Akathisia

Akathisia is a movement disorder characterized by a feeling of inner restlessness and a compelling need to be in constant motion, as well as by actions such as rocking while standing or sitting, lifting the feet as if marching on the spot, and crossing and uncrossing the legs while sitting. People with akathisia are unable to sit or keep still, complain of restlessness, fidget, rock from foot to foot, and pace.^[1]

The term was coined by the Czech neuropsychiatrist Ladislav Haskovec (1866–1944), who described the phenomenon in 1901.^[2][3]

Antipsychotics (also known as neuroleptics), particularly the first generation antipsychotics, may cause akathisia. Other known causes include side effects of certain medications, and nearly any physical dependence-inducing drug during drug withdrawal.^[4] It is also associated with Parkinson's disease and related syndromes.^[5] The term is from Greek καθίζειν kathízein – "to sit", a- indicating negation or absence, lit. "inability to sit".

Signs and symptoms

Akathisia may range in intensity from a sense of disquiet or anxiety, to excruciating discomfort, particularly in the knees. Patients typically pace for hours because the pressure on the knees reduces the discomfort somewhat; once their knees and legs become fatigued and they are unable to continue pacing, they sit or lie down, although this does not relieve the akathisia. At high doses or with potent drugs such as haloperidol (Haldol) or chlorpromazine (Thorazine/Largactil), the feeling can last all day from awakening to sleep. When misdiagnosis occurs in antipsychotic neuroleptic-induced akathisia, more antipsychotic neuroleptics may be prescribed, potentially worsening the symptoms.^[5] High-functioning patients have described the feeling as a sense of inner tension and torment or chemical torture. A term many sufferers use is the feeling like they want to "peel off their own skin." It feels like an agitated depression. This is problematic for many patients and doctors because many don't realize this is a drug-induced state; they simply write off the symptoms as a worsening of their mental illness or condition. The treatment for many doctors, then, is to raise the dose of the akathisia-causing medication. When the patient's condition gets even worse, they prescribe anti-anxiety medication, which are usually ineffective in mitigating the anxiety caused by akathisia, since the anxiety produced by the condition is generated in a different part of the brain than regular anxiety. Many patients show very little outer movement, and the akathisia affects the sufferer inside, causing feelings of despair, agitation, intense panic and worry, an augur of disaster that feels completely real, and in some cases, the person actually has a physical sensation of pain in the solar plexus area of the body that they claim feels hot to the touch, a burning ache that is unbearable. Neuro-psychologist Dr. Dennis Staker had drug-induced akathisia for two days. His description of his experience was this: "It was the worst feeling I have ever had in my entire life. I wouldn't wish it on my worst enemy." Many patients describe symptoms of neuropathic pain akin to fibromyalgia and restless legs syndrome.^[6] In Han et al. (2013), the authors describe restless legs syndrome's relation to akathisia, "Some researchers regard RLS as a 'focal akathisia' [in the legs]."^[7] Although these side effects disappear quickly and remarkably when the medication is stopped, tardive, or late-persisting akathisia may go on long after the offending drug is discontinued, sometimes for a period of years. Healy, et al. (2006), described the following regarding akathisia: tension, insomnia, a sense of discomfort, motor restlessness, and marked anxiety and panic. Increased labile affect can result, such as weepiness.^[8]

Severe akathisia can become a very harrowing experience. Jack Henry Abbot (1981) describes the sensation:^[9]

...[It comes] from so deep inside you, you cannot locate the source of the pain … The muscles of your jawbone go berserk, so that you bite the inside of your mouth and your jaw locks and the pain throbs. … Your spinal column stiffens so that you can hardly move your head or your neck and sometimes your back bends like a bow and you cannot stand up. … 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 …

In a psychiatric setting, patients who suffer from neuroleptic-induced akathisia often react by refusing treatment.^[10]

Causes

Pathophysiological

Han et al. (2013)^[7] reported that upon examination of three patients who experienced abrupt onset of restlessness characteristic of akathisia and RLS, magnetic resonance imaging of the brain revealed pontine ischemia (lack of blood to the pons area of the brain) potentially leading to infarction - the death of oxygen-starved tissue. Han et al. wrote, "The features of our three patients suggest that RLS and akathisia may have a common pathophysiological mechanism related to the pontine region of the brain."^[7]

