Acute akathisia

Figure 1.1

Schematic proposal of pathways comparing normal (A) to akathisia (B). Reduced dopaminergic stimulation from the ventral tegmental area (VTA) may create unopposed stimulation of the pathway from the locus coeruleus to the surface portion of the nucleus accumbens. Thickness of arrows represent strength of input. Increased thickness of the serotonin input in bottom right corner of figure (B) exclusively relates to possible explanation of selective serotonin reuptake inhibitors (SSRI)-induced akathisia. Blue arrows = noradrenergic, Green arrows = glutamatergic, Red arrows = serotonergic, Black arrows = dopaminergic.


Figure adapted from 11,86.


The existence of SSRI-induced akathisia suggests that the serotoninergic system is also involved. The role of 5-HT2 receptors in the pathophysiology of akathisia is supported by the presence of these receptors in the VTA, the response of akathisia to 5HT2A antagonists, and treatment failure of buspiron, a 5-HT1a partial agonist, and granisetron, a 5-HT3 receptor antagonist (see treatment section below).14,15 The dorsal raphe nucleus has serotonergic projections directly to the basal ganglia inhibiting dopaminergic neurons, potentially via 5-HT2 receptors. The midbrain raphe nuclei also projects inhibitory serotonergic input to the VTA and substantia nigra. Studies evaluating SSRI-induced inhibition of the dopamine system have provided inconsistent results. This may relate to the varying distribution of different serotonin receptors in the midbrain and basal ganglia.




Etiologies


Akathisia is most often iatrogenic, caused by antipsychotic medications, but also by SSRI antidepressants. Medication-induced acute akathisia typically begins within hours of administering the offending drug but may be delayed up to several days after initiation, during escalation of treatment, or upon switching to a more potent dopamine receptor blocking agent. There are several other etiologies of acute akathisia that have also been reported (see Table 1.1).



Table 1.1 Etiologies of acute akathisia












Medications:


Antipsychotics (including metoclopramide, prochlorperazine & droperidol)



SSRI antidepressants



Mood stabilizers (lithium)



Catecholamine-depleting agents (tetrabenazine & reserpine)



Antiepileptics (carbamazepine, ethosuximide, gabapentin & pregabalin*)



Calcium channel blockers and antihistamines (flunarizine, cinnarizine)



Calcium channel blocker (diltiazem)*

Toxic:


Central stimulants (amphetamine and cocaine)*

Neurodegenerative:


Parkinson’s disease



Spinocerebellar ataxia 3*



Wilson’s disease*

Structural


Traumatic brain injury*



Encephalitis*



Stroke*





* Case reports or series



Antipsychotics


Antipsychotics have been classified into two categories: first generation (typical) and second generation (atypical) antipsychotics. This classification system was originally developed partially by the pharmaceutical industry with the expectation that newer developed antipsychotics created in the 1990s would have less extrapyramidal adverse effects compared with the traditional first generation antipsychotics developed in the 1950s. First generation antipsychotics are potent dopamine D2 antagonists. In contrast, second generation antipsychotics, which are also D2 antagonists, are characterized by relatively low-affinity or rapid dissociation from D2 receptors and are potent antagonists of serotonin 5HT2A receptors (see Table 1.2).



Table 1.2 D2 receptor affinity of commonly used first and second generation antipsychotic medications divided into low, medium, and high potency


































































First Generation Second Generation
Low (8–16) High (1–4) Low (126–380) Medium (20) High (2–6)
Chlorpromazine Haloperidol Clozapine Olanzapine Risperidone
Levomepromazine Fluphenazine Quetiapine Paliperidone
Mesoridazine Loxapine Aripiprazole *
Periciazine Molindone Ziprasidone
Pipamperone Perphenazine Amisulpride
Thioridazine Pimozide Lurasidone
Thiothixene Iloperidone
Zuclopenthixol Cariprazine *


Ranges reported as Ki.




* denominate agonists


Second generation antipsychotics are thought to be less prone to cause extrapyramidal symptoms, including akathisia, due to lower affinity for D2 receptors, although clinical evidence is conflicting. However, they do have more antimuscarinic and antiadrenergic activity, resulting in greater sedation and hypotension compared with first generation antipsychotics. For example, the risk of akathisia with haloperidol, a first generation antipsychotic, may be as high as 75%, while it is approximately 5% with clozapine, a second generation antipsychotic.16 In a three arm double blind 8-week treatment study, akathisia developed in 19% and 22% of patients treated with second generation antipsychotics, olanzapine and risperidone, respectively, in comparison to 45% of patients treated with the first generation agent, molindone, with 18% of patients in this treatment arm reporting moderate to severe symptoms.17 Furthermore, in comparing medications within the second generation class, those with higher D2 affinity are more likely to cause akathisia. Certain D2 receptor blockers are used as antiemetics, particularly chlorpromazine and prochlorperazine. In the emergency department, the incidence of akathisia with these medications has been reported to be 44%.18


