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Clinical Pharmacist, Western Missouri Mental Health Center, Kansas City, MO
Director of Residency Training, Western Missouri Mental Health Center
Assistant Professor, School of Pharmacy, University of Missouri—Kansas City, Kansas City
Reprints: Dr. Nelson, Division of Pharmacy Practice, School of Pharmacy, University of Missouri—Kansas City, 2464 Charlotte St., Kansas City, MO 64108, fax 816/512-7478, nelsonla{at}umkc.edu
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DATA SOURCES: MEDLINE (1966–February 2008) and PsycINFO (1967–February 2008) were searched using the terms akathisia and mirtazapine. A bibliographic search was conducted as well.
STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the search were evaluated. All primary literature was included in the review.
DATA SYNTHESIS: Antipsychotic-induced akathisia can be difficult to manage and may respond to mirtazapine based on its antagonist activity at the serotonin 5-HT2A/5-HT2C receptors. Three case reports (N = 9 pts.), 1 placebo-controlled trial (N = 26), and 1 placebo- and propranolol-controlled study (N = 90) that evaluated mirtazapine for antipsychotic-induced akathisia have been published. Mirtazapine demonstrated a response rate of 53.8% compared with a 7.7% response rate for placebo, based on at least a 2-point reduction on the Barnes Akathisia Scale (global subscale; p = 0.004). Using the same criterion, mirtazapine and propranolol demonstrated efficacy based on response rates of 43.3% and 30.0% compared with placebo (6.7%; p = 0.0051). Mirtazapine was better tolerated than propranolol. In both studies, drowsiness was the most common adverse event associated with mirtazapine.
CONCLUSIONS: Mirtazapine may be considered a treatment option for antipsychotic-induced akathisia. It may be especially useful for patients with contraindications or intolerability to β-blockers and for those with comorbid depression or negative symptoms. Additional studies should be conducted to provide further evidence of mirtazapine's effectiveness in treating akathisia.
Key Words: akathisia, extrapyramidal symptoms, mirtazapine
Published Online, May 6, 2008. www.theannals.com, DOI 10.1345/aph.1K672
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The pathophysiology of akathisia remains unknown and may not involve the nigrostriatal dopamine pathway. Akathisia does not respond favorably to anticholinergic agents (eg, benztropine). Although the treatment of choice is to lower the antipsychotic dose or switch to a different antipsychotic, this may lead to worsening psychosis or relapse. Thus, using an adjunctive medication to treat akathisia may be the best treatment option for some patients. Anticholinergics, β-blockers, clonidine, benzodiazepines, buspirone, and amantadine have all been studied for the treatment of akathisia.10 β-Blockers, specifically propranolol, have been studied extensively and are perceived to be the most efficacious antiakathisia agent.10,11 The success rate of β-blockers is less than optimal and can be associated with significant adverse effects.12
Clinical and experimental data suggest that serotonin plays a pivotal role in the pathophysiology of akathisia. First-generation antipsychotics, especially high-potency agents, which are potent D2 (dopamine) antagonists and possess little if any activity at 5-HT2 (serotonin) receptors, are associated with higher rates of akathisia. The second-generation antipsychotics possess preferential antagonist activity at the 5-HT2A receptor relative to the D2 receptor, supporting clinical evidence of lower rates of akathisia with second-generation antipsychotics. Additionally, selective serotonin-reuptake inhibitors (SSRIs) are reported to cause EPS, including an "akathisia-like" syndrome, which may be caused by a serotonergically mediated inhibition of dopamine.13
Propranolol may exert its anti-akathisia activity through
5-HT1A presynaptic antagonist
activity.14
Further investigation into the serotonergic theory has led to the evaluation
of drugs that block 5-HT2A/5-HT2C
receptors, including
cyproheptadine,15,16
trazodone,17
ritanserin,18,19
and
mianserin.20,21
Only a handful of case reports and studies exist for these agents, but all
published findings were
positive.15-21
More recently, mirtazapine, a potent antagonist of central
2 auto- and hetero-adrenergic receptors, as well as
an antagonist at the H1,
5-HT2A/2C, and 5-HT3
postsynaptic receptors, was studied for
akathisia.22-27
Anti-akathisia activity is thought to result from
5-HT2A/2C antagonism and not
5-HT3
blockade.28
Mirtazapine, an oral tablet, is approved by the Food and Drug Administration for the treatment of depression. Two studies have demonstrated the benefit of mirtazapine augmentation in the treatment of negative symptoms associated with schizophrenia.29,30 The potential to treat these comorbidities, in addition to akathisia, with one drug would be beneficial.
