an outpatient medication before admission, if psychiatry was not consulted, if mirtazapine was initiated before psychiatric consultation, or if mirtazapine was not administered to the patient. Given the nature of this retrospective evaluation, descriptive statistics were used to describe outcome variables as means with standard deviations or proportions where appropriate. RESULTS Pharmacy records revealed that 3954 individual patients were dispensed mirtazapine during the 4.5year study period. Screening these records yielded a total of 528 patients with a psychiatric consult specifically recommending mirtazapine. In this cohort 2
www.psychosomaticsjournal.org
TABLE 1.
Primary Service Type (n ¼ 528).
Service Type
N ¼ (%)
BMT/Transplant Cardiac Critical Care Gastroenterology Hematology/Oncology Medical Neurology PMR Surgical
63 (11.9) 34 (6.5) 27 (5.1) 15 (2.8) 29 (5.5) 148 (28) 23 (4.4) 21 (4) 168 (31.8)
of patients, the mean age (þ standard deviation [SD]) was 60.8 þ 17.3 years and 54% of them were male. Mirtazapine was initiated at a mean dose of 9.6 þ 3.5 mg and titrated to a mean maximal dose of 12.3 þ 6.2 mg. Patients treated on a wide variety of medical services (Table 1) received mirtazapine for 1 of 3 documented reasons: (1) solely for mood or anxiety (n ¼ 53), (2) mood or anxiety plus one or more somatic symptoms (i.e., sleep, appetite, nausea, and pain) (n ¼ 340), or (3) one or more somatic symptoms without a diagnosis of comorbid depression or anxiety (n ¼ 135). Thus, 475 patients received mirtazapine to target at least 1 somatic symptom. The 475 patients were often started on mirtazapine for multiple proposed benefits. The most common target symptom documented was insomnia, for which 432 (90.1%) patients received mirtazapine. The other documented rationales for mirtazapine included appetite stimulation, nausea, and pain in 251 (52.8%), 46 (9.7%), and 46 (4.6%) patients, respectively. Supplementary rationales included the smaller effect on the corrected QT interval compared with another prescribed antidepressant, favorable use in the setting of hyponatremia compared with selective serotonin reuptake inhibitors, less risk of sexual side effects, selection over a selective serotonin reuptake inhibitor or tricyclic in the setting of gastrointestinal bleeding, availability as an orally-disintegrating tablet, minimal drug-drug interactions, cost, rapid onset of action, anxiolytic effects, and low abuse potential. It was difficult to characterize the response to mirtazapine for a specific target symptom due to poor documentation in many cases. Any improvement of a somatic symptom or a lack of benefit related to mirtazapine was documented in only 246 of 475 patients. Of the 432 patients given mirtazapine for sleep, 163 (37.7%) patients had documented improvement. Nausea reduction was reported in 17 (37.0%) of 46 patients, and improved Psychosomatics ]:], ] 2016
Allen et al. TABLE 2.
Documented Side Effects (n ¼ 528).
Side Effect
N ¼ (%)
Oversedation Worsening mental status Nightmares Other (agitation, akathisia, diarrhea, hypertension, and nausea)
28 (5.3) 12 (2.3) 5 (1) 6 (1.1)
pain was documented in 8 (36.4%) of 22 patients receiving mirtazapine for this purpose. A total of 251 patients were given mirtazapine to stimulate appetite and 59 (23.5%) had documented benefit. These rates of improvement are conservative as there was a lack of any documentation in 229 patients who were counted as having no improvement. Only 40 patients had documentation that mirtazapine provided no benefit for the targeted symptom. Mirtazapine was discontinued in 86 patients for reasons both related and unrelated to the effects of mirtazapine. Documentation of a suspected adverse event (Table 2) associated with mirtazapine occurred in 51 patients, with the most common side effects being daytime sedation (n ¼ 28), worsening mental status (n ¼ 10), and nightmares (n ¼ 5). DISCUSSION Mirtazapine is a tetracyclic antidepressant that exhibits its main antidepressant action via alpha-2 adrenergic receptor antagonism, as well as inhibiting alpha-2 heteroreceptors in serotonergic nerve terminals. The resulting effects are the synaptic increase of both norepinephrine and serotonin. As mirtazapine inhibits 5-HT2 and 5-HT3 receptors, the primary serotonergicmediated neurotransmission is via 5-HT1A receptors.3 Mirtazapine also has a high affinity for H1 receptors. Mirtazapine is rapidly absorbed and peaks within 1–2 hours, whereas the antidepressant effects may take several weeks to begin, and other pharmacologic effects can be seen after the administration of a single dose.4 With potent H1 receptor antagonism, mirtazapine can produce significant sedation. Additionally, 5HT2A antagonism has been reported to increase the slow wave sleep, thereby deepening sleep.5 In a large meta-analysis, the incidence of reported drowsiness was 23.4%, when compared to 14.2% with placebo (p o 0.05), but it has been reported to be as high as 53.3% Psychosomatics ]:], ] 2016
