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Research updates on mirtazapine in anxiety, insomnia, methamphetamine abuse, and controversial news about the abuse potential of this antidepressant. Also new side effects and withdrawal symptoms discovered.

Published On: 7/19/21

Duration: 16 minutes, 28 seconds

Related Article: “Two Negative Studies of Mirtazapine and Riluzole for PTSD in Veterans,” The Carlat Psychiatry Report, June/July 2021

Transcript:

It’s never too late to take a fresh look at an old medication, and today we’ll do just that with mirtazapine.

Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

Kellie Newsome: On June 4, 1996, Organon pharmaceuticals received a much anticipated letter from the FDA, granting their antidepressant mirtazapine US approval in major depression. The drug had already been used for 2 years in the Netherlands, and had a similar structure to mianserin, a novel antidepressant that was popular in Europe. Looking at the original approval, we knew a lot about mirtazapine at the time. Its main side effects were fatigue, weight gain, and a very rare but concerning problem of agranulocytosis. But research has not slowed down on this long-generic antidepressant, and in this month’s issue we feature a new study on mirtazapine in PTSD. In this companion podcast, we’ll cover 9 other new findings on mirtazapine that have come out in the past year, starting with its use in anxious depression.

1. Anxious Depression

Dr. Aiken: In the past few years mirtazapine has had some disappointing news – mainly in a series of large randomized controlled trials where it failed to augment antidepressants in treatment resistant depression. We covered that in a Sept 2019 podcast, Remeron Runs Low on Rocket Fuel. One of those negative studies was undertaken in 480 primary care patients with depression in the UK, and although mirtazapine failed to augment SSRIs and SNRIs in that study there was a small signal suggesting benefit on secondary measures of anxiety.

This new study took a second look at that data, carving it up in a way that paints a more encouraging picture. They stratified the patients by the severity of their generalized anxiety symptoms, and found that mirtazapine did make a significant difference – both in anxiety and depression – in those with high anxiety. The difference looks clinically meaningful in those with severe anxiety – they had a 6 point reduction in their beck depression score on mirtazapine compared to placebo. For those with mild or no anxiety, there was practically no difference on mirtazapine.

So with the caveat that this is a secondary analysis, we can say that mirtazapine augmentation of other antidepressants may be best reserved for those with high levels of anxiety and depression. 

2. Insomnia in depression

Insomnia is another comorbidity we use mirtazapine for in depression, and this new study, though small with only 27 patients from China, provides some reassuring data that mirtazapine’s sleep benefits are not limited to sedation but may extend to sleep architecture as well. The patients – who had depression and insomnia – were randomized to mirtazapine or agomelatine for 8 weeks. Agomelatine is a melatonergic antidepressant used outside the US, and the fact that it works through the melatonin receptors cues you in to the fact that this – like mirtazapine – is an antidepressant that is well known to improve sleep. In this study, both medications improved subjective measures of sleep as well as objective measures of sleep architecture: increased stage 2 and 3 sleep, and REM sleep. The effects were similar between the 2 drugs, but mirtazapine worked faster on stage 3 sleep. The investigators also looked at Functional magnetic resonance imaging before and after the treatment and found improvements in the connectivity in areas of the prefrontal cortex and the right precuneus. The precuneus is one of the “hot spots” in the default mode network – which is involved in self-consciousness. Of course, it’s a good thing to be aware of yourself – but if you’ve talked to a depressed patient you’ve probably seen how self-awareness can go too far – into excruciating self-doubt, self-criticism, and depressive rumination.  So to simplify a little, the idea here is that treatment allowed the prefrontal cortex – which is in charge of prioritizing and suppressing thoughts and emotions that we don’t need to waste energy on – is dampening down all that depressive rumination. It’s not known if these MRI changes were due to the sleep effects or the overall antidepressant effects, but they were a little greater in the mirtazapine group. 

3. Mirtazapine Withdrawal

Kellie Newsome: Recently there were 2 case reports of withdrawal problems on mirtazapine. One involved itching, and the other loss of appetite and anxiety. Withdrawal problems are best known with the SSRIs, but nearly every antidepressant has been associated with withdrawal problems, and since mirtazapine is known to improve itching, raise appetite, and lower anxiety, and those symptoms went the opposite direction in these case reports, they probably have some truth to them. A word to the wise: Never tell a patient that a drug has no withdrawal problems. We just don’t know – it’s an understudied area. Lithium, the SSRIs, and the benzos have the worst withdrawal problems. If they are not on those drugs, you might reassure them there are no dangerous withdrawal phenomena, but you can expect your patient will experience some changes as they come off any drug and should be prepared for that.

4. Is Mirtazapine a Drug of Abuse?

Dr. Aiken: Mirtazapine may have some withdrawal symptoms, but is it a drug of abuse? Possibly, suggests this new report. Researchers from Greece compared two streams of data – Google searches and reports of abuse to the FDA’s FAERS database. They found a significant correlation – as search terms related to abuse of mirtazapine rose, so did reports of actual abuse in the FDA system. As a comparison, they ran a similar analysis with the benzo clonazepam (Klonopin) and the SSRI escitalopram (Lexapro). Mirtazapine’s abuse signal was more in line with the benzo’s than the SSRI, although it was not as strong as the benzo’s. However, mirtazapine generated nearly as many search queries in Google about getting “high” as the benzo did.

The time period for this study was 2004-2017, and mirtazapine’s abuse association was not a new spike but a steady trickle over those years.