LITERATURE REVIEW
MEDLINE (1966–February 2008) and PsycINFO (1967–February 2008)
were searched, using the terms akathisia and mirtazapine. A bibliographic
search was conducted as well. All English-language articles identified from
the search were evaluated, and all primary literature was included in the
review. Three case reports and 2 placebo-controlled studies that evaluated the
efficacy of mirtazapine for the treatment of akathisia were
found.22-26
CASE REPORTS
Three case reports describe the use of mirtazapine at varying doses in the
treatment of antipsychotic-induced
akathisia.22-24
The first reported a 28-year-old male with schizophreniform disorder who
developed akathisia following 4 days of treatment with haloperidol 10
mg/day.22
Akathisia was rated as 4 (marked) using the Barnes Akathisia Scale (BAS) and
did not respond to biperiden or diazepam. The BAS is a validated,
clinician-administered scale used to evaluate the severity of drug-induced
akathisia.31
It consists of 4 items including objective akathisia, subjective awareness of
restlessness, subjective distress related to restlessness, and global clinical
assessment. The BAS global subscale is scored on a 6-point scale ranging from
0 to 5, with a higher score reflecting more severe impairment.
Mirtazapine 15 mg/day was initiated. On the second day, akathisia was reduced to a BAS score of 1 (ie, questionable akathisia). Stopping mirtazapine led to a resurgence of akathisia. When mirtazapine was reintroduced, the patient fully responded. The only reported adverse effect of mirtazapine was mild sedation.22
The second publication evaluated low-dose mirtazapine treatment for akathisia in 3 patients with bipolar disorder.23 These patients were all in their thirties; 2 had baseline global BAS scores of 3, and 1 had a baseline score of 4. All patients demonstrated good response to antipsychotic therapy (olanzapine, aripiprazole, or their combination) but experienced akathisia. Each patient began mirtazapine 7.5 mg/day and was evaluated within 7–14 days. All 3 patients demonstrated considerable improvement in BAS scores, with all scores reaching 1 within this time. Reemergence of akathisia occurred in 1 patient when the mirtazapine dose was tapered; another patient was able to taper mirtazapine to discontinuation over a month without recurrence of symptoms. In all cases, emergence of mania did not occur.
A third publication described the response of 5 inpatients, in their thirties and forties, to mirtazapine.24 Each patient developed akathisia after treatment with either risperidone or olanzapine for varying diagnoses including schizophrenia, delusional disorder, or bipolar disorder. Four patients had comorbid depression. Each patient was given mirtazapine 15 mg/day. The global BAS ratings reached zero (absence of akathisia) after one week of treatment in 3 patients with baseline scores of 2–3. Two patients were not rated on the BAS, but the report described disappearance of akathisia at each 2-week follow-up; one patient was not continued on mirtazapine because of continued depressive symptoms. Concomitant medications and adverse effects were not discussed in the report; however, there was a report that one person failed propranolol as a treatment for akathisia.
