Reassessing mirtazapine and akathisia: A case report on its efficacy in treating severe,treatment-resistant akathisia and a review of the evidence

Abstract

Antipsychotic-induced akathisia is a distressing movement disorder marked by intense internal restlessness and an urge to move. This report discusses a 44-year-old man with a diagnosis of schizophrenia who developed severe, treatment-resistant akathisia after taking haloperidol, a first-generation antipsychotic. Standard treatments for antipsychotic-induced akathisia, including benzodiazepines (Clonazepam) and benztropine, failed to alleviate the patient’s persistent symptoms, causing considerable distress. However, the introduction of mirtazapine at a low dose of 15 mg led to substantial improvement, as indicated by a gradual reduction in the Barnes Akathisia Rating Scale score from 8 to 0 and improvements in mood, mobility, and daily activity participation. This case highlights the potential efficacy of mirtazapine in treating severe, resistant akathisia, adding to its established use in antipsychotic-induced akathisia management and contributing to the limited literature on its application in patients unresponsive to other conventional treatments.

Introduction

Akathisia is a common and distressing movement disorder characterized by an intense feeling of inner restlessness and the compulsive urge to move. It is primarily associated with antipsychotic medications. Therefore, it is crucial to promptly recognize and treat acute akathisia, as the associated psychological distress can lead to nonadherence to antipsychotic medication.^1–3 Although antipsychotics are generally considered the primary class of medications associated with akathisia, this condition can also be induced by various other factors, including antidepressants such as Selective serotonin Reuptake Inhibitors (SSRIs), Serotonin and norepinephrine reuptake inhibitors (SNRIs), and tricyclics, as well as antiemetics like metoclopramide and prochlorperazine. ⁴ A recent meta-analysis by Rissardo et al. suggests that lithium may also be associated with a risk of inducing akathisia. ⁵

Furthermore, akathisia has been linked to several conditions, including iron deficiency, traumatic brain injury, and certain infections affecting the central nervous system. ⁶ Risk factors for akathisia include younger age, non-Caucasian ethnicity, antipsychotic-naïve status, and polypharmacy.^7–11 Accurate diagnosis is crucial for effectively managing this complex condition. The patient described in this case exhibited established risk factors associated with akathisia, including non-Caucasian ethnicity and the administration of high-dose first-generation antipsychotics (FGAs). Although his age did not fit the typical “younger age” risk profile, individual susceptibility can vary significantly. This case emphasizes the importance of considering patient-specific factors and thoroughly evaluating medication selection in clinical practice.

The identification of antipsychotic-induced akathisia (AIA) is complex due to its diverse manifestations. ¹² Acute akathisia typically occurs upon initial administration of antipsychotic medication, and when symptoms persist for >3 months, it is classified as chronic. Withdrawal akathisia can occur when the dosage of antipsychotics is reduced or discontinued. Tardive akathisia, analogous to tardive dyskinesia, develops later in treatment, exacerbates with dosage reduction or discontinuation, and ameliorates temporarily with dosage increase. ¹²

A reduced likelihood of extrapyramidal symptoms (EPS) is often attributed to second-generation antipsychotics (SGAs); however, this may not be true for akathisia. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study found no significant differences between the incidence of AIA with the administration of the moderate-potency FGA perphenazine versus that with treatment using four SGAs (olanzapine, quetiapine, risperidone, and ziprasidone) in patients with long-term schizophrenia. ¹³ The European First Episode Schizophrenia Trial reported notable rates of AIA in patients treated with SGAs: amisulpride (200–800 mg, 16%), olanzapine (5–20 mg, 10%), quetiapine (200–750 mg, 13%), and ziprasidone (40–160 mg, 28%). ¹⁴ Additionally, a study on adolescents with early-onset schizophrenia spectrum disorders showed no significant difference in the incidence of moderate-to-severe akathisia (Barnes Akathisia Rating Scale (BARS) ¹² score ⩾3) between patients treated with the FGA molindone (10–140 mg) and those treated with SGAs (olanzapine, 2.5–20 mg and risperidone, 0.5–6 mg), with rates of 18%, 13%, and 8%, respectively. ¹⁵