Drug-induced

Akathisia is frequently associated with the use of dopamine receptor antagonist antipsychotic drugs.^[11] Understanding is still limited on the pathophysiology of akathisia, but it is seen to be associated with medications which block dopaminergic transmission in the brain. Additionally, 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 benzodiazepines, β-adrenergic blockers, and serotonin antagonists.^[11] Another major cause of the syndrome is the withdrawal observed in dependent individuals. Since dopamine deficiency (or disruptions in dopamine signalling) appears to play an important role in the development of RLS, the sudden withdrawal or rapidly decreased dosage of drugs which increase dopamine signalling may create similar deficits of the chemical which mimic dopamine antagonism and thus can precipitate RLS. This is why sudden cessation of opioids, cocaine, serotonergics, and other euphoria-inducing substances commonly produce RLS as a side-effect.^[4][11]

It has been correlated with Parkinson's disease and related syndromes.^[5] It is unclear, however, whether this is due more to Parkinson's or the drugs used to treat it, such as carbidopa/levodopa (levocarb).^[12]

Antidepressants can also induce the appearance of akathisia, due to increased serotonin signalling within the central nervous system. This also explains why serotonin antagonists are often a very effective treatment.^{[13][14][15][16]} The 2006 UK study by Healy et al. observed that akathisia is often miscoded in antidepressant clinical trials as "agitation, emotional lability, and hyperkinesis (overactivity)".^[8] The study further points out that misdiagnosis of akathisia as simple motor restlessness occurs, but that this is more properly classed as dyskinesia.

It was discovered that akathisia involves increased levels of the neurotransmitter norepinephrine, which is associated with mechanisms that regulate aggression, alertness, and arousal.^[17]

The table below summarizes factors that can induce akathisia, grouped by type, with examples or brief explanations for each:

Diagnosis

The presence and severity of akathisia can be measured using the Barnes Akathisia Scale,^[21][22] which assesses both objective and subjective criteria.^[21] Precise assessment of akathisia is problematic, as it is difficult to differentiate from a multitude of disorders with similar symptoms. In a study of movement disorders induced by neuroleptics, akathisia was found in only 26% of patients originally diagnosed with akathisia.^[10] The primary distinguishing features of akathisia in comparison with other syndromes are primarily subjective characteristics, such as the feeling of inner restlessness.^[23] Akathisia can commonly be mistaken for agitation secondary to psychotic symptoms or mood disorder, antipsychotic dysphoria, restless legs syndrome (RLS), anxiety, insomnia, drug withdrawal states, tardive dyskinesia, or other neurological and medical conditions.^[11]

Additionally, the controversial diagnosis of "pseudoakathisia" is given, as noted by Mark J. Garcia. In his article discussing akathisia among adults with severe and profound intellectual disability, he describes pseudoakathisia as "comprising all the symptoms of abnormal movements seen with akathisia, but without a sense of restlessness".^[24]

Classification

Treatment

Akathisia is sometimes reversible once the causative agent has been identified and discontinued, but in some cases may become permanent.^[25] Case reports and small randomized studies suggest benzodiazepines, propranolol, and anticholinergics may help treat acute akathisia, but are much less effective in treating chronic akathisia.^[26] Taylor et al. found success in lowering the dose of antipsychotic medication as an initial response to drug-induced akathisia,^[24] which should be done gradually, if possible.^[26] To minimize the risk of akathisia from antipsychotics, the clinician is advised to be conservative when increasing dosages.^[24]

If the patient is experiencing akathisia due to opioid withdrawal, and continuing use of opioids is not viable, drugs typically prescribed for acute idiopathic akathisia can be effective. GABA analogues pregabalin and gabapentin, as well as drugs approved for treating RLS, may also be effective in certain cases.

One study showed vitamin B₆ to be effective for the treatment of neuroleptic-induced akathisia.^[27]

N-acetylcysteine also showed a positive effect on akathisia in a randomized control trial.^[28]

Additional pharmacologic interventions found to have antiakathisia effects (especially for neuroleptic-induced akathisia) include ß-adrenergic antagonists (e.g., propranolol), benzodiazepines (e.g., lorazepam), anticholinergics (e.g., benztropine), and serotonin antagonists (e.g., cyproheptadine) as an alternative.^[11]

Trihexyphenidyl has also been prescribed to treat akathisia.

Epidemiology

Published epidemiological data for akathisia are mostly limited to treatment periods preceding the arrival of second-generation antipsychotics.^[26] Sachdev (1995)^[29] reported an incidence rate of acute akathisia of 31% for 100 patients treated for 2 weeks with antipsychotic medications. Sachdev (1995) reported a prevalence range from 0.1% to 41%.^[29] In all likelihood, rates of prevalence are lower for current treatment as second-generation antipsychotics carry a lower risk of akathisia.^[26]

References