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Akathisia (IPA: /æ.kə.ˈθɪ.si.ə/) is a
movement disorder Movement disorders are clinical syndromes with either an excess of movement or a paucity of voluntary and involuntary movements, unrelated to weakness or spasticity. Movement disorders present with extrapyramidal symptoms and are caused by basa ...
characterized by a subjective feeling of inner restlessness accompanied by mental distress and/or an inability to sit still. Usually, the legs are most prominently affected. Those affected may fidget, rock back and forth, or pace, while some may just have an uneasy feeling in their body. The most severe cases may result in poor adherence to medications, exacerbation of psychiatric symptoms, and, because of this, aggression, violence, and/or suicidal thoughts. Akathisia is also associated with threatening behaviour and physical aggression in mentally disordered patients. However, the attempts to find potential links between akathisia and emerging suicidal or homicidal behaviour were not systematic and were mostly based on a limited number of case reports and small case series. Apart from these few low-quality studies, there is another more recent and better quality study (a systematic review from 2021) that concludes akathisia cannot be reliably linked to the presence of suicidal behavior in patients treated with antipsychotic medication. Antipsychotic medication, particularly the first generation antipsychotics, are a leading cause. Other agents commonly responsible for this side-effect may also include selective serotonin reuptake inhibitors,
metoclopramide Metoclopramide is a medication used to treat nausea, vomiting, gastroparesis, and gastroesophageal reflux disease. It is also used to treat migraine headaches. Common side effects include feeling tired, diarrhea, akathisia, and tardive dyski ...
, and
reserpine Reserpine is a drug that is used for the treatment of hypertension, high blood pressure, usually in combination with a thiazide diuretic or vasodilator. Large clinical trials have shown that combined treatment with reserpine plus a thiazide diur ...
, though any medication listing agitation as a side effect may trigger it. It may also occur upon stopping antipsychotics. The underlying mechanism is believed to involve
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
. When antidepressants are the cause, there is no agreement regarding the distinction between
activation syndrome In chemistry and biology, activation is the process whereby something is prepared or excited for a subsequent reaction. Chemistry In chemistry, "activation" refers to the reversible transition of a molecule into a nearly identical chemical or ...
from akathisia. Akathisia is often included as a component of activation syndrome. However, the two phenomena are not the same since the former, namely antipsychotic-induced akathisia, suggests a known neuroreceptor mechanism (e.g., dopamine-receptor blockade). Diagnosis is based on the symptoms. It differs from restless leg syndrome in that akathisia is not associated with sleeping. However, despite a lack of historical association between restless leg syndrome and akathisia, this does not guarantee that the two conditions do not share symptoms in individual cases. If akathisia is caused by an antipsychotic, treatment may include switching to an antipsychotic with a lower risk of the condition. The
antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...
mirtazapine Mirtazapine, sold under the brand name Remeron among others, is an atypical antidepressant, atypical tetracyclic antidepressant, and as such is used primarily to treat Depression (mood), depression. Its effects may take up to four weeks but ca ...
, although paradoxically associated with the development of akathisia in some individuals, has demonstrated benefit, as have
diphenhydramine Diphenhydramine, sold under the brand name Benadryl among others, is an antihistamine and sedative. Although generally considered sedating, diphenhydramine can cause paradoxical central nervous system stimulation in some individuals, particula ...
, trazodone, benzatropine, cyproheptadine, and beta blockers, particularly
propranolol Propranolol is a medication of the beta blocker class. It is used to treat hypertension, high blood pressure, some types of cardiac dysrhythmia, irregular heart rate, thyrotoxicosis, capillary hemangiomas, akathisia, performance anxiety, and ...
. The term was first used by Czech neuropsychiatrist Ladislav Haškovec, who described the phenomenon in 1901 long before the discovery of antipsychotics, with drug-induced akathisia first being described in 1960. It is from Greek ''a-'', meaning "not", and ''kathízein'', meaning "to sit", or in other words an "inability to sit".