Acute akathisia is the most common important adverse effect of antipsychotics. The reported incidence of antipsychotic-induced akathisia (AIA) ranges greatly, from 8%–76%, but more conservative estimates utilizing clear subjective and objective findings report an incidence of 20%–30%.19 As noted above, accurate epidemiological data comes from studies using validated rating scales that include subjective and objective findings to consistently diagnose akathisia. Other causes of inaccurate prevalence estimates include the facts that patients are less inclined to spontaneously report milder symptoms to care providers, and symptoms of akathisia may be misinterpreted as psychiatric symptoms. In a study of 100 patients taking antipsychotics for two weeks, 40% developed mild akathisia that did not require a change in therapy. Moderate to severe symptoms necessitating change or reduction of medication were evident in 21% of patients.20


The CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study included 1493 patients with schizophrenia randomly assigned to receive ziprasidone (40–160mg/day), olanzapine (7.5–30mg/day), perphenazine (8–32mg/day), quetiapine (200–800mg/day), or risperidone (1.5–6mg/day) for up to 18 months. Surprisingly, this study did not demonstrate significant difference in the incidence of akathisia among the various treatment groups, which ranged from 5%–9%.21 The lack of difference between first and second generation antipsychotics in this study may partially be the effect of underreporting of mild symptoms (BARS score of 3) or maybe the fact that all subjects had been taking neuroleptics for long periods of time with only a short washout before enrolling in the study.


Several potential risks factors for the development of AIA have been reported. As previously noted, one of the greatest risks is increasing dosage or switching to more potent medications with greater D2 affinity. A number of studies have also identified an association between other extrapyramidal symptoms and the development of akathisia, indicating that they often occur together; but one does not necessarily predict the occurrence of the other. Patients with bipolar disorder may have twice the risk of developing AIA as patients with schizophrenia.22 Homozygosity for the Ser9Gly variant of the dopamine D3 receptor (DRD3) gene has been identified in eight of nine patients with schizophrenia and AIA.23 Interestingly, DRD3 receptors are mainly localized in mesolimbic brain regions and therefore may play a role in the pathogenesis of acute akathisia. In addition, the TaqI_D polymorphism in the DRD2 gene was significantly associated with akathisia in patients treated on antipsychotics. For each extra C-allele a 2.3% times higher risk of having akathisia was found.24


Results are inconsistent with respect to several other reported risk factors. Smoking tobacco has been proposed to be protective against akathisia; however, a study of 250 patients with schizophrenia failed to demonstrate any association between akathisia and heavy smoking.25 There is conflicting data regarding women having a potentially increased risk of AIA. Sandyk and Kay (1990) reported in schizophrenic hospitalized patients that akathisia was more common in women compared with men, although they did not separate acute and tardive akathisia.26 However, most epidemiology studies have failed to identify any significant gender difference in the occurrence of AIA. Age and race are not associated with akathisia.20 It is possible that low iron stores increase the risk of AIA. Several studies have been performed supporting this finding. Serum iron and ferritin levels were compared in 33 patients with AIA and 23 patients on antipsychotics without akathisia. Patients with AIA had significantly lower serum ferritin levels, although the differences were small and levels were within a normal range. There was no correlation between serum iron or ferritin levels and akathisia ratings.27 However, other studies contradict these findings. Two prospective studies failed to demonstrate any differences in serum iron and transferrin levels between patients with and without AIA.28


Below we will provide more detail on selected commonly prescribed second generation agents. Table 1.3 summarizes information on AIA induced by other second generation medications not discussed below.



Table 1.3 Summary miscellaneous second generation antipsychotic-induced akathisia

























































Medication Study Design Dosage Incidence Reference
Paliperidone Case Report 37.5mg biweekly 64
Aripiprazole RCT and case reports 2–24mg/day 23% 42,65,66
Ziprasidone RCT and case reports 80–160mg/day 36% 67,68
Amisulpride Prospective studies and case reports ~ 400mg/day 11% 69,70
Lurasidone RCT 20–120mg/day 11–24% 71,72
Iloperidone RCT 4–24mg/day 1–9% 73
Cariprazine RCT 1.5–4.5mg/day 10% 74


RCT = Randomized controlled trial


Clozapine – There are relatively few reports of AIA induced by clozapine. In one, hospitalized schizophrenic patients were enrolled in a double blind multicenter study aimed at comparing treatment with clozapine (N=75) to chlorpromazine (N=76). Akathisia occurred in comparable numbers of clozapine and chlorpromazine treated patients, 5 and 4, respectively. However, other extrapyramidal symptoms including rigidity, tremor, and dystonia were much less common in the clozapine treated group.29 In a nonrandomized, nonblinded study of patients with a variety of psychiatric disorders the prevalence of akathisia was 39% with clozapine compared with 45% in patients treated with miscellaneous antipsychotics. A greater number of patients taking first generation antipsychotics had severe akathisia.30 Selection bias was a limitation, as those treated with clozapine had more severe mental illness and often had previously failed conventional medications. In addition, the dose of clozapine was higher from other studies reporting a 7% incidence of akathisia.31 The majority of patients treated with clozapine had been previously tried on other antipsychotics and it is unclear whether this past exposure increases the risk of developing AIA.


