Akathisia is a common adverse effect of treatment with antipsychotics, with an incidence of 5 to 50% depending on the duration of treatment and the drug used.
Although most commonly seen with dopamine D2 receptor antagonists, it can also complicate treatment with other psychiatric drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), mirtazapine, and dopamine D2 receptor antagonists. vesicular monoamine transporter 2 (VMAT2) that reduce dopamine and other monoamine neurotransmitters.
Akathisia is a side effect of psychiatric drugs, but can also occur from opioid or stimulant withdrawal and rarely from traumatic brain injury or stroke. It is described as an intense feeling of inner restlessness accompanied by a need to constantly remain in motion. It is usually accompanied by intense dysphoria that worsens when voluntarily remaining still.
The underlying mechanism is inhibition of dopaminergic neurotransmission in the nigrostriatal pathway for acute events, while tardive dyskinesia has been attributed to D2 receptor upregulation and subsequent dopamine hypersensitivity following prolonged exposure to D2 antagonists. It has a strong subjective component and can cause significant distress even in the absence of typical motor symptoms.
Pseudoakathisia is defined as the presence of behavior typical of akathisia in the absence of the subjective component. Akathisia is considered acute if it lasts ≤ 3 months, chronic if it lasts ≥ 3 months, and late if it occurs after long-term treatment.
It occurs after ≥ 2 weeks after starting neuroleptic treatment or increasing doses of drugs with a long half-life (aripirpazol, cariprazine). Drugs that reach therapeutic concentrations after a single dose (haloperidol, risperidone) can induce akathisia within a few hours of starting treatment or adjusting the dose. The objective of this article is to review the presentation, pathophysiology and management of akathisia.
| Presentation and differential diagnosis of akathisia |
The presentation of akathisia is different from that of restless legs syndrome (RLS), although the pathophysiology is similar. RLS presents as a feeling of discomfort in the legs and an overwhelming urge to move them, which is worse at night and disturbs sleep.
Akathisia affects the entire body, is associated with intense dysphoria and symptoms that are constant all day.
It can dissipate completely during sleep, although there are usually frequent awakenings. It is common with high doses of certain neuroleptics (aripiprazole, haloperidol, lurasidone).
Akathisia may be misdiagnosed as agitation depending on the underlying psychiatric condition for which a drug was initially prescribed. In patients chronically exposed to neuroleptics it may be masked by an extrapyramidal syndrome (EPS), so it is important to investigate the subjective component.
An atypical presentation may be seen in patients who experience intense restlessness while physically unable to move (due to pre-existing disability or mechanical restraint); is a state of unfathomable torment observed when a high-potency antipsychotic (haloperidol) is administered as monotherapy for the management of acute agitation.
Any D2 receptor antagonist substance can cause akathisia, some more likely than others.
Haloperidol causes akathisia along with full spectrum EPS, a property it shares with higher potency antipsychotics (fluphenazine, trifluoperazine, flupenthixol, benperidol, pimozide), while lower potency antipsychotics are more likely to cause akathisia than EPS when administered. They use low doses. This is particularly important for levomepromazine, which is used at low doses as a sedative, potentiator of opioid analgesics, and to prevent opioid-induced nausea and vomiting.
Despite its anticholinergic, antiadrenergic and antisertotonergic properties, it can cause akathisia that can be misdiagnosed as delirium. Clozapine and quetiapine can also cause it, although the risk is lower. The antipsychotic least likely to induce akathisia is iloperidone, which has an extremely high affinity for α1 adrenergic receptors.
| Observations on the pathophysiology of akathisia |
The mechanisms underlying akathisia are more complex than the simple inhibition of D2-mediated nigrostriatial signaling involved in other forms of EPS. The bodies of the dopaminergic neurons involved are located in the ventral tegmental area, which projects to the limbic system through the nucleus accumbens.
Various animal models support the hypothesis that antipsychotics induce an imbalance between noradrenergic and dopaminergic neurotransmission. Overactivation of noradrenergic neurons leads to b1 adrenergic receptor-mediated activation of the amygdala and nucleus accumbens cortex, resulting in movements and intense dysphoria.
Under normal conditions, both the cortex and the center of the nucleus accumbens are innervated by dopaminergic neurons from the ventral tegmental area, which control behavior by inhibiting inhibitory GABAergic neurons that project to the limbic system and the cortex, but in the presence of antipsychotics the cortex becomes hyperactive. due to its noradrenergic innervation.
This response can be attenuated by b1 antagonists or a2 agonists such as clonidine, which reduce norepinephrine release by activating inhibitory autoreceptors in locus coeruleus neurons. This mechanism could explain the effectiveness of sympatholytic drugs such as beta blockers and clonidine in the treatment of akathisia.
