CHPR: Please begin by reviewing the main manifestations of akathisia.

Dr. Poyurovsky: Akathisia is a subjective sense of restlessness, like an overwhelming urge to move or a constant inner agitation, with or without restless motor movements such as pacing, shifting positions, or fidgeting. The term comes from the Greek for “inability to sit,” reflecting its primary impact on the legs. It is rare that a patient will tell you about restlessness in the hands or upper body. 

CHPR: Can akathisia present in different forms?

Dr. Poyurovsky: Yes, there are several subtypes. Acute akathisia develops shortly after starting or increasing an antipsychotic drug treatment. When akathisia lasts for more than three months, it’s considered chronic akathisia. Tardive akathisia shows up after long-term use of antipsychotics, often following months or years of treatment, similar to tardive dyskinesia. It’s unclear why some patients develop this delayed form, but it may be linked to long-term dopamine receptor changes. Tardive akathisia can be more persistent and challenging to treat, and it often overlaps with other tardive movement disorders. Withdrawal akathisiaarises from reducing or discontinuing medication and may occur despite long-term use of the drug without prior symptoms. Pseudo-akathisia involves motor movements without the subjective component of true akathisia. Understanding these subtypes is essential for effective treatment strategies. 

CHPR: Interesting. I hadn’t realized there were so many subtypes.

Dr. Poyurovsky: There’s a paper by Theodore Van Putten, “The Many Faces of Akathisia,” that I always recommend to my residents. It was published 50 years ago and is only three pages long, but if you want to know what akathisia is, read this paper (Van Putten T, Compr Psychiatry 1975;16(1):43–47). It describes the many manifestations, including, for example, rare cases of panic attacks or sexual disinhibition as expressions of akathisia. It’s very important to be aware of these various manifestations when treating patients with schizophrenia and other psychiatric disorders. I read Van Putten’s work early in my career, and it prompted me to focus on researching this phenomenon. I went to work with Professor Thomas Barnes, author of the Barnes Akathisia Rating Scale (BARS), to explore treatment options for akathisia. After years of researching this clinical phenomenon, I want to highlight how challenging it can be to identify and treat akathisia. 

CHPR: Please say more about this scale.

Dr. Poyurovsky: The BARS is a reliable and valid rating scale and has clinical utility. It is quick and easy to use. It measures the severity of drug-induced akathisia by assessing observable restlessness, the patient’s subjective awareness of restlessness, the distress caused by the condition, and the clinician’s overall judgment of severity (Editor’s note: See www.thecarlatreport.com/BARS to view the scale).

CHPR: Are there any other symptoms that might represent akathisia?

Dr. Poyurovsky: Actually, I have noticed that obsessive-compulsive-like phenomena can sometimes be manifestations of akathisia. For example, you might see an abrupt change in behavior where a patient keeps coming to you with repetitive questions and inquiries, seeking reassurance. This compulsive, repetitive, intrusive behavior can sometimes be a sign of akathisia. This phenomenon is quite frequent, so it is important to be on the lookout for it. Unfortunately, it is not included in the BARS. 

CHPR: Often I meet patients who are clearly experiencing akathisia, pacing from one foot to the other, yet when asked if they’d like treatment for that symptom, they say, “No, I’m fine.” So, would that be considered pseudo-akathisia., like you said?

Dr. Poyurovsky: A patient’s ability to describe what they are feeling and to attribute uneasy feelings to the effect of medication may vary. You have to ask precise questions to figure out if it’s akathisia or other extrapyramidal side effects or psychotic agitation, anxiety, or anxious depression. 

CHPR: What types of questions do you recommend asking? 

Dr. Poyurovsky: I ask about an inner sense of restlessness specifically attributed to the lower extremities; a physical need to move and change body position; and inability to sit still or remain in one place for extended periods. I also inquire about specific times of day when the restlessness is more pronounced and the proximity of symptoms to taking the medication. 

CHPR: With our patients, I worry that akathisia can sometimes manifest as agitation or can exacerbate agitation, and then they can end up getting more antipsychotic medication, which in turn worsens the akathisia. 