Quetiapine – Overall, similar to clozapine, quetiapine is generally well tolerated with only case reports of akathisia that typically have resolved with reduction of dosage. Data combined from four randomized double blind 3-week to 12-week studies of 1003 patients with bipolar disorder indicated that extrapyramidal symptoms, including akathisia, were comparable between quetiapine and placebo.32 Furthermore, patients with AIA who switched from conventional antipsychotics to quetiapine (400–800mg/day) have reported resolution of symptoms.20


Olanzapine – A pooled analysis from four randomized, open label, parallel trials of 6 weeks in patients with schizophrenia compared olanzapine 5–20mg/day (N=77) to chlorpromazine 200–800mg/day (N=32). Akathisia was reported in 2.4% in the olanzapine and 10% of the chlorpromazine groups.33 Similar results were reported from a 12-week study comparing olanzapine monotherapy with the combination of olanzapine and other antipsychotics, antidepressants, or mood stabilizers. Three percent of patients in the olanzapine monotherapy group experienced akathisia compared to twice this in the combination medication group.34 Similar to oral formulations, intramuscular olanzapine injections were also well tolerated with low risk of akathisia.


Risperidone – In a comparison double blind 8-week study involving 296 patients, akathisia was reported in 26% treated with risperidone compared with 32% receiving haloperidol at similar strengths.16 Risperidone appears to carry a slightly higher risk of developing severe akathisia necessitating medication adjustments compared with second generation antipsychotics with less D2 receptor affinity.35



Other Dopamine Antagonists


Antiemetics are also a cause of akathisia. Metoclopramide is a presynaptic D2 antagonist prescribed as an antiemetic and intestinal prokinetic. There are several reports of metoclopramide-induced akathisia. It remains unclear if the rate of infusion is associated with risk of akathisia. A randomized double blind study comparing slow intravenous infusion of metoclopramide at 20 mg over 15 min (N=102) compared with a bolus of 20 mg (N=103) found no difference in development of akathisia (12% in both groups).36 In contrast, another randomized prospective double blind study of 10 mg metoclopramide in bolus (N=36) or slow infusion over 15 minutes (N=32) reported an incidence of 11% in the bolus treated group while none of the patients in the slow infusion group experienced akathisia.37 Droperidol, an antidopaminergic used as an antiemetic, but more often for induction of anesthesia and sedation, has also been reported to result in acute dystonia and akathisia.38



Antidepressants


Selective serotonin reuptake inhibitors (SSRI) including fluoxetine, paroxetine, sertraline, fluvoxamine, and citalopram are associated with akathisia. Fluoxetine is reported to have the greatest risk of akathisia among the SSRIs with an incidence of 9.8%–25%. It is possible that the incidence with newer SSRIs will increase as we gain experience. Similar to antipsychotics, the onset of SSRI-related akathisia typically occurs within 1 week of starting medication. Risk factors for the development of akathisia include simultaneous use of antipsychotics and higher SSRI dosages. Individuals with variant alleles in the CYP450 gene (involved in the metabolism of antidepressants) may be at increased risk of violent behavior when they develop akathisia.39


Other antidepressants and mood stabilizers have also been associated with akathisia. Atomoxetine, a selective norepinephrine reuptake inhibitor used in the treatment of attention-deficit/hyperactivity disorder (ADHD), has been reported to cause akathisia in a patient receiving a dose of 18 mg/day.40 Venlafaxine has serotonergic properties at low dose and noradrenergic effects at higher doses. Akathisia was reported in a single patient treated with venlafaxine XR 150mg/day with resolution of symptoms in response to biperidin 4 mg/day.41 Lithium has been reported to be associated with akathisia. In a double blind 52-week study comparing lithium to aripiprazole, nine of 159 patients treated with lithium experienced akathisia compared with 24 of 154 with aripiprazole.42