Neurons in the ventral tegmental area receive serotonergic inhibitory pathways from the dorsal raphe nucleus, which explains why 5-HT2A and 5-HT2C antagonists induce dopamine release in the mesocorticolimbic pathway. This may be the underlying mechanism for akathisia induced by serotonergic drugs such as SSRIs, which may be distinct from akathisia induced by D antagonists.
Although the incidence of acute akathisia appears to be ubiquitous with certain drugs, the intensity of symptoms appears to decrease over time as the condition becomes chronic. This would explain the low incidence of akathisia in crossover studies, since patients with constant exposure to antipsychotics may have stable chronic akathisia that is not significantly affected by switching to another drug.
| Clinical management of akathisia |
The first step in treating akathisia is to identify the causative agent and, if possible, discontinue treatment immediately.
It must be considered that akathisia, especially as an adverse effect of antidepressant treatment, is associated with suicide and aggression. Any antipsychotic prescribed off-label to augment antidepressant treatment should be discontinued and short-term pharmacological treatment for akathisia should be offered.
In cases in which treatment with neuroleptics is absolutely indicated, it is recommended to prescribe antipsychotics at the lowest dose that controls symptoms well. High doses of neuroleptics can cause or exacerbate akathisia in anyone, but this is increased with the use of typical high-potency agents, rapid dose titration, younger age, and lack of prior exposure to antipsychotics. Clozapine, quetiapine, and iloperidone are less likely to cause akathisia, although it may occur in some patients.
The first-line treatment is propranolol, a prototypical non-selective β-blocker. It lacks intrinsic sympathetic activity, and is prescribed at 40-120 mg/day. Its action does not appear to be dose dependent, and the response is often partial, in which case a further dose reduction of the causative agent or addition of another drug for akathisia may be needed.
Anticholinergic drugs (biperiden, trihexyphenidyl, benztropine, diphenhydramine) are used together with antipsychotics to minimize their adverse effects and improve treatment adherence. They are the first-line treatment for EPS and are prescribed together when using high doses of agents with a high probability of inducing it (haloperidol, fluphenazine). They are very effective for acute dystonia, but less so for neuroleptic-induced parkinsonism. Its benefit in akathisia is not entirely clear.
Serotonergic antagonists, specifically mirtazapine at low doses (7.5-15 mg/day) and trazodone (50-100 mg/day), are effective for akathisia induced by typical antipsychotics with negligible affinity for 5-HT2A and 5-HT2A receptors. HT2C.
Antagonism of these receptors may attenuate akathisia by promoting dopamine release in the mesocorticolimbic pathway. Akathisia is commonly seen with antipsychotics that saturate 5-HT2 receptors throughout their clinical dosing range, such as risperidone, ziprasidone, and olanzapine.
Benzodiazepines are the final first-line treatment for akathisia, as they provide important symptomatic relief due to their sedative and anxiolytic action. They may be especially helpful for patients with severe symptoms that negatively affect sleep.
There may be a risk of paradoxical disinhibition in young and elderly adults, which decreases with the use of an antipsychotic. The lowest appropriate dose should be used for the shortest duration possible due to the potential for physical dependence, cognitive impairment, and delirium.
Recent reports suggest that gabapentin and its analogue gabapentin enacarbil may be effective in akathisia, in addition to being a first-line treatment for RLS. Pregabalin may also be effective.
If there were more solid evidence to support their effectiveness, they would be recommended as first-line treatment since they are safer than propranolol and benzodiazepines, they have no organic contraindications, dependence and withdrawal reactions are mild, they are not associated with paradoxical disinhibition and Its potential for abuse is limited. Because they are safe for long-term use, they are particularly attractive for the treatment of late akathisia, although prolonged treatment at high doses may be required.
Amantadine, an NMDA antagonist indicated for early stages of Parkinson’s disease, should be considered as a possible adjunctive treatment, although its physical toxicity and psychotomimetic effects require caution. Dopamine agonists are generally not indicated as they may exacerbate psychosis.
D2 receptors tend to be upregulated after prolonged exposure to antipsychotics and other D2 antagonists, and this compensatory mechanism may favor both the development of tardive dyskinesia and increased sensitivity to the psychotomimetic effects of dopamine agonists. This option may be considered if the problem neuroleptic has been discontinued and akathisia persists despite treatment with first-line drugs, despite the substantial risk of hypersensitivity psychosis.
Mu opioid receptor agonists may be considered as a last resort in the pharmacological management of acute akathisia and are an option to consider in hospitalized or nursing home patients who do not respond adequately to other treatments.
| Conclusions |
Akathisia is one of the most common adverse effects of antipsychotic drugs and the one most likely to be involved in treatment discontinuation and adverse clinical outcomes.
Although it can be managed with the use of other drugs, the best option is usually to discontinue the offending agent.
Its management is challenging as it can persist after stopping antipsychotics, requiring prolonged treatment to achieve symptomatic relief. Furthermore, in the long term, abrupt or even gradual discontinuation of the antipsychotic has significant risks due to D2 receptor upregulation and the risk of rebound psychosis.