This doesn’t prove that abuse of mirtazapine – it just suggests a signal. But other evidence points to real abuse. PsychonautWiki is a website that catalogues psychoactive substances, and it boasts of mirtazapine’s hallucinogenic, sedative, and delirium-like effects. In Finland, mirtazapine was the most common nonprescribed psychoactive drug found in the post-mortem analysis of drug poisoning deaths. My best guess to what is going on here is that people are using mirtazapine, perhaps in high doses, to create altered states of consciousness or simply to sedate themselves, effects that could be related to its antagonism at adrenergic alpha2, histaminergic H1, and muscarinic receptors.

Part of this abuse also involves people who use mirtazapine to manage the effects of another drug. Opioid users believe that mirtazapine can enhance the opioid highs, and users of methamphetamine often take mirtazapine to ease the withdrawal effects of that drug. And that brings us to our next study: #4 Effects of Mirtazapine for Methamphetamine Use Disorder Among Cisgender Men and Transgender Women Who Have Sex With Men: A Placebo-Controlled Randomized Clinical Trial.

5. Mirtazapine Lowers Methamphetamine Abuse

Kellie Newsome: Methamphetamine often occurs among people at risk for HIV transmission, and an earlier study suggested that mirtazapine lowered both the frequency of meth abuse and of risky sexual behaviors among homosexual men. This study, conducted in San Francisco, expanded that finding to include transgendered women who have sex with men, along with cisgender men who have sex with men.  “Cisgender” means that the person identifies with their gender of birth.

Dr. Aiken: As a brief aside, I sometimes hear people express dismay about the growth of terms for gender and sexual identity in recent years. But science is about specificity – so from a medical viewpoint the more terms the better. 150 years ago we didn’t even have a specific word for homosexual orientation – the concept did not even exist. Homosexual acts were seen as deviant acts that people engaged in on the down low and not a reflection of their identity. It was a German psychiatrist Karl Westphal who first shook that up in his 1870 article Contrary Sexual Feeling where he attempted to lay out a taxonomy of sexual orientations. Wesphal also gave us the term agoraphobia, and was the first to describe cataplexy and narcolepsy. 

Kellie Newsome: In the case of this study, part of the aim was to see if mirtazapine could reduce behaviors that put people at risk for HIV – so they included people who have sex with men – whether they were cisgendered men, transgendered women, or transgendered men – although they didn’t actually end up recruiting any transgendered men who have sex with men.

Back to the details of the study – and these are important because it was pretty well designed – double-blind randomized clinical trial of mirtazapine 30 mg at night vs placebo for 6 months in 120 people with methamphetamine abuse who had sex with other men. 

Mirtazapine worked in this study, but it took a little while – the changes in methamphetamine-positive urine test results (the main outcome measure) were first detectable at 3 months and continued to grow as the treatment continued. Changes in risky sexual behaviors were not as impressive – overall there was no difference, but those on mirtazapine did have sex with fewer partners and were more likely to use condoms so they may be clinically meaningful. Depression and sleep also improved on mirtazapine.

This promising study is a replication of an earlier randomized trial by the same group – the current study lasted twice as long and involved twice as many subjects. It is thought that mirtazapine helps people stay off methamphetamine by modulating the monoamine depletion that characterizes the withdrawal state and leads people to keep returning to meth use.

6. Mirtazapine and Movement Disorders

Dr. Aiken: Another database review found possible movement disorders associated with mirtazapine. These are likely rare – they found 179 cases across 6 – but are likely associated with the drug as most came on within a week of starting it. The movement disorders associated with mirtazapine were – in order from most common to least – restless legs syndrome (RLS), tremors, akathisia, periodic limb movements of sleep, dystonia, rapid eye movement sleep behavior disorders, dyskinesia, parkinsonism, and 1 case of tics. Notably, most psychotropic medications are also associated with similar problems. One that stands out here is akathisia, as there are also case reports of mirtazapine treating akathisia, but that one may be dose dependent. My reading of the literature suggests that mirtazapine may treat akathisia at doses below 30mg, but at above 30mg/day it may cause akathisia.

Kellie Newsome: If you’ve stayed with us this long, congratulations, and take heart – we’re going to go through the final 3 real quickly.

Other New Findings on Mirtazapine: IBS, Restrictive Eating, Optimal Dose,  

1. A small randomized controlled trial found it was effective for irritable bowel syndrome with frequent diarrhea.
2. A case report found benefit in a patient with restrictive eating patterns – normally we wouldn’t mention case reports but avoidant-restrictive eating disorder, which is new to DSM-5 and reads like a description of anorexia without the body image concerns and more of an OCD pattern of to eating – doesn’t have many other studies to guide us
3. A meta-analysis concluded that 30mg/night is the optimal dose for mirtazapine, and that beyond that the drug only tended to cause side effects – on average.

Dr. Aiken: And now for the word of the day…. delayed sleep phase disorder

Kellie Newsome: In everyday speech they’re called night owls, but the medical term is delayed sleep phase disorder. In DSM-5, it’s a circadian disorder of sleep, and it’s defined by a delay in the onset of sleep by at least 2 hours. The problem is more common in adolescents, but for many patients it is a lifelong trait with strong genetic influences. These patients are more active at night. They have trouble winding down, and likewise trouble waking up in the morning. Their circadian rhythm does not seem to run on a 24 hour cycle, but instead is running on a cycle closer to 26. One way to treat the problem is to reset the circadian clock each morning with a bright lightbox. Join us next week, where we’ll cover the nuts and bolts of how to use light therapy. 

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