PLACEBO-CONTROLLED TRIALS
Poyurovsky et
al.25
conducted a prospective, double-blind, placebo-controlled study of mirtazapine
15 mg/day added to stable antipsychotic regimens of 26 patients with
schizophrenia who met the Diagnostic and Statistical Manual of Mental
Disorders, 4th ed., text revision, criteria for neuroleptic-induced
akathisia. Participants were included based on a BAS global subscale score of
at least 2 (mild akathisia). An equal number of male and female inpatients
were randomized to mirtazapine (n = 13) or placebo (n = 13) and all were being
treated with a first-generation antipsychotic. Antipsychotic doses remained
unchanged for 3 days prior to baseline and throughout the study
period.25
Study groups were similar with regard to baseline demographic and clinical characteristics, except the BAS subjective subscale was higher at baseline in the mirtazapine group compared with the placebo group (mean ± SD, 2.3 ± 0.5 vs 1.8 ± 0.4, respectively; p = 0.024). The BAS global subscale was the primary outcome measure and was assessed at baseline, day 3, and day 5. A clinically relevant response was defined as at least a 2-point reduction on the BAS global subscale. The Positive and Negative Symptom Scale (PANSS), Hamilton Rating Scale for Depression (HAM-D), and Simpson-Angus Scale (SAS) for drug-induced parkinsonism were assessed at baseline and day 5.25
The BAS global subscale scores revealed significant group x time effects in favor of mirtazapine in the completer and intent-to-treat analysis (p = 0.001 and p = 0.01, respectively). Mean BAS global subscale scores decreased in the mirtazapine group from 3.0 ± 0.7 to 1.0 ± 1.0 compared with placebo, which showed little change (2.5 ± 0.5 to 2.4 ± 0.8; p = 0.001). The BAS objective subscale demonstrated a similar effect in favor of mirtazapine versus placebo for both the completer and intent-to-treat analysis (p = 0.011 and p = 0.012, respectively). Response rate based on the BAS global subscale was 53.8% (7/13) in the mirtazapine group and 7.7% (1/13) in the placebo group (p = 0.004). Complete resolution of akathisia (BAS global subscale score of zero) was achieved in 38.4% (5/13) of patients in the mirtazapine group and none with placebo. The PANSS and SAS demonstrated a small but significant change in favor of mirtazapine. No difference between groups was found for HAM-D scores.25
Three patients in each treatment arm discontinued participation due to lack of efficacy prior to day 3. Mirtazapine was well tolerated. Mild sedation was reported in 5 patients on mirtazapine compared with 1 patient on placebo.25
The authors concluded that the addition of mirtazapine to antipsychotic therapy was superior to the addition of placebo in treating antipsychotic-induced akathisia, despite the significant difference in baseline BAS subjective scores. One could postulate that more improvement may be found when initial impairment is more severe. The response rate of 53.8% with mirtazapine was greater than that previously reported with propranolol (37.5%).32 Additionally, the authors reported a slight reduction in parkinsonian symptoms in the mirtazapine group based on the reduction in SAS scores.25 One concern regarding this study is the short duration of treatment. This study supports the use of mirtazapine to treat antipsychotic-induced akathisia and warrants further exploration of long-term efficacy and tolerability.
