[129] Mirtazapine: Update on efficacy, safety, dose response

[129] Mirtazapine: Update on efficacy, safety, dose response

Soon after mirtazapine was licensed in Canada, a 2002 Therapeutics Letter concluded that it has “no proven efficacy or safety advantage over other antidepressant therapies”.1 Mirtazapine was approved for symptomatic relief of depressive illness and marketed as an alternative to selective serotonin reuptake inhibitors (SSRIs) which had dominated the antidepressant market from the late 1980s.2 As with all antidepressants, mechanism(s) of therapeutic benefit are unknown. Mirtazapine inhibits adrenergic, serotonergic, histaminic and muscarinic type cholinergic receptors, making it distinctive pharmacologically from tricyclics, SSRIs or monoamine oxidase inhibitors. This Letter updates evidence on mirtazapine’s efficacy (both alone and in combination with other antidepressants), dose response, and harms.

Comparative efficacy

A 2018 systematic review and network meta-analysis of 21 antidepressants examined published and unpublished randomized clinical trials (RCTs). The proportion of responders (defined by a 50% reduction in depression symptom severity using a standardised observer-rating scale) was 42% – 53% for active treatments versus 35% for placebo after approximately 8 weeks of treatment. “Response” for mirtazapine was 50%.3,4 When all drug-drug comparisons were considered using network meta-analysis, mirtazapine was deemed relatively more efficacious than 3 other antidepressants available in Canada: fluoxetine, fluvoxamine and trazodone (moderate-quality evidence).4 The authors did not consider the differences in efficacy between antidepressants as clinically meaningful, given that they describe the drug effect compared to placebo as “modest”.4

Dose response and safety

A 2019 systematic review and meta-analysis of dose-response in double-blind RCTs for acute treatment of adults with major depression found the proportion of responders to mirtazapine increased slightly up to 30 mg, but decreased at higher doses (see Figure, left graph).

Withdrawals due to adverse events increased steeply with dose (see Figure, right graph). Therefore, exceeding 30 mg per day decreases benefits and markedly increases harms.5
The 2019 Beers Criteria update for potentially inappropriate medication use in older adults recommends caution when using mirtazapine (moderate evidence, strong recommendation) as it may exacerbate or cause the syndrome of inappropriate antidiuretic hormone (SIADH) or hyponatremia.6

Mirtazapine has a long average half-life that is prolonged after age 55 in men from 22 to 32 hours and in women from 38 to 41 hours.2 Dose should also be lowered with reduced kidney or liver function.

Figure: Dose-outcome relationships for mirtazapine (Furukawa 2019)5

Figure

RR: relative risk of “response” or withdrawal for adverse effects. Dotted lines represent 95% confidence intervals.

Harms

The 2002 Therapeutics Letter cautioned that mirtazapine “has a prominent sedative effect and patients should be warned that it may cause mental or motor impairment”.1 Somnolence was experienced by about 50% of RCT participants, but insomnia is not a Health Canada approved indication.7-10 Mirtazapine was found to have one of the highest rates of somnolence (second only to fluvoxamine) and lowest rates of insomnia (only agomelatine was lower) in a meta-analysis of antidepressant harms.11 A 2018 Cochrane review of antidepressants for insomnia found no eligible trials of mirtazapine for adults with a primary diagnosis of insomnia.12

Mirtazapine was associated with the greatest adjusted rate ratio of weight gain (1.50, 95% CI 1.45 to 1.56) among 12 antidepressants used by a cohort of patients followed for 10 years.13 It is also more likely than SSRIs to cause dry mouth and fatigue (reduced physical and mental capacity due to tiredness), but less likely to cause sweating, nausea or vomiting.10

Mirtazapine was found to have fewer sexual side effects in 4 reviewed RCTs comparing mirtazapine with SSRIs; OR 0.31 (95% CI 0.13 to 0.74).10 Other reviewers caution that “the current degree of evidence does not allow a precise estimate of comparative risk of sexual dysfunction associated with a specific antidepressant”.14

Adding mirtazapine to another antidepressant not supported

One high-quality primary care trial, reviewed in a 2019 Cochrane review of persistent depressive symptoms after initial antidepressant treatment, compared adding mirtazapine or placebo to SSRI or serotonin–norepinephrine reuptake inhibitors (SNRI) treatment in people who had not adequately responded at 6 weeks.15,16 There was no clinically significant difference in depressive symptoms at 12 weeks (1.83 difference between mirtazapine and placebo on the Beck Depression Inventory, BDI-II score range 1 to 63). Adding mirtazapine to SSRI or SNRI treatment increased anticholinergic, CNS adverse events, and weight gain.