Classification

Akathisia is usually classified as a medication-induced
movement disorder Movement disorders are clinical syndromes with either an excess of movement or a paucity of voluntary and involuntary movements, unrelated to weakness or spasticity. Movement disorders present with extrapyramidal symptoms and are caused by basa ...
. It can also be considered a neuropsychiatric concern, however, as it can be experienced purely subjectively without apparent movement abnormalities. Akathisia is generally associated with antipsychotics, but was previously described in
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
and other neuropsychiatric disorders. It can also present with the use of non-psychiatric medications, including calcium channel blockers,
antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...
s, anti-nausea and anti-vertigo drugs.


Signs and symptoms

Symptoms of akathisia are often described in vague terms, such as feeling nervous, uneasy, tense, twitchy, restless, and unable to relax. Reported symptoms also include
insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...
, a sense of discomfort, motor restlessness, marked anxiety, and panic. Symptoms have also been said to resemble symptoms of
neuropathic pain Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuo ...
similar to
fibromyalgia Fibromyalgia (FM) is a functional somatic syndrome with symptoms of widespread chronic pain, accompanied by fatigue, sleep disturbance including awakening unrefreshed, and Cognitive deficit, cognitive symptoms. Other symptoms can include he ...
and restless legs syndrome. When caused by psychiatric drugs, akathisia usually disappears quickly once the medication is reduced or stopped. However, late-onset akathisia, or ''tardive akathisia,'' may persist for months or years after the medication is discontinued. When misdiagnosis occurs in antipsychotic-induced akathisia, more antipsychotics may be prescribed, potentially worsening the symptoms. If not identified, akathisia symptoms can increase in severity and lead to suicidal thoughts, aggression and violence. Visible signs of akathisia include repetitive movements, such as crossing and uncrossing the legs and constant shifting from one foot to the other. Other noted signs include rocking back and forth, fidgeting, and pacing. However, not all observable restless motion is akathisia. For example, while
mania Mania, also known as manic syndrome, is a Psychiatry, psychiatric Abnormality (behavior), behavioral syndrome defined as a state of Abnormality (behavior), abnormally elevated arousal, affect (psychology), affect, and energy level. During a mani ...
, agitated depression, and
attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...
may present like akathisia, movements resulting from them feel voluntary, rather than being due to restlessness. Jack Henry Abbott, who was diagnosed with akathisia, described the sensation in 1981 as: "You ache with restlessness, so you feel you have to walk, to pace. And then as soon as you start pacing, the opposite occurs to you; you must sit and rest. Back and forth, up and down you go … you cannot get relief …"


Causes


Medication-induced

Medication-induced akathisia is termed ''acute akathisia'' and is frequently associated with the use of
antipsychotic Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...
s. Antipsychotics block dopamine receptors, but the pathophysiology is poorly understood. Even so, drugs with successful therapeutic effects in the treatment of medication-induced akathisia have provided additional insight into the involvement of other transmitter systems. These include
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...
s, β-adrenergic blockers, and serotonin antagonists. Another major cause of the syndrome is the withdrawal observed in drug-dependent individuals. Akathisia involves increased levels of the neurotransmitter
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...
, which is associated with mechanisms that regulate
aggression Aggression is behavior aimed at opposing or attacking something or someone. Though often done with the intent to cause harm, some might channel it into creative and practical outlets. It may occur either reactively or without provocation. In h ...
, alertness, and arousal. It has been correlated with
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
and related syndromes, with descriptions of akathisia predating the existence of pharmacologic agents. Akathisia can be miscoded in side effect reports from antidepressant clinical trials as "agitation, emotional lability, and hyperkinesis (overactivity)"; misdiagnosis of akathisia as simple motor restlessness occurred, but was more properly classed as dyskinesia.