The second prospective, double-blind, placebo-controlled trial included an active comparator, propranolol, to investigate the efficacy of low-dose mirtazapine in antipsychotic-induced akathisia.26 This 7-day study evaluated the effects of mirtazapine 15 mg, propranolol 80 mg, or placebo in 90 patients. The majority of patients were male (n = 57), diagnosed with schizophrenia (n = 80), and were receiving a first-generation antipsychotic. Concomitant psychotropic medications, including mood stabilizers, antidepressants, anticholinergic agents, and/or benzodiazepines, were allowed as long as the doses remained unchanged for 3 days prior to baseline evaluation and throughout the study. Demographic and clinical characteristics were similar between groups. Baseline mean BAS global subscale scores were 3.2 in the mirtazapine group, 3.0 in the propranolol group, and 3.2 in the placebo group, reflecting moderate severity. The BAS was performed at baseline, on day 3, and at endpoint. Other psychiatric rating scales used included the Brief Psychiatric Rating Scale (BPRS), the HAM-D, and the SAS, assessed at baseline and endpoint.26
At endpoint, both active treatment groups demonstrated a greater reduction of the BAS global subscale versus placebo (p = 0.0121 and p = 0.0233, respectively). There was a mean ± SD reduction of 1.10 ± 1.37 points for mirtazapine, 0.80 ± 1.11 points for propranolol, and 0.37 ± 0.72 points for placebo. There were no significant differences between the 2 active treatment groups (p = 0.58). However, the study was only powered to compare mirtazapine with placebo. Response rate, defined as a 2-point or greater reduction in the BAS global subscale score, was 43.3% (13/30) for mirtazapine, 30.0% (9/30) for propranolol, and 6.7% (2/30) for placebo (p = 0.0051). Resolution or almost complete resolution, as defined by a BAS global subscale score of 0 or 1, was higher for mirtazapine (33.3% [10/30]; p = 0.0098) and propranolol (30% [9/30]; p = 0.0195) compared with placebo (6.7% [2/30]). Number-needed-to-treat was calculated as 3 for mirtazapine and 4 for propranolol. There were no differences between the groups on the BPRS, HAM-D, or SAS.26
Twenty-four (26.6%) patients dropped out of the study (7 mirtazapine, 8 propranolol, 9 placebo), primarily due to lack of efficacy (n = 19) and adverse effects (n = 5). Mirtazapine was well tolerated, with the primary adverse effect being drowsiness (36.7%). All of the dropouts secondary to adverse effects were in the propranolol group, and the adverse reactions involved cardiovascular effects including hypotension and bradycardia.26
The authors concluded that treatment with mirtazapine was both safe and effective for antipsychotic-induced akathisia and demonstrated similar efficacy and better tolerability compared with propranolol. Although the authors reached conclusions based on mirtazapine compared with propranolol, the study was not powered to detect such differences. Rather, the study was powered to detect a difference of 40% in response rates between the mirtazapine and placebo groups, which was almost achieved (36.6%). The difference in response between the mirtazapine and placebo groups is clinically significant. This study was short and limits understanding of long-term tolerability and effectiveness of mirtazapine. The use of many adjunctive medications may also have confounded the results.
A recent study evaluating mirtazapine monotherapy compared with a combination of mirtazapine and aripiprazole for the treatment of depression without psychotic features provides further insights.33 Studies evaluating aripiprazole as adjunctive therapy to an SSRI for the treatment of depression have been complicated by reports of akathisia or restlessness.34-36 The most recent study combining mirtazapine with aripiprazole found lower rates of akathisia.33
To counter the evidence for treating antipsychotic-induced akathisia with
mirtazapine, there are only 2 publications describing motor restlessness
induced by this
drug.37,38
The first report described 2 cases of restless legs syndrome (RLS) with the
use of mirtazapine for
depression.37
Both patients developed RLS after at least 5 weeks of treatment with
mirtazapine 30 mg/day, which then resolved upon discontinuation of
mirtazapine. Girishchandra et
al.38
described 2 cases of akathisia, 1 in a 52-year-old male, the other in a
73-year-old female, both of whom experienced akathisia upon their first doses
of mirtazapine 30 mg/day. In the first case, akathisia was successfully
treated with clonazepam, while the second case resolved when the dose of
mirtazapine was reduced to 15 mg/day. The authors postulated that antagonism
of 2-adrenoceptors may have played a role.
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Summary |
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Based on the current evidence, mirtazapine 7.5–15 mg/day may be considered a treatment option for antipsychotic-induced akathisia, as it offers once-daily dosing without need for dosage titration, has a more favorable cardiovascular adverse effect profile compared with β-blockers, demonstrates early efficacy, and is available generically. Common adverse effects include somnolence, dry mouth, and weight gain. Mirtazapine may be especially useful for patients with contraindications or intolerability to β-blockers or for those with comorbid depression or negative symptoms associated with schizophrenia.
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