Conclusions

  • Mirtazapine’s efficacy for depression is similar to other commonly-prescribed antidepressants.
  • It causes drowsiness, weight gain, and dry mouth.
  • Doses above 30 mg daily provide fewer benefits but markedly increase harms.
  • Prescribing mirtazapine for insomnia has not been validated by clinical trials.
  • Adding mirtazapine to an SSRI or SNRI does not improve efficacy but increases harm.
The draft of this Therapeutics Letter was submitted for review to over 130 experts and primary care physicians in order to correct any inaccuracies and to ensure that the information is concise and relevant to clinicians.
The Therapeutics Initiative is funded by the BC Ministry of Health. The Therapeutics Initiative provides evidence-based advice about drug therapy, and is not responsible for formulating or adjudicating provincial drug policies.
ISSN 2369-8691 (Online) <||> ISSN 2369-8683 (Print)

References

  1. Therapeutics Initiative. New Drugs VII – Mirtazapine (Remeron), Salmon-Calcitonin Nasal Spray (Miacalcin), Gatifloxacin (Tequin), Moxifloxacin. Therapeutics Letter 2002; 44. https://ti.ubc.ca/letter44
  2. Health Canada. Product Monograph. PrAPO-Mirtazapine Tablets USP 15 mg, 30 mg and 45 mg Antidepressant. Drug Product Database 2021; https://pdf.hres.ca/dpd_pm/00058110.PDF
  3. Cipriani A, Salanti G, Furukawa TA, et al. Antidepressants might work for people with major depression: where do we go from here? The Lancet. Psychiatry. 2018;5(6):461-3. DOI: 10.1016/S2215-0366(18)30133-0
  4. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 2018; 391(10128):1357-66. DOI: 10.1016/S0140-6736(17)32802-7
  5. Furukawa TA, Cipriani A, Cowen PJ, et al. Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis. The Lancet. Psychiatry 2019; 6(7):601-9. DOI: 10.1016/S2215-0366(19)30217-2
  6. American Geriatrics Society. 2019 Updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Journal of the American Geriatrics Society 2019; 67(4):674-94. DOI: 10.1111/jgs.15767
  7. Lopes Rocha F, Fuzikawa C, Riera R, et al. Antidepressant combination for major depression in incomplete responders–a systematic review. Journal of affective disorders 2013; 144(1-2):1-6. DOI: 10.1016/j.jad.2012.04.048
  8. BC Provincial Academic Detailing Service. Drug information question: Is there a relationship between mirtazapine (Remeron) dose and sedation? PAD Refills March 2021; https://www2.gov.bc.ca/assets/gov/health/practitioner-pro/provincial-academic-detailing-service/pad-refills/pad_refills_march_2021_mirtazapine.pdf
  9. BC Provincial Academic Detailing Service. Antidepressants for Major Depressive Disorder. Drug Information to Support Drug Therapy Decisions March 2020; https://www2.gov.bc.ca/assets/gov/health/practitioner-pro/provincial-academic-detailing-service/antidepressant-drug-information-newsletter.pdf
  10. Watanabe N, Omori IM, Nakagawa A, et al. Mirtazapine versus other antidepressive agents for depression. Cochrane Database of Systematic Reviews 2011; Issue 12. Art. No.: CD006528. DOI: 10.1002/14651858.CD006528.pub2
  11. Alberti S, Chiesa A, Andrisano C, Serretti A. Insomnia and somnolence associated with second-generation antidepressants during the treatment of major depression: a meta-analysis. Journal of Clinical Psychopharmacology 2015; 35(3):296-303. DOI: 10.1097/JCP.0000000000000329
  12. Everitt H, Baldwin DS, Stuart B, et al. Antidepressants for insomnia in adults. Cochrane Database of Systematic Reviews 2018; Issue 5. Art. No.: CD010753. DOI: 10.1002/14651858.CD010753.pub2
  13. Gafoor R, Booth HP, Gulliford MC. Antidepressant utilisation and incidence of weight gain during 10 years’ follow-up: population based cohort study. BMJ 2018; 361:k1951. DOI: 10.1136/bmj.k1951
  14. Reichenpfader U, Gartlehner G, Morgan LC, et al. Sexual dysfunction associated with second-generation antidepressants in patients with major depressive disorder: results from a systematic review with network meta-analysis. Drug Safety 2014; 37(1):19-31. DOI: 10.1007/s40264-013-0129-4
  15. Davies P, Ijaz S, Williams CJ, et al. Pharmacological interventions for treatment-resistant depression in adults. Cochrane Database of Systematic Reviews 2019; Issue 12. Art. No.: CD010557. DOI: 10.1002/14651858.CD010557.pub2
  16. Kessler DS, MacNeill SJ, Tallon D, et al. Mirtazapine added to SSRIs or SNRIs for treatment resistant depression in primary care: phase III randomised placebo controlled trial (MIR). BMJ 2018; 363:k4218. DOI: 10.1136/bmj.k4218
10 Comments
  • juliana zeqollari
    Posted at 16:30h, 07 May Reply

