Vitamin B6 best bet against antipsychotic-induced akathisia

Mirtazapine, biperiden, and vitamin B₆ are all beneficial in the treatment of antipsychotic-induced akathisia (AIA), with vitamin B₆ having the best efficacy and tolerability profile, according to the results of a meta-analysis.

Pooled data from 15 trials involving 492 participants showed that the following drugs had superior efficacy in the treatment of AIA when compared with placebo: mirtazapine (15 mg/d for ≥5 days; standardized mean difference [SMD], −1.20, 95 percent confidence interval [CI], −1.83 to −0.58), biperiden (6 mg/d for ≥14 days; SMD, −1.01, 95 percent CI, −1.69 to −0.34), vitamin B₆ (600–1200 mg/d for ≥5 days; SMD, −0.92, 95 percent CI, −1.57 to −0.26), trazodone (50 mg/d for ≥5 days; SMD, −0.84, 95 percent CI, −1.54 to −0.14), mianserin (15 mg/d for ≥5 days; SMD, −0.81, 95 percent CI, −1.44 to −0.19), and propranolol (20 mg/d for ≥6 days; SMD, −0.78, 95 percent CI, −1.35 to −0.22). [JAMA Netw Open 2024;7:e241527]

There was low to moderate heterogeneity across the studies (I²=34.6 percent).

Meanwhile, cyproheptadine (16 mg/d), clonazepam (0.5-2.5 mg/d), zolmitriptan (7.5 mg/d), and valproate (1,700 mg/d) had no significant advantage over placebo.

“Sensitivity analyses generally confirmed the results for all drugs except for cyproheptadine and propranolol. No association between effect sizes and psychotic severity was found,” the investigators reported.

In terms of safety, significant adverse effects reported included drowsiness and dizziness with trazodone and mirtazapine, hypersalivation and depression with valproate, dry mouth and sedation with biperiden and valproate, hypotension with propranolol, and transient sedation with mianserin. 

Favourable risk-benefit ratio

“Mirtazapine consistently ranked first in both the main analysis and all subgroup analyses. However, mirtazapine may be poorly tolerated due to its sedative effects and the potential for weight gain,” the investigators said. “Mianserin is also effective, similar to mirtazapine, in reducing akathisia symptoms. This antidepressant also has a good tolerability profile except for sedation.”

Despite the therapeutic potential of mirtazapine and mianserin, treatment failure occurs in 10–20 percent of patients, which indicate that mechanisms beyond serotonin blockade may be involved in AIA, as the investigators pointed out. [Clin Neuropharmacol 2006;29:68-72]

Vitamin B₆, on the other hand, stands out for AIA treatment because of its risk-benefit profile. With a moderate to large effect size that also extends to different subgroup analyses and an excellent tolerability and acceptability profile, “vitamin B₆ may be considered the best [treatment] option,” the investigators said.

Evidence suggests a potential role for vitamin B₆ in AIA therapy, particularly via the correction of dopamine dysregulation and the scavenging of free radicals. [J Clin Psychiatry 2004;65:1550-1554; Clin Neuropharmacol 2006;29:68-72]

In the event of vitamin B₆ and mirtazapine failure, biperiden may be the next best option, as the investigators pointed out. The drug’s anticholinergic action has been tested for both oral and intramuscular administration, with the optimal dosage being 12 mg/d and optimal treatment duration being 14 days. The only downside is that sedation is likely to occur. [Acta Psychiatr Scand 1983;67:178-187; J Clin Psychopharmacol 2007;27:289-294]

The meta-analysis had several limitations, including the small number of trials with low risk of bias included in the subgroup analysis, the possible underestimation of the efficacy of propranolol due to study design, and the limited generalizability of results to patients taking multiple antipsychotic medications because the studies involved very few participants with antipsychotic polytherapy, among others.

Nevertheless, the investigators believed that the findings may aid prescribers in selecting an appropriate medication for treating AIA.