The current case highlights mirtazapine’s potential efficacy in managing refractory AIA, especially when conventional treatments such as benztropine and benzodiazepines fail. Extant literature demonstrates mirtazapine’s efficacy in managing AIA; however, there is a paucity of documented cases regarding its application in treatment-resistant scenarios. This case study may provide additional evidence supporting mirtazapine’s potential utility in challenging clinical situations where conventional treatments prove ineffective.

Case presentation

A 44-year-old man with a history of schizophrenia was admitted to our hospital with severe extrapyramidal side effects (EPS), particularly akathisia, bradykinesia, and rigidity. He had been hospitalized elsewhere 1 month prior to admission, where treatment with oral and later injectable haloperidol (150 mg IM) had been initiated to treat his schizophrenia symptoms. On arrival at the hospital, the patient informed us that he had received a haloperidol long-acting injection 5 days prior. Unfortunately, we were unable to determine why an FGA was prescribed as the first-line treatment.

Upon admission, the patient reported severe restlessness, describing the discomfort as a painful sensation throughout his body that subsided only with movement. He had a BARS ¹² score of 8. The patient was initially treated with clonazepam 0.5 mg bid; however, his symptoms persisted. Given his continued urge to move and to avoid the risk of falls, his treatment was switched to benztropine, which was gradually up-titrated to 6 mg daily; it alleviated his EPS symptoms, apart from the akathisia. Unfortunately, as a side effect of the benztropine treatment, the patient developed urinary retention with a post-void residual >800 mL, requiring Foley catheter insertion. The benztropine was tapered off, and low-dose mirtazapine (15 mg) treatment was simultaneously initiated. Mirtazapine was selected over propranolol because he had sleeping difficulties and a lack of appetite, in addition to orthostatic hypotension. His akathisia symptoms improved within a few days. The patient and his family reported no history of akathisia, although he had previously been prescribed an antipsychotic for a few months. However, he discontinued the treatment of his own volition when he went to live alone. Unfortunately, neither the patient nor his family can recall the name of the previous treatment. To avoid the use of FGAs, given their higher propensity to cause akathisia, and bearing in mind the patient’s history of noncompliance, a long-acting SGA was selected to avoid further noncompliance and a relapse of his symptoms. Treatment with paliperidone (3 mg), an SGA, was then initiated; it was gradually increased to 6 mg daily for the management of his schizophrenia, as the haloperidol had been discontinued due to its side effects.

Seven days later, during the same hospital stay, the patient reported a significant reduction in restlessness; he had observed a noticeable improvement after initiating mirtazapine. Three weeks after the initiation of mirtazapine treatment, his BARS ¹² score had decreased to 0, indicating the absence of akathisia symptoms. No evidence of psychomotor agitation or slowing was observed. The patient demonstrated a normal gait on assessment, with heel-toe, toe lift, and upright posture.

The patient was followed up at the outpatient clinic after 3 and 6 months. He remained stable and performed well under the same medication regimen with no reported treatment-related side effects. He now lives with his family, who reported that he is stable, with a sustained lack of akathisia and psychotic symptoms. His walking ability has improved, and he is more engaged in daily activities. The patient noted that his mood is better, he is sleeping and eating well, and he is more active. He denied having perceptual abnormalities, delusions, or negative thoughts, and his family reported no safety concerns.

