Akathisia

• Akathisia (Greek for “not to sit”) is a movement disorder associated with an intense inner sense of subjective motor restlessness leading to difficulty remaining still.
• In most cases the movement is repetitive and involves the lower extremities, such as crossing, uncrossing, and swinging of legs, or shifting weight from one foot to the other.
• Antipsychotic-related akathisia is the most common form of akathisia and can be classified according to the time of onset in the course of antipsychotic treatment (acute, tardive, withdrawal, and chronic akathisia).

Synonyms

• Acathisia
• Restless Legs Syndrome
• Medication-induced acute akathisia

Epidemiology & Demographics

Incidence – How common is this condition?

Varies widely from 21% to 75%. Occurrence higher with first generation, or typical, antipsychotics, particularly high-potency agents such as haloperidol, than with atypical antipsychotics.

Prevalence

Varies from 20% to 35%. Reported prevalence rates vary between 5% and 36.8%.

Predominant Sex and Age

Akathisia occurs predominantly in younger patients. Incidence appears to decrease with age.

Risk Factors

Risk increases with younger age, Parkinson’s disease, traumatic brain injury (TBI), encephalitides, and iron deficiency. Patients on first generation antipsychotics or higher doses of antipsychotics are at higher risk.

Akathisia usually occurs within first few days of treatment but also with dosage advancements or switch to a higher potency neuroleptic or withdrawal of an antiparkinsonian drug.

Genetics

Generally, akathisia is not considered a highly heritable condition, but a genetic predisposition to or family history of akathisia can confer some added risk. There is recent evidence of PI4K2A deficiency leading to intellectual disability, epilepsy, myoclonus, and an akathisia syndrome beginning in childhood as products of a consanguineous relationship.

Physical Findings & Clinical Presentation

• •Patients typically describe a subjective feeling of restlessness with the impulse to move and will objectively be seen pacing, rocking, and shifting position. Motor activity consists of complex, quasi-purposeful and repetitive movements. Milder cases present with subjective inner restlessness deep in the legs predominantly. Moderate cases are characterized by a tendency to rock back and forth from foot to foot accompanied by a coarse tremor or foot myoclonus. Severe akathisia patients have difficulty maintaining a position, often shuffling their feet when sitting and then getting up repeatedly and pacing. Akathisia is most severe when the patient cannot tolerate any position for more than a few moments.
• •Acute cases usually last less than 6 mo. Chronic cases last for more than 6 mo after last dose increase. Dysphoria and subjective restlessness may be less marked in chronic cases, but dyskinesias are not uncommon. Pseudoakathisia, occurring mostly in men, is associated with motor signs such as fidgetiness without subjective restlessness complaints and with less dysphoria. Tardive akathisia can occur in situations with delayed onset in the setting of a tardive dyskinesia/tardive syndrome. Rebound withdrawal akathisia refers to onsets within 6 wk of discontinuation or dose decrease of an antipsychotic.
• •To assess the severity of akathisia, tools such as the Barnes Akathisia Rating Scale (BARS), the Hillside Akathisia Scale, or the Drug-Induced Extrapyramidal Symptoms Scale are used.
• •The inner restlessness of patients with akathisia can lead to extreme anxiety and depressed mood. In chronic cases, akathisia has also been associated with a high risk of self-harm, suicidal behavior, or aggression. A careful evaluation for depression, anxiety, and suicidal ideation is necessary.
• •Prognosis is good if the condition is recognized and the offending drug is discontinued. If the condition is left untreated, it can become disabling with high morbidity (i.e., suicidal ideation).
• •Use of the term akathisia is often reserved for medication-related and antipsychotic-induced akathisia, although the broad definition of akathisia includes the inner and motor restlessness observed in patients with idiopathic Parkinson’s disease, postencephalitic parkinsonism, and restless legs syndrome.

Etiology

• •Pathophysiology is poorly understood, though a complex mixture of neurotransmitter effects is suspected. Given its association with extrapyramidal side effects such as dystonia and parkinsonism, akathisia is suspected to be secondary to antipsychotic-related dopamine type 2 receptor downregulation and acetylcholine upregulation in basal ganglia regions. Given the effective treatment response to beta blockers, the adrenergic system is likely involved as well. GABAergic mechanisms possibly play a role, and neurosteroids have been implicated. Serotoninergic drugs can exacerbate akathisia. The pathophysiologies of acute akathisia and tardive akathisia may differ in that neuroleptics worsen the former and tend to be less distressing in the latter.
• •In addition to antipsychotics, akathisia has been associated with calcium channel blockers, antiemetics, antimigraine agents, antivertigo drugs, antidepressants (selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors), and sedatives used in anesthesia. Akathisia has also been noted to occur following acute intoxication of stimulants (e.g., cocaine, methamphetamine) and during withdrawal from alcohol, benzodiazepines, barbiturates, or opiates.