    Does mirtazapine doses higher than 30 mg have a wakening effect (makes it difficult to sleep) therefore should be taken in the morning rather than at night time? (I realize that the above update does not advise taking doses higher than 30 mg, but higher doses are often encountered in practice)

    Thanks,
    Juljana

    • Alan Cassels
      Posted at 12:56h, 10 May Reply

      Thank you for the question. We found nothing notable in the literature that indicates what time of day is best. The product monograph indicates it should be taken in the evening before sleep. Sorry this doesn’t really answer your question but as we note, doses above 30 mg daily provide fewer benefits but markedly increase harms.

      • juliana zeqollari
        Posted at 13:49h, 10 May Reply

        Thank you for your answer.
        While I was completing a webinar presented by a clinical pharmacist in the psychiatric department, it was mentioned that doses of mirtazapine higher than 30 mg have a wakening effect, thus should be taken in the morning. I haven’t been able to find any further information regarding this in literature. It could be that this effect of mirtazapine at high doses is more noticable and receives more attention in clinical settings such as in hospital, where assessments by health care teams are more accessible.
        Thanks,
        Juljana 🙂

  • Melodie Herbert
    Posted at 07:47h, 08 May Reply

    It seems to me that Mirtazapine is rarely prescribed. Do you have information on what percentage of patients with depression get a prescription for this drug? What percentage of patients feel sufficient benefit, to continue taking it, perhaps even for years?
    Is it effective for the concomitant anxiety that many patients with depression experience?
    So many depressed patients have poor sleep, as do patients with chronic fatigue, and fibromyalgia. I wonder if this drug should be prescribed more often for these indications.
    Lack of ongoing compliance with medication, due to sexual dysfunction as a side effect of SSRI’s, may be another good reason to prescribe Mirtazapine, seeing as sexual dysfunction may be less troublesome with this drug.

    • Alan Cassels
      Posted at 12:50h, 10 May Reply

      Thanks for the comments and questions. You are right that mirtazapine is rarely prescribed in BC, and more than 80% of antidepressants prescribed in BC are for SSRIs. I don’t have exact numbers of the percentage of patients with depression who are prescribed mirtazapine. We will post a more complete answer to your question about anxiety soon.

      • Melodie Herbert
        Posted at 20:24h, 10 May Reply

        Given that depression is often a recurrent, virtually life long problem for many patients, with episodes of worsening symptoms, and some episodes of improvement, I was taught that if a person responds to an antidepressant, and then stops it, and relapses within about 2 years, it is probably best to recommend they stay on the drug that works, indefinitely into the future. Yet most of the studies are about initiating treatment, and comparing the drug to other antidepressants or to a placebo or to psychotherapy, and not about long term satisfaction with effects and side effects. Why isn’t there any better information from RCT’s or even qualitative analysis of overall benefits and harms? I do feel Mirtazapine may not be the ideal drug, due to the weight gain associated with it and over sedation for many. The lack of information for doctors and patients, about the long term use of this drug and SSRI’s — is frustrating.

        • Lori
          Posted at 13:07h, 06 September Reply

          Yes, I agree! I am struggling to taper off this drug. Side effects not talked about. It’s effects such as histamine intolerance, SNS damage. Difficulty of coming off this drug. So much unknown and so little knowledge and research.

  • Mark Horowitz
    Posted at 15:07h, 10 May Reply

    This TI letter is misleading and should be updated so that it is helpful for prescribers. It follows the lead of the Cipriani et al. (2018) network meta-analysis in comparing the efficacy of mirtazapine to other antidepressants. This is misleading for several reasons. The Cipriani review evaluates the effect of antidepressants on ‘response’ (reduction in half of baseline depression scores). ‘Response’ has never been demonstrated to be a clinically relevant outcome (https://bmjopen.bmj.com/content/9/6/e024886). Evaluating response involves dichotomising a continuous variable (HAM-D or MADRS), recognised to lose information and to exaggerate the small differences between groups (as is present in this case) https://pubmed.ncbi.nlm.nih.gov/17182286/. Although data has not been evaluated for mirtrazapine specifically, in other antidepressants with similar effects evaluation of the primary continuous variable finds that although there are statistically significant effects for antidepressant versus placebo they are not clinically significant (https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-016-1173-2). Moreover, this estimate of 2 points on the HAM-D as the placebo-antidepressant difference has been converged on by multiple meta-analyses.