Discussion

Akathisia is characterized by profound restlessness and an uncontrollable urge to move constantly. ¹⁶ It overlaps with other disorders, making diagnosis challenging. The poorly understood neurobiological basis hinders the development of standardized diagnostic criteria and effective treatment protocols, limiting clinicians’ options for managing this distressing condition. ¹⁷

To address these challenges, a primary clinical goal in managing akathisia is to adjust antipsychotic regimens to prevent its onset. Clinicians are advised to use the lowest effective dose of antipsychotic medications, as higher doses increase the risk of akathisia. Rapid dose escalations should be avoided, as they can trigger or worsen symptoms. The use of multiple drug combinations is discouraged to prevent complicating the clinical picture and increasing adverse effects. These strategies aim to mitigate akathisia while maintaining the therapeutic efficacy of antipsychotic treatment.^3,18 If preventive measures fail, clinicians may consider gradually reducing the dosage of the causative antipsychotic or switching to a medication with a lower risk of inducing akathisia. ¹⁹ However, this approach is not without potential adverse consequences. Reducing the dosage or changing the medication may lower therapeutic efficacy, potentially worsening the patient’s underlying psychiatric condition. This creates a complex clinical dilemma where resolving one issue may aggravate another, necessitating careful evaluation and continuous monitoring by healthcare professionals.

In this reported case, managing the patient’s akathisia presented several challenges. The initial difficulty stemmed from prior treatment with a long-acting FGA, and adding an SGA without an adequate washout period potentially exacerbated the condition. Given the patient’s EPS-related rigidity, benztropine was initially chosen but discontinued due to urinary retention. Clonazepam was also tried but failed to improve symptoms. The patient’s orthostatic hypotension, need for multiple daily doses, and persistent motor restlessness raised concerns about fall risk, prompting the exploration of alternative treatments. While propranolol was considered, mirtazapine was ultimately deemed more suitable due to the patient’s sleep difficulties and orthostatic hypotension. This decision to choose mirtazapine aimed to address multiple issues simultaneously, including insomnia, lack of appetite, and akathisia, which ultimately resulted in a significant improvement in the patient’s presentation.

Mirtazapine, a tetracyclic antidepressant, inhibits central presynaptic alpha-2-adrenergic receptors, thereby enhancing serotonin and norepinephrine release. Classified as a noradrenergic and specific serotonergic antidepressant, it antagonizes H1 histamine receptors and 5-HT2A, 5-HT2C, and 5-HT3 serotonin receptors, resulting in sedative and anxiolytic effects. ²⁰ Its potent presynaptic alpha-2 adrenergic antagonism underlies its antidepressant action, while significant 5-HT2A blockade at low doses contributes to its anti-akathisia properties. ²⁰

In a randomized double-blind study involving 26 patients with schizophrenia treated with FGAs who had AIA, participants received either mirtazapine (15 mg/day) or a placebo as an adjunctive treatment for 5 days. ²¹ The low-dose mirtazapine group demonstrated rapid and significant improvements in akathisia scores. A statistically significant proportion of patients in the mirtazapine group (53.8%) met the response criterion (a decrease of at least two points on the BARS global subscale), whereas the placebo group did not (7.7%, p = 0.004). Mirtazapine administration also resulted in modest improvements in psychotic symptoms, with mild sedation being the sole reported adverse effect. These findings were further substantiated by a randomized placebo-controlled trial that compared the efficacy of treatment using low-dose mirtazapine and propranolol in 90 patients with FGA-induced akathisia. ²² Mirtazapine administered once daily (15 mg) demonstrated efficacy comparable to that of propranolol (40 mg twice daily) in eliciting a greater improvement in AIA than the placebo. Response analysis (BARS global scale reduction ⩾2) revealed a similarly robust anti-akathisia effect in the mirtazapine and propranolol groups compared with the placebo. Furthermore, a comprehensive systematic review and meta-analysis ²³ evaluated the global akathisia score for 10 medications used to treat AIA across 15 clinical trials involving 492 participants. The investigation revealed that mirtazapine, vitamin B6, and biperiden had the three most promising efficacy and tolerability profiles. Mirtazapine ranked highest in both the primary analysis and all subgroup assessments. ²³