 Diagnosis

Differential Diagnosis

Akathisia is often underdiagnosed because symptoms often mimic or overlap other psychiatric disorders such as psychosis, mania, attention deficit hyperactivity disorder (ADHD), or agitated depression. Agitation is transdiagnostic, occurring in psychoses, affective disorders, anxiety disorders, restless legs syndrome, insomnia, and substance intoxication/withdrawal. Thus, it is important to obtain a complete medical history and rule out other psychiatric disorders as in the below table.

TABLE

•Agitation secondary to multiple psychiatric conditions •Attention deficit hyperactivity disorder •Antipsychotic-induced dysphoria •Restless legs syndrome •Tardive dyskinesia •Substance intoxication/withdrawal •Insomnia •Neuropsychiatric disorders including catatonic excitement, traumatic brain injury, delirium, encephalitides, hypoglycemia, central nervous system autoimmune diseases •Neurodegenerative disorders including dementia, Parkinson’s disease, Huntington disease

Workup

The Barnes Akathisia Rating Scale or another akathisia scale may be used to assess patients with akathisia. However, most clinicians will rely on clinical observation.

Laboratory Tests

There are no discriminatory laboratory tests involved in the diagnosis of akathisia. A toxicology test can be useful to rule out substance intoxication/withdrawal.

Imaging Studies

There are no discriminatory radiographic tests involved in the diagnosis of akathisia.

Treatment

The most reliable treatment for acute akathisia is the reduction or the withdrawal of antipsychotic medication. However, this is often not possible because of the patient’s mental condition. Use of adjunctive medications that dampen akathisia can be helpful.

TABLE

•Beta-adrenergic antagonists (e.g., propranolol: Initiate at low doses 10 mg TID with titration up every few days to a maximum of 90-120 mg/day) •Benzodiazepines (e.g., lorazepam 1.5-3 mg/day in divided doses or clonazepam 0.5 mg/day) •Anticholinergics (e.g., benztropine 2 mg/day if other EPS in addition to akathisia) •5-HT2A antagonist (e.g., cyproheptadine 16 mg/day)•Alpha-2-adrenergic agonists (e.g., clonidine 0.2-0.8 mg/day) •Noradrenergic and specific serotonergic antidepressant (e.g., mirtazapine 7.5-15 mg/day; do not use higher dose that increases noradrenergic action) •NMDA antagonist/indirect dopamine agonist (e.g., amantadine, 100 mg BID-TID)

Complementary & Alternative Medicine

If anxiety and stress are major contributors to subjective complaints, mind-body approaches such as relaxation breathing, meditation, or progressive muscle relaxation can be tried.

Disposition

Patients can generally be managed in psychiatric and neurologic outpatient care, unless a thorough safety assessment reveals that patient would benefit from higher level of care.

Referral

Once the diagnosis of akathisia is made, the patient should be referred to a psychiatrist or a neurologist. Making decisions on the medications can be challenging because most patients rely on antipsychotics for their mental health condition.

 Pearls & Considerations

• •It may be difficult to determine whether a patient is experiencing akathisia, anxiety, or agitation.
• •Early identification and management are important as akathisia may be associated with treatment nonadherence or increased safety risk.
• •Antipsychotic-induced akathisia may be managed by reducing the dose of the offending agent or switching to an alternative antipsychotic agent.
• •Beta-blockers (e.g., propranolol) and benzodiazepines have historically been used.
• •Anticholinergic agents such as benztropine may be used if concomitant parkinsonism is present.

Prevention

As a medication side effect, prevention is the best approach to minimizing akathisia. Knowledge of past medication effects is essential. Strict adherence to standard titration and dose schedules, recognition of drug-drug interaction challenges, and preference for second generation antipsychotic medications all aid in akathisia prevention.

Patient & Family Education

Patient education is essential. It should include open discussion of benefits and risks of medications. Time of onset, duration of symptoms, other treatment options, and need to call parameters are important topic areas. Clear discussion of the therapeutic strategies that can be helpful if akathisia emerges should be discussed. Establishment of a trusting relationship is important to navigate treatment of akathisia.

Suggested Readings

• Alkhater R.A., et al.: PI4K2A deficiency in an intellectual disability, epilepsy, myoclonus, akathisia syndrome. Ann Clin Transl Neurol 2018; 5 (12): pp. 1617-1621.
• Medication-Induced Movement Disorders and Other Adverse Effects of Medication. Diagnostic and statistical manual of mental disorders. DSM Library. 2013. American Psychiatric Association,
• Salem H., et al.: Revisiting antipsychotic-induced akathisia: current issues and prospective challenges. Curr Neuropharmacol 2017; 15 (5): pp. 789-798.