Dr. Poyurovsky: Absolutely. It’s of primary importance to distinguish akathisia from the psychomotor agitation that frequently occurs in psychotic patients. It’s one of the reasons I use the BARS in my daily practice, not just in research, as it helps accurately differentiate between agitation and akathisia. 

CHPR: What’s known about the pathophysiology of akathisia?

Dr. Poyurovsky: The exact cause is unknown, but it’s believed to be related to dopamine receptor blockade in the brain, particularly in areas that regulate movement, like the nigrostriatal pathway.

CHPR: Going back to withdrawal akathisia, how soon after stopping the medications does the akathisia begin, and how long does it take for symptoms to resolve?

Dr. Poyurovsky: Withdrawal akathisia typically begins within a few days to a few weeks after stopping or reducing the dose of an antipsychotic medication. The timeline for resolution of symptoms can vary, but in many cases, symptoms resolve within days or weeks.However, in some patients, withdrawal akathisia can persist for a longer period, particularly if the medication was used for a long time or at a high dose. In these cases, reintroducing the medication at a lower dose may be necessary to manage the condition.

CHPR: How does the incidence of akathisia vary depending on underlying factors like the choice of medications or in different patient populations?

Dr. Poyurovsky: Akathisia is a common phenomenon. With first-generation antipsychotics, the rate is as high as 25%–30% and probably higher, especially if you use high-potency antipsychotics such as haloperidol. We initially hoped the use of second-generation antipsychotics would resolve the issue, but while the incidence of akathisia is lower, it is still a problem. A recent meta-analysis reported that depending on the type of medication, up to 17% of patients treated with second-generation antipsychotics develop akathisia (Demyttenaere K et al, CNS Drugs 2019;33(6):549–556). Special attention is needed when prescribing partial dopamine agonists such as aripiprazole and cariprazine, which have notable rates of akathisia. Increasingly, I see akathisia in patients with affective disorders who are given aripiprazole or cariprazine as augmentation therapy. 

CHPR: Are patients with affective disorders more susceptible to developing akathisia?

Dr. Poyurovsky: Patients with affective disorders, especially depression, seem to be more vulnerable to acute antipsychotic-induced movement disorders and akathisia than those with schizophrenia. However, the mechanism for this is yet to be clarified (Gao K et al, J Clin Psychopharmacol 2008;28(2):203–209).

CHPR: What other factors are associated with a higher incidence of akathisia?

Dr. Poyurovsky: Patients with schizo-obsessive disorder—schizophrenia and OCD—are particularly at risk. While there don’t appear to be significant gender differences in the incidence of akathisia, age is an important factor: Children and adolescents are especially susceptible and may present with more agitation, hyperactivity, and disruptive behaviors compared to adults. Ethnicity also plays a role, with Black and Asian patients appearing to be more vulnerable, and White patients less so. However, the estimates are less robust than for tardive dyskinesia. 

CHPR: Can you tell us about treatment approaches? 

Dr. Poyurovsky: First, I want to say that you should deal with akathisia as soon as you identify it. Akathisia can be an emergency because it can cause severe distress potentially leading to suicidal and aggressive behaviors. Don’t arrange a follow-up visit without first initiating an intervention. To address it, the first approach is to modify the treatment regimen by either reducing the dose of the offending antipsychotic by 25%–50% or switching to an antipsychotic with a lower propensity to induce akathisia. Both interventions run the risk of producing withdrawal akathisia or psychotic exacerbation, so you have to be vigilant for that. The second approach is to add an anti-akathisia medication. 

CHPR: When switching to a different medication, what would be your go-to antipsychotic?

Dr. Poyurovsky: Haloperidol, aripiprazole, risperidone, and cariprazine are associated with the highest risk, whereas clozapine, quetiapine, and iloperidone have the lowest (Editor’s note: For a table comparison, visit www.thecarlatreport.com/akathisiaantipsychs). But we cannot predict individual responses to medication. For clinicians, predicting who will develop akathisia with a particular antipsychotic and who will respond best to an anti-akathisia medication is a major challenge. We certainly would like to have better predictors of response. 