Managing refractory akathisia is difficult, and switching to an SGA with lower akathisia risk, such as quetiapine or clozapine, can be effective. ²⁴ However, this was impractical in our case due to the patient being on a long-acting FGA, complicating the transition. The literature lacks clear preferences or robust studies on specific adjuvant medications to treat akathisia. This is mirrored in our case, in which various treatments were considered and applied based on the patient’s unique circumstances and responses. Our case involved the sequential use of benztropine, clonazepam, and mirtazapine, highlighting the need for personalized treatment. Mirtazapine was chosen to address the akathisia, as well as the patient’s insomnia and appetite issues, showcasing the importance of considering multiple factors in treatment selection. This case emphasizes the complexity of managing refractory akathisia and the necessity for individualized treatment strategies. It also highlights the gaps in current literature on optimal treatments for refractory cases, indicating a need for further research.

While the advantages of mirtazapine in treating refractory akathisia have been presented in this case, our literature review revealed a few case reports of mirtazapine-induced akathisia, as shown in Table 1. Upon closer examination of these cases, several significant observations can be made:

Table 1.

Case reports of mirtazapine-induced akathisia.

Authors	Summary of case report	Limitations
Deniz Ozturan and Unal Demir 25	A 52-year-old woman who had been taking fluoxetine 40 mg/day for 5 months to treat major depressive disorder had mirtazapine 15 mg/day added to her treatment. She developed akathisia 3 h after the initial dose. Symptoms resolved within 1 day of discontinuing mirtazapine.	The patient was also on fluoxetine; therefore, the akathisia could have been related to the combination of medications. There is no mention of the use of any akathisia rating scales.
Koller 26	A 30-year-old man developed akathisia after starting mirtazapine, which resolved with the addition of propranolol.	No rating scale was used to assess the severity of akathisia systematically.
Raveendranathan and Swaminath 27	A 42-year-old woman developed akathisia after switching from fluoxetine 40 mg to mirtazapine 15 mg for depression. The Barnes Akathisia Rating Scale score dropped from 6 to 0 within 2 days of stopping mirtazapine.	The patient was also on fluoxetine; therefore, the akathisia could have been related to the switch or interaction between the two medications.
Markoula et al. 28	A 72-year-old woman developed akathisia after 20 years of continuous mirtazapine treatment.	Long-term mirtazapine use was reported, and no mention was made of standardized akathisia rating scales. In addition, no information was provided regarding the dose of mirtazapine or concomitant medications that could have contributed to the akathisia.

The main limitations of these case reports include the concomitant use of other psychotropic medications, lack of systematic rating scales to assess akathisia severity, and limited details in addition to inconsistency provided in some reports.

The number of case reports linking mirtazapine to akathisia is limited (refer to Table 1). On the other hand, substantial data, including systematic reviews, demonstrate its positive outcomes in treating akathisia. However, there is no available data regarding its use in refractory cases. Additionally, the few case reports that suggest an association between mirtazapine and akathisia did not use standardized assessment tools, such as the BARS, ¹² to evaluate akathisia severity. Furthermore, these case reports frequently involved the concurrent use of other medications that could be implicated as a cause of akathisia, complicating the establishment of a direct causal relationship with mirtazapine.

These findings suggest that while mirtazapine-induced akathisia is a possibility, it is infrequent. The evidence supporting its incidence is limited and often confounded by other factors. Conversely, the evidence supporting mirtazapine’s efficacy in treating akathisia is more robust, although its application in refractory cases warrants further investigation. Our case highlights the complexities involved in managing akathisia, particularly when it is refractory to conventional therapies. It underscores the importance of carefully considering individual patient factors, potential side effects, and the need for a multifaceted approach to treatment selection.

Conclusion

This case report underscores the potential of low-dose mirtazapine administration as an effective treatment for severe treatment-resistant akathisia due to haloperidol in patients with schizophrenia. The significant reduction in severe akathisia symptoms observed in this patient suggests that mirtazapine may be a viable alternative when conventional treatments are inadequate. Further research is required to explain the mechanisms and broader applicability of mirtazapine in akathisia management, particularly in complex cases where interventions fail.