Low-Dose Mirtazapine: A New Option in the Treatment of Antipsychotic-Induced Akathisia. A Randomized, Double-Blind, Placebo- and Propranolol-Controlled Trial

Poyurovsky, Michael; Pashinian, Artashez; Weizman, Ronit; Fuchs, Camil; Weizman, Abraham

doi:10.1016/j.biopsych.2005.12.007

Cited by 92 publications

(91 citation statements)

References 22 publications

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“…It has been associated with severe distress, suicidal thoughts, impulsive/violent behavior, 3,4 a risk of developing tardive dyskinesia, 4 drug use, 5 medication noncompliance, 5,6 and poor treatment response. 6 For patients with schizophrenia and bipolar I disorder, [6][7][8] who are the usual target population of antipsychotic medications, this could mean very real, negative healthcare consequences.…”

Section: Background and Pathophysiology Of Akathisiamentioning

confidence: 99%

“…6 For patients with schizophrenia and bipolar I disorder, [6][7][8] who are the usual target population of antipsychotic medications, this could mean very real, negative healthcare consequences. 4 As a result, several rating scales and criteria have been developed to identify akathisia. The Diagnostic and Statistical Manual of Mental Disorders provides a guideline for identifying akathisia but does not provide a quantifiable assessment.…”

Section: Background and Pathophysiology Of Akathisiamentioning

confidence: 99%

“…2,10 Although some clinicians may forego scales in favor of clinical observation, akathisia can be confused in the clinical setting with other disorders, such as agitation related to mood or psychotic disorders, restless legs syndrome, anxiety states, drug-withdrawal states, antipsychotic dysphoria, organic medical/neurological disorders, or tardive dyskinesia. [2][3][4]6 As such, a rating scale may be useful in diagnosis and early treatment.…”

Section: Background and Pathophysiology Of Akathisiamentioning

confidence: 99%

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Akathisia: Case Presentation and Review of Newer Treatment Agents

Sethuram¹,

Gedzior²

2014

Psychiatric Annals

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Akathisia is a common and potentially debilitating adverse effect of many psychotropic agents. To a physician not specifically screening for this phenomenon, symptoms can appear similar to depression, anxiety, and/or psychosis. Further complicating matters, akathisia may also occur at different points during the treatment period with varying levels of severity in terms of patient distress. Treatment options have been limited by our somewhat poor understanding of akathisia’s neurological basis, but dopamine dysregulation is theorized to play a central role. Most pharmacotherapy regimens focus on beta-adrenergic antagonists (eg, propranolol, the current gold-standard), which are thought to affect noradrenergic inputs into the dopamine pathways of the brain. However, new research suggests a role for serotonin-based pharmacotherapy, particularly those affecting 5-HT2a/c receptors (eg, mirtazapine) in regulating dopamine. [ Psychiatr Ann . 2014; 44(8):391–396.]

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Section: Background and Pathophysiology Of Akathisiamentioning

confidence: 99%

Section: Background and Pathophysiology Of Akathisiamentioning

confidence: 99%

Section: Background and Pathophysiology Of Akathisiamentioning

confidence: 99%

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Akathisia: Case Presentation and Review of Newer Treatment Agents

Sethuram¹,

Gedzior²

2014

Psychiatric Annals

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“…4 Owing to its marked 5-HT 2A antagonistic properties, the addition of low-dose mirtazapine to typical antipsychotics that exert predominant D 2 receptor antagonism, was suggested to test this hypothesis. When given QD, low-dose mirtazapine (15 mg) revealed a robust antiakathisia effect comparable to that of propranolol, the "gold standard" for akathisia, 5 mirtazapine's H 1 , α 2 and 5-HT 3 antagonistic effects are unlikely to play a role, since antihistamines, α 2 and 5-HT 3 antagonists are apparently ineffective in the treatment of akathisia. 6 Notably, mirtazapine administered in higher doses (≥30 mg/day) may induce akathisia in susceptible individuals, 7 putatively due to stimulation of adrenergic neurotransmission via α 2 auto-receptor blockade.…”

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confidence: 99%

“…Overall, the revealed robust effect of low-dose mirtazapine on antipsychotic-induced akathisia, in addition to its beneficial safety and tolerability profile, encourage modification of treatment guidelines for acute akathisia, by recommending low-dose mirtazapine along with propranolol as first-line anti-akathisia treatments. 5,9 Mirtazapine seems to be an additional example of a multifunctional agent used as an efficacious antidepressant in the approved dose range, and an effective antiakathisia compound at a lower dose range. …”

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confidence: 99%

Mirtazapine – A Multifunctional Drug: Low Dose for Akathisia

Poyurovsky¹,

Weizman²,

Weizman³

2011

CNS Spectr.