across US clinical trials.6 Although this property has been exploited to specifically enhance sleep in patients, sedation is seen less prominently at higher doses. Therefore, clinicians should be mindful to use a lower dosing range of mirtazapine if specifically targeting sleep.7 Studies have evaluated the sleep benefits of mirtazapine in different patient populations, including healthy volunteers and patients with cancer, obstructive sleep apnea, neuropathic pain, or depression with varying results.5,8,9 A small study suggested the advantage of mirtazapine over imipramine for initial, middle, and terminal insomnia in patients with cancer.10 Another prospective, open-label study of orallydisintegrating mirtazapine showed improvement in ease of sleep initiation, duration, and quality of sleep in depressed patients with cancer.11 Another metaanalysis reported the sleep-promoting effects of mirtazapine in patients with major depressive disorder to be significantly greater than placebo and similar to tricyclic antidepressants.12 In our sample, mirtazapine was prescribed to improve sleep in 90.1% of patients. These data parallel the recently reported rise of lowdose mirtazapine prescriptions in the Netherlands for sleep enhancement.13 In our cohort, the most common adverse effect with mirtazapine was related to the sedative properties of the drug, i.e., causing a documented oversedation or next-day somnolence. Finally, despite the sedative benefits to promote sleep restoration, a number of case reports suggest possible disruption of sleep exhibited by sleep-related eating disorder, periodic leg movements, REM sleep behavior disorder, restless leg syndrome, and nightmares; all with different suggested mechanisms.14–18 Interestingly, we did note that 5 patients in our cohort had mirtazapine discontinued for nightmares. Given the potential for mirtazapine to disrupt sleep, careful ongoing monitoring for these adverse events must be conducted. Histamine-1 receptor antagonism also affects appetite, and in combination with 5-HT2C receptor antagonism, mirtazapine may lead to weight gain.19,20 In the literature, a meta-analysis describes weight gain of about 1.5 kg associated with the use of mirtazapine.21 Mirtazapine-related weight gain has been reported in cancer-related cachexia and weight loss.22,23 Less convincing evidence has been published regarding mirtazapine's use for weight gain in elderly patients with unintentional weight loss.24,25 Related to appetite are additional benefits of mirtazapine in www.psychosomaticsjournal.org
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Mirtazapine for Symptomatic Relief preventing or treating nausea and vomiting. These effects in part may also be mediated by H1 antagonism, but mirtazapine is a 5-HT3 antagonist as well, similar to other anti-emetics with this mechanism of action (e.g., ondansetron).1 Mirtazapine is reported to relieve nausea and vomiting in a wide variety of clinical scenarios. This includes patients receiving cancer chemotherapy or bariatric patients following surgical intervention, as well as those with hyperemesis gravidarum during pregnancy, functional vomiting, and cyclic vomiting syndrome.26–30 Additional noted benefits of mirtazapine as an anti-emetic include the availability of an orally-disintegrating tablet with an increased half-life and decreased cost when compared with “setron” medications.1 With mirtazapine available as generic, the estimated cost is between $2–5/day, compared with other antinausea medicines, which can cost upward of $140/day.1 Mirtazapine was only used in approximately 10% of our patients to target nausea and vomiting with documentation of benefit or lack thereof in only one-third of these patients. Compared to use for other somatic symptoms, evidence to support mirtazapine as an analgesic is less established in the literature, and this correlates with the low frequency in which mirtazapine was suggested for pain in our sample. Proposed analgesic mechanisms of mirtazapine include alpha adrenergic-2 receptor (alpha-2) and 5-HT1A agonism. There are case studies indicating that it may be useful for chronic and neuropathic pain syndromes.2,31 In addition, 1 randomized placebo-controlled pilot study suggested that the drug may be useful in treating patients with fibromyalgia.32 Finally, a small, doubled-blinded crossover study demonstrated mirtazapine’s ability to increase pain tolerance in healthy participants compared with placebo.33 Although the pharmacologic profile and certain side effects of mirtazapine may be exploited to target somatic symptoms, other rare adverse effects may result in discontinuation or therapy modification. Based on premarketing trials, agranulocytosis is estimated to occur at an incidence of approximately 1.1 per 1000 patients exposed to mirtazapine; this has
implications when used in medically ill patients with a pre-existing or predisposition to neutropenia from disease processes or other medication exposures.19,34 In the setting of baseline liver dysfunction, mirtazapine clearance may be decreased by up to 30%. In kidney dysfunction, mirtazapine clearance may be decreased by 30% and 50% in patients with moderate and severe renal disease, respectively.34 Baseline kidney and liver function should be assessed before starting mirtazapine. In both kidney and hepatic impairment, there is no clear guidance for dose adjustments, but clinically, lower doses may be required. Unfortunately, we did not assess baseline liver or kidney function in this cohort to assess if any dose adjustments were made. There were no documented mirtazapine discontinuations due to agranulocytosis/neutropenia, induced liver dysfunction, or suspicion of drug accumulation secondary to organ disfunction.
CONCLUSION Though the sample size is robust, we acknowledge the limitations inherent in a descriptive, retrospective study. Specifically, the lack of standardized questionnaires and complete quantitative data leaves us with incomplete qualitative data. More deliberate monitoring and documentation of the effect on specific somatic symptoms would improve our assessment of mirtazapine's clinical use. Concomitant psychotropics abounded in this heterogenous population, but this gives a truer reflection of real world clinical practice. Regardless, many of our patients reported global improvement with relatively few and mostly innocuous adverse events. Controlled trials are needed to assess these benefits more systematically, and it is not clear how long mirtazapine should be used for these symptoms. Disclosure: The authors disclosed no proprietary or commercial interest in any product mentioned or concept discussed in this article.
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