Diagnosis

The presence and severity of akathisia can be measured using the Barnes Akathisia Scale, which assesses both objective and subjective criteria. Precise assessment of akathisia is problematic, as there are various types making it difficult to differentiate from disorders with similar symptoms. The primary distinguishing features of akathisia in comparison with other syndromes are primarily subjective characteristics, such as the feeling of inner restlessness and tension. Akathisia can commonly be mistaken for agitation secondary to psychotic symptoms or
mood disorder A mood disorder, also known as an affective disorder, is any of a group of conditions of mental and behavioral disorder where the main underlying characteristic is a disturbance in the person's mood. The classification is in the ''Diagnostic ...
, antipsychotic dysphoria, restless legs syndrome, anxiety,
insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...
,
drug withdrawal A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...
states, tardive dyskinesia, or other neurological and medical conditions. The controversial diagnosis of "pseudoakathisia" is sometimes given.


Treatment

Acute akathisia induced by medication, often antipsychotics, is treated by reducing or discontinuing the medication. Low doses of the
antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...
mirtazapine Mirtazapine, sold under the brand name Remeron among others, is an atypical antidepressant, atypical tetracyclic antidepressant, and as such is used primarily to treat Depression (mood), depression. Its effects may take up to four weeks but ca ...
may be of help. Biperiden, an antipsychotic antidote, commonly used to improve acute extrapyramidal side effects related to antipsychotic drug therapy, is also used to treat akathisia.
Benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...
s, such as
lorazepam Lorazepam, sold under the brand name Ativan, Tavor among others, is a benzodiazepine medication. It is used to treat anxiety (including anxiety disorders), insomnia, severe agitation, active seizures including status epilepticus, alcoh ...
;
beta blocker Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms ( arrhythmia), and to protect the heart from a second heart attack after a first heart attack ( secondary prevention ...
s such as
propranolol Propranolol is a medication of the beta blocker class. It is used to treat hypertension, high blood pressure, some types of cardiac dysrhythmia, irregular heart rate, thyrotoxicosis, capillary hemangiomas, akathisia, performance anxiety, and ...
;
anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central nervous system, central and peripheral nervous system. These agents inhibit the parasympatheti ...
s such as benztropine; and serotonin antagonists such as cyproheptadine may also be of help in treating acute akathisia but are much less effective for treating chronic akathisia. Vitamin B, and iron supplementation if deficient, may be of help. Although they are sometimes used to treat akathisia, benzodiazepines and antidepressants can actually cause akathisia.


Epidemiology

Approximately one out of four individuals treated with first-generation antipsychotics have akathisia. Prevalence rates may be lower for modern treatment as second-generation antipsychotics carry a lower risk of akathisia. In 2015, a French study found an overall prevalence rate of 18.5% in a sample of outpatients with schizophrenia.


History

The term was first used by Czech neuropsychiatrist Ladislav Haškovec, who described the phenomenon in a non-medication induced presentation in 1901. Reports of medication-induced akathisia from
chlorpromazine Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar d ...
appeared in 1954. Later in 1960 there were reports of akathisia in response to phenothiazines (a related drug). Akathisia is classified as an extrapyramidal side effect along with other movement disorders that can be caused by antipsychotics. In the former
Soviet Union The Union of Soviet Socialist Republics. (USSR), commonly known as the Soviet Union, was a List of former transcontinental countries#Since 1700, transcontinental country that spanned much of Eurasia from 1922 until Dissolution of the Soviet ...
, akathisia-inducing drugs were allegedly used as a form of torture. Haloperidol, an antipsychotic medication, was used to induce intense restlessness and Parkinson's-type symptoms in prisoners. In 2020
clinical psychologist Clinical psychology is an integration of human science, behavioral science, theory, and clinical knowledge for the purpose of understanding, preventing, and relieving psychologically-based distress or dysfunction and to promote subjective well ...
and professor of
psychology Psychology is the scientific study of mind and behavior. Its subject matter includes the behavior of humans and nonhumans, both consciousness, conscious and Unconscious mind, unconscious phenomena, and mental processes such as thoughts, feel ...
Jordan Peterson was diagnosed with akathisia after being treated for insomnia and depression with
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...
s that was associated with an autoimmune disorder and was subsequently treated in Russia.Mikhaila Peterson's Response to The Times Article (and subsequent articles)
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See also

* Stimming


Notes


References


External links

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