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CNS Spectrums should be commended for drawing the attention of clinicians and researchers to the concept of multifunctional drugs. 1 Multifunctional drugs are agents with multiple therapeutic effects at different doses, depending upon their potency at diverse pharmacologic targets. 2 Quetiapine, trazadone, and doxepine are examples of multifunctional drugs. 1,3 Thus, quetiapine at high doses exerts dopamine (D) 2 and serotonin (5-HT) 2A receptor antagonism and is used as an antipsychotic and antimanic agent. In contrast, quetiapine, like doxepine, at very low doses acts as a potent histamine (H) 1 receptor antagonist exhibiting robust hypnotic properties. Similarly, trazodone at low doses antagonizes 5-HT 2A , H 1 , and α 1-adrenergic receptors that account for its sedative and hypnotic therapeutic effects. Trazodone in doses 3-5 times higher exerts an additional inhibitory effect at the serotonin transporter and becomes an antidepressant. 3 Mirtazapine is a widely used antidepressant and anti-anxiety medication. In therapeutic doses (range 30-90 mg/day) mirtazapine is characterized by a potent pre-synaptic α 2-adrenergic receptor blockade which accounts for its antidepressant activity. Low-dose mirtazapine predominantly antagonizes 5-HT 2A/2C and H 1 postsynaptic receptors. The preponderance of the 5-HT 2A receptor antagonism over D 2 receptor blockade was put forward as a putative explanation for the low propensity of atypical antipsychotic agents to induce extrapyramidal side effects (eg, akathisia, parkinsonism, acute dystonia). 4 Owing to its marked 5-HT 2A antagonistic properties, the addition of low-dose mirtazapine to typical antipsychotics that exert predominant D 2 receptor antagonism, was suggested to test this hypothesis. When given QD, low-dose mirtazapine (15 mg) revealed a robust antiakathisia effect comparable to that of propranolol, the "gold standard" for akathisia, 5 mirtazapine's H 1 , α 2 and 5-HT 3 antagonistic effects are unlikely to play a role, since antihistamines, α 2 and 5-HT 3 antagonists are apparently ineffective in the treatment of akathisia. 6 Notably, mirtazapine administered in higher doses (≥30 mg/day) may induce akathisia in susceptible individuals, 7 putatively due to stimulation of adrenergic neurotransmission via α 2 auto-receptor blockade. It seems that mirtazapine is unique in its dose-related bi-directional effect on akathisia: low doses have an anti

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Drug Efficacy in the Treatment of Antipsychotic-Induced Akathisia

Gerolymos,

Barazer,

Yon

et al. 2024

JAMA Netw Open

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ImportanceAntipsychotic-induced akathisia (AIA) occurs in 14% to 35% of patients treated with antipsychotics and is associated with increased suicide and decreased adherence in patients with schizophrenia. However, no comprehensive review and network meta-analysis has been conducted to compare the efficacy of treatments for AIA.ObjectiveTo compare the efficacy associated with AIA treatments.Data SourcesThree databases (MEDLINE, Web of Science, and Google Scholar) were systematically searched by multiple researchers for double-blind randomized clinical trials (RCTs) comparing active drugs for the treatment of AIA with placebo or another treatment between May 30 and June 18, 2023.Study SelectionSelected studies were RCTs that compared adjunctive drugs for AIA vs placebo or adjunctive treatment in patients treated with antipsychotics fulfilling the criteria for akathisia, RCTs with sample size of 10 patients or more, only trials in which no additional drugs were administered during the study, and RCTs that used a validated akathisia score. Trials with missing data for the main outcome (akathisia score at the end points) were excluded.Data Extraction and SynthesisData extraction and synthesis were performed, estimating standardized mean differences (SMDs) through pairwise and network meta-analysis with a random-effects model. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed.Main Outcomes and MeasuresThe primary outcome was the severity of akathisia measured by a validated scale at the last available end point.ResultsFifteen trials involving 492 participants compared 10 treatments with placebo. Mirtazapine (15 mg/d for ≥5 days; SMD, −1.20; 95% CI, −1.83 to −0.58), biperiden (6 mg/d for ≥14 days; SMD, −1.01; 95% CI, −1.69 to −0.34), vitamin B6 (600-1200 mg/d for ≥5 days; SMD, −0.92; 95% CI, −1.57 to −0.26), trazodone (50 mg/d for ≥5 days; SMD, −0.84; 95% CI, −1.54 to −0.14), mianserin (15 mg/d for ≥5 days; SMD, −0.81; 95% CI, −1.44 to −0.19), and propranolol (20 mg/d for ≥6 days; SMD, −0.78; 95% CI, −1.35 to −0.22) were associated with greater efficacy than placebo, with low to moderate heterogeneity (I2 = 34.6%; 95% CI, 0.0%-71.1%). Cyproheptadine, clonazepam, zolmitriptan, and valproate did not yield significant effects. Eight trials were rated as having low risk of bias; 2, moderate risk; and 5, high risk. Sensitivity analyses generally confirmed the results for all drugs except for cyproheptadine and propranolol. No association between effect sizes and psychotic severity was found.Conclusions and RelevanceIn this systematic review and network meta-analysis, mirtazapine, biperiden, and vitamin B6 were associated with the greatest efficacy for AIA, with vitamin B6 having the best efficacy and tolerance profile. Trazodone, mianserin, and propranolol appeared as effective alternatives with slightly less favorable efficacy and tolerance profiles. These findings should assist prescribers in selecting an appropriate medication for treating AIA.

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Low-Dose Mirtazapine: A New Option in the Treatment of Antipsychotic-Induced Akathisia. A Randomized, Double-Blind, Placebo- and Propranolol-Controlled Trial

Cited by 92 publications

References 22 publications

Akathisia: Case Presentation and Review of Newer Treatment Agents

Akathisia: Case Presentation and Review of Newer Treatment Agents

Mirtazapine – A Multifunctional Drug: Low Dose for Akathisia

Drug Efficacy in the Treatment of Antipsychotic-Induced Akathisia

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