CHPR: Speaking of anti-akathisia medications, which are most effective?

Dr. Poyurovsky: Two recent meta-analyses of medications with anti-akathisia effects identified propranolol and low-dose mirtazapine as the best evidence-based choices (Gambolo L et al, CNS Spectr 2024:1–9; Gerolymos C et al, JAMA Netw Open 2024;7(3):e241527). Benzodiazepines also offer some therapeutic benefit for akathisia, likely due to their nonspecific antianxiety and sedative effects. While anticholinergic agents like biperiden are effective in treating antipsychotic-induced Parkinsonism and dystonia, their clinical utility in akathisia is less clear. They may be better suited for patients with akathisia who also exhibit parkinsonian symptoms. 

CHPR: Are there any drawbacks to using propranolol for akathisia?

Dr. Poyurovsky: Yes. Beta-blockers, especially propranolol, carry the risk of side effects that are often underestimated, such as bradycardia and orthostasis. In our study comparing propranolol, mirtazapine, and placebo, about one in six patients on propranolol withdrew due to these side effects (Poyurovsky M et al, Biol Psychiatry 2006;59(11):1071–1077). This is a significant rate, particularly when propranolol is combined with antipsychotic medications that have alpha-adrenergic effects and can also cause orthostasis. Akathisia can be an emergency, so we want to use a medication with immediate and robust effects. But propranolol needs to be titrated gradually to achieve the desired effect. Some patients respond to 20 mg, while others need up to 120 mg a day. We typically use immediate-release propranolol for quicker symptom relief, but extended release can be an option for patients who prefer once-daily dosing or require more consistent control. We generally avoid going beyond 40–50 mg with either formulation because of the risk of side effects such as orthostasis, especially when combined with medications such as antipsychotics.

CHPR: So, what’s an alternative option?

Dr. Poyurovsky: Mirtazapine, a 5-HT2A antagonist, can effectively treat akathisia at low doses (15 mg). My colleague Professor Avi Weizman and I developed this approach. At this dose, the 5-HT2A serotonin antagonism of postsynaptic receptors is prominent and may account for mirtazapine’s anti-akathisia effect. At higher doses, the noradrenergic effects will become significant, potentially inducing akathisia instead. Our studies showed that even 7.5 mg of mirtazapine could alleviate aripiprazole-induced akathisia (Poyurovsky M and Weizman A, J Clin Psychopharmacol 2018;38(6):609–611). But do not increase to 30 or 45 mg due to the risk of opposite effects. Importantly, mirtazapine achieved an anti-akathisia effect with more convenient dosing and better tolerability than propranolol, with mild transient sedation as the only observed side effect and no significant changes in vital signs. Low-dose mirtazapine did not interfere with the antipsychotic effect of medications, but long-term use can be associated with weight gain and, rarely, agranulocytosis (Maidwell-Smith A and Kirk C, J Med Case Rep 2023;17(1):163).

CHPR: What about vitamin B6?

Dr. Poyurovsky: Vitamin B6 at 600 mg/day has been efficacious for antipsychotic-induced akathisia in two small randomized controlled trials conducted by the same research group (Lerner V et al, J Clin Psychiatry 2004;65(11):1550–1554; Midownik C et al, Clin Neuropharmacol 2006;29(2):68–72). Its major advantage lies in high tolerability and acceptability. However, we still need independent replication of the study results and a demonstration of its clinical utility. 

CHPR: And do you treat pseudo-akathisia, or does it not need addressing, given that the patients don’t report subjective distress?

Dr. Poyurovsky: This side effect should be addressed as true akathisia and adequately treated. The same holds true for akathisia with a predominance of subjective over objective fidgety movements. 

CHPR: Are there any nonpharmacologic approaches that are helpful?

Dr. Poyurovsky: Psychoeducation is essential before initiating an antipsychotic. I always describe the typical symptoms of akathisia and ask patients to immediately contact me if they start feeling fidgety or restless leg movements. We tend to focus on educating patients about weight gain and metabolic syndrome, but we need to remember to talk about akathisia as well.

CHPR: Thank you for your time, Dr. Poyurovsky.