11. MIRTAZAPINE INDUCED TARDIVE DYSKINESIA IN AN OLDER ADULT

Introduction

Mirtazapine, first sold in the United States as Remeron in 1996, is a noradrenergic and specific serotonergic antidepressant FDA-approved for major depressive disorder. Its mechanism of action is referred to as NaSSA due to its alpha-2, 5-HT2, and 5-HT3 antagonism. It has also been used off-label as a third-line treatment option for akathisia, appetite stimulation, and SSRI-induced sexual dysfunction. Incidents of hyperkinetic movement disorders caused by mirtazapine have been reported, but even more infrequent for cases involving tardive dyskinesia (TD). The aim of this presentation is to highlight a case of TD with the use of mirtazapine in an older adult and search for more literature involving mirtazapine-induced tardive dyskinesia.

Methods

This case involved an older adult with a history of major neurocognitive disorder with behavioral disturbance and stroke in 2012 who was initially seen by geriatric medicine for a chief complaint of worsening memory loss. Prior history was noted for chronic use of amitriptyline and clonazepam, MoCA score of 8/30, medical history of Crohn’s disease (controlled), and psychiatric history of depression and anxiety. Trials of donepezil and memantine were used in the past but were discontinued due to lack of tolerance. Attempts were made to taper off amitriptyline and clonazepam with buspirone and citalopram, but this was unsuccessful. The primary care provider was eventually able to wean off clonazepam to 0.5 mg oral once daily from three times a day while amitriptyline was continued at PTA 250 mg dose at bedtime. Symptoms during that visit were noted for paranoia about strangers damaging the house, poor sleep, and poor appetite; ADLs 5/6 and IADLs 3/8; updated MoCA of 9/30. During consultation and follow-up appointments with geriatric psychiatry, medication adjustments were made, which eventually led to the development of tardive dyskinesia (TD). For this poster presentation, geriatric psychiatry and medicine department notes were chart reviewed along with the patient's profile. Informed consent was obtained for this presentation. Consensus AI, a research assistant tool that has access to millions of academic papers and accurately pulls peer-reviewed papers, was used to generate literature investigating or reporting findings of tardive dyskinesia with mirtazapine use. “Mirtazapine-induced tardive dyskinesia in older adults” was used as a search feature. All study types and countries were included, and no specific timeline was selected with regards to the publishing date.

Results

Over the course of 6-7 months after the geriatric psychiatry consultation visit, amitriptyline was tapered off to 50 mg at bedtime while clonazepam was continued at 0.5 mg oral daily. Towards the end of the summer, risperidone was added at 0.25 mg due to worsening psychosis, while clonazepam and amitriptyline were continued. By fall, risperidone was increased to 0.5 mg, and trazodone 50 mg was added for continuous sleep issues. Towards the end of that month, clonazepam was discontinued. Later, concerns over hand swelling and increased itching led to discontinuation of both risperidone and trazodone; amitriptyline 50 mg was continued while mirtazapine was added at 3.75 mg at bedtime for one week with a plan to titrate up to 7.5 mg afterwards. At the beginning of 2024, the patient complained about “mouth on fire,” which was attributed to her dentures, while MoCA showed improvement with a score of 11/30 during that visit. The next follow-up appointment was noted for amitriptyline continuation, while mirtazapine was increased to 15 mg oral at bedtime for sleep. From spring to early summer, further titration of mirtazapine occurred from 22.5 mg to 45 mg due to insomnia, and amitriptyline was decreased to 25 mg. During the next follow-up appointment at midpoint of summer, the patient had reported concerns over movement of her mouth and jaw pain ongoing for the past one to two months; ADLs and IADLs were 6/6 and 4/8, respectively. A recommendation was made to decrease the mirtazapine dose down to 30 mg and add trazodone 25 mg three times daily as needed for any episodes of agitation and anxiety. However, due to continued dyskinesia, the family decided to discontinue mirtazapine while trazodone as needed and amitriptyline 25 mg at bedtime were continued. In the interim, trazodone was discontinued secondary to rash, while sertraline was initiated at 50 mg for anxiety. Finally, the most recent visit was noted for an abnormal involuntary movement scale (AIMS) score of mild with a total score of 8/40 (question 8 was 3 and moderate, question 10 was 2 and mild, and questions 11-14 were all positive). A plan was made to increase sertraline to 75 mg daily for 30 days and then to 100 mg afterwards, while amitriptyline was continued at 25 mg oral at bedtime. Future goals included switching amitriptyline to low-dose doxepin. Chain of events summarized in Figure.

When using Consensus AI, 10 studies were generated initially, which included a combination of RCTs, case reports, observational studies, and systemic reviews. Out of these, only one study (a case report published by European Psychiatry in 2017) commented on tardive dyskinesiawithSSRIuse.Somestudiesdidreporthyperkineticmovement disorders/dyskinesias with mirtazapine use, but none with TD.

Conclusions

Based on the timeline of medication changes, it is apparent that higher doses of mirtazapine led to the development of mouth soreness and jaw pain. It is possible that ongoing use of amitriptyline made this event more likely to occur as well. Per FDA, mirtazapine dosing ranges from 7.5 mg to 45 mg (maximum), but a 60 mg dose has been used for clinical depression. Kinetic interactions are noted for CYP1A2, 2D6, and 3A4. Combination with Venlafaxine (Effexor) has been used for boosting serotonin and norepinephrine neurotransmission and was reported by the STAR-D trial to be of similar efficacy as tranylcypromine (Parnate). At higher doses, its noradrenergic effects become more prominent when compared with its antihistamine effects; therefore, it can become less sedating and cause less appetite stimulation. At doses of 15 mg, it can be used as a third-line option for treatment for akathisia, but there is potential for exacerbation with higher doses. As noted by one case report, there is potential for mirtazapine to induce acute dyskinesia, and symptoms can resolve without treatment (S. Konitsiotis et al., 2005). A rare case of tardive dyskinesia in a middle-aged Australian aboriginal woman was reported with a trial of sertraline and use of mirtazapine, which reduced orofacial dyskinetic movement scores from 22/36 to 4/36 over 16 weeks (D. Roy et al., 2017). Per NIH PubChem, both noradrenergic and serotonergic activity increases following administration of mirtazapine. Antagonistic activity occurs at both presynaptic alpha2-adrenergic inhibitory auto-receptors and heteroreceptors in the central nervous system.

In summary, despite evidence of mirtazapine alleviating symptoms of dyskinesias, careful consideration should be used when making medication adjustments in older adults. Our case appears to be unique with its presentation of tardive dyskinesia rather than other various hyperkinetic movement disorders induced by mirtazapine. This case illustrates the complex interaction that exists between mirtazapine and movement disorders. To further our understanding, ongoing research is still needed. For now, clinicians should continue to tailor psychiatric management to the individual conditions and needs of the patient, along with weighing risks and benefits.