    The Cipriani meta-analysis measures effects at 8 weeks – this is clinically uninformative as depression is often chronic and in patients are often treated for years with antidepressants (more than half of people on antidepressants in the UK are on them for more than 2 years, for the US more than half are on them for more than 5 years). The Cipriani meta-analysis does not take into account withdrawal effects provoked by rapidly removing patients who were on antidepressants before the study from those antidepressants in the placebo run-in period which would tend to increase the apparent efficacy of antidepressant (which would resolve withdrawal effects). There are a number of other limitations of the Cipriani meta-analysis outlined by a Cochrane research group (Munkholm et al., 2019) which leads the authors to conclude “the [Cipriani} review should not inform clinical practice.” The authors comment “It seems misleading to rank the antidepressants when we have very low confidence in the evidence” (https://bmjopen.bmj.com/content/9/6/e024886).

    It is therefore unfortunate that the TI editors have chosen to follow this misleading analysis, rather than drawing the evidence-based conclusion that there is no evidence that mirtazapine has clinically significant effects, there is clear evidence of adverse effects, and therefore there is no current evidence to suggest prescription of mirtazapine as an antidepressant. An analysis of its dose-dependent effects seems correspondingly misleading in the context of a lack of evidence for efficacy. The induction of hope is no reason to prescribe a substance with clear adverse effects and no evidence of a positive benefit/harm ratio: there are less harmful ways to achieve this.

    Doctor Horowitz has completed the ICMJE Conflict of Interest Declaration and has no interests to declare.

    • Alan Cassels
      Posted at 13:28h, 20 May Reply

      Dear Dr Horowitz,

      Thank you for extending our Therapeutics Letter on mirtazapine with your critique of the measures and methods used by primary and secondary researchers investigating antidepressants. More effective and less harmful alternatives to currently used antidepressants are urgently needed. We agree short duration 8-week RCTs are inadequate for informing prescribers and patients on the long-term effects of medications. We applaud your efforts as a psychiatrist to educate physicians and patients on best practices in SSRI deprescribing and the harms of this drug class.

      As reviewers we report on the available RCTs and research syntheses. The standard for efficacy evidence on antidepressants as a class at this time is the ‘response’ outcome (50% reduction in depression using an observer-rating scale such as HAM-D or MADRS). The Therapeutics Initiative aims to support better prescribing amongst physicians and pharmacists who are prescribing mirtazapine. In the case of mirtazapine, the harm benefit profile is likely to be skewed towards harm by prescribing patterns that tend towards higher dosages than optimal.

      The findings we report from the Cipriani et al., 2018 network meta-analysis are not impressive with regard to mirtazapine or the other antidepressants included in the comparative analysis in our view. The evidence available to Cipriani et al, 2018 and network meta-analysis approach they used both have substantial limitations. The Therapeutics Initiative enthusiastically endorses the Munkholm et al., 2019 reanalysis of Cipriani et al., 2018. This is the type of analysis and critical approach that is needed to advance medicine, even as we seek to inform prescribers who have few alternatives to the antidepressant drug class to offer the patients and families who seek their help. The critical psychiatry movement is injecting valuable appraisal of existing scientific approaches into the discourse on psychopharmacology.

  • Ciprian Jauca
    Posted at 10:46h, 22 October Reply

    A randomised, double-blind, placebo-controlled trial studying mirtazapine for agitated behaviours in dementia (SYMBAD) published in The Lancet found no benefit of mirtazapine compared with placebo, and observed a potentially higher mortality with use of mirtazapine. The trial was conducted from Jan 26, 2017 to March 6, 2020 and involved 204 participants with Alzheimer’s disease, agitation unresponsive to non-drug treatment , and a CMAI score of 45 or more. It was conducted in 26 UK centres. The study was funded by the UK National Institute for Health Research Health Technology Assessment Programme.
    This study shows that mirtazapine, which is one of the most widely prescribed antidepressants for older people in the UK, is no more effective than placebo in the treatment of agitation in dementia. The observation of potentially higher mortality in the group receiving mirtazapine than the group receiving placebo, although not definitive, provides further reason for caution.
    Banerjee S, High J, Stirling S, et al. Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial. The Lancet; 23 October 2021. 398(10310):1487-97. DOI: 10.1016/S0140-6736(21)01210-1

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