Miscellaneous Medications


Cinnarizine and flunarizine (calcium channel blockers and antihistamines) have been reported to cause akathisia as well as concurrent dystonia, orofacial tremor, parkinsonism, and even acute dystonic reactions, possibly supporting a dopamine antagonist effect.43 There are rare case reports of diltiazem, a calcium channel blocker, inducing akathisia. Tetrabenazine (often used in the treatment of tardive akathisia) and reserpine, catecholamine-depleting medications, have also been associated with akathisia with an estimated incidence of 7%–15%.44 Finally, gabapentin and pregabalin (GABA analogs) have been reported to be associated with akathisia in case reports.45



Treatment


As in the other section of this chapter, we will limit our discussion on treatment to the management of acute akathisia. The treatment of chronic tardive akathisia is distinctly different and generally similar to that of other tardive syndromes, which are covered elsewhere in this volume. There are two main treatment strategies for medication-induced acute akathisia: modification of the drug regimen and the addition of antiakathitic medications. The first treatment strategy should be to identify the offending medication and to withdraw this if possible. In situations where this is not possible, a dose reduction or switching to a less potent D2 blocking agent is recommended. Unlike tardive akathisia, acute akathisia typically responds well to this approach. However, in severe acute akathisia or where drug adjustments are not possible, it may be necessary to treat with medication. The most commonly used medications in the treatment of AIA are antiadrenergics (β-adrenergic antagonists and α-2-agonists) and anticholinergics, while other treatments have also been investigated (see Table 1.4). A problem in the literature regarding treatment of AIA is that the majority of studies are small with short duration of follow-up and often combine akathisia subtypes. Studies are open-labeled, and given the marked response these patients have to placebo, interpretation must be made cautiously. We have summarized many studies on AIA treatment in Table 1.4.



Table 1.4 Summary of treatment studies of acute akathisia












































































































































































































































































































































Medication Study Design (number of studies) N Mean Dose (mg/day) Outcome Ref.
Antiadrenergics
Propranolol Double blind placebo crossover studies (2) 32 20–60 All patients noted improvement 46,47
Double blind crossover & unblinded parallel D-propranolol & placebo study 11 D-propranolol 80 and D/L-propranolol 80 No improvement in D-propranolol and placebo but 8 patients subsequently treated with D/L-propranolol noted significant improvement of symptoms 46,47
Single blind crossover lorazepam (2mg) & placebo study 6 20–30 All patients demonstrated benefit 46,47
Open studies (4) 46 30–160 All studies reported patients responded with a combined response rate of 81% 46,47
Pindolol Open study 9 5 4 patients with benefit 46,47
Metoprolol Single blinded crossover propranolol (60mg) study 8 75 6 patients had equivalent benefit with either β-blocker 46,47
Unblinded crossover study with propranolol (15–80mg) 5 200–400 All patients demonstrated benefit comparable to propranolol 46,47
Open study 9 50–100 All patients noted benefit 46,47
Betaxolol Double blind crossover with propranolol (20–40mg) 19 10 Equivalent beneficial results to propranolol 46,47
Open crossover with propranolol (60mg) 8 5 Equivalent beneficial results to propranolol 46,47
Unblinded open study 16 10–20 Improvement in 10 of 16 patients 46,47
α2 adrenergic agonist
Clonidine Single blind trials (2) 12 0.15–0.8 Noted benefit but sedation reported as an adverse effect 46,47
Anticholinergics
Benztropine Double blind crossover propranolol (1mg iv) & placebo study 6 2 mg iv Greatest benefit evident in subjective findings 46,47
Open studies (2) 16 1.5–6 Mixed results of minimal to significant improvement 46,47
Open study including trihexyphenidyl (<15mg/day) 32 <8 14 of 32 patients with complete resolution 46,47
Double blind vs benztropine (N=11) vs amantadine (N=13; 200mg) study 11 2–8 Improvement in all patients in both treatment groups 46,47
Unblinded co-administration propranolol (30–60mg) trial in mixed subtype akathisia (9 AIA) 19 2–4 im Improvement in subjective and objective assessments 75
Unblinded benztropine (N=8) and propranolol (N=9; 40–80mg) parallel study 8 1.5–4 50% improvement in assessments of akathisia in both groups 46,47
Biperiden Double blind biperiden (N=15) vs placebo (N=15) controlled study 15 10 im No significant difference between placebo, 7 patients in the biperiden and 5 in the placebo group responded 49
Open study 23 5 All patients had complete resolution of akathisia 76
Case report 1 10 Resolution of symptoms 77
Benzodiazepines
Diazepam Open clinical trials (2) 31 5 iv & 15 po Overall effect of 75% 46,47
Double blind diazepam (N=9) vs diphenhydramine (N=11; 50mg) study 9 5 Mean ratings significantly improved for both treatments 46,47
Case report 1 15 Resolution of symptoms 46,47
Lorazepam Case report 1 2 Resolution of symptoms 46,47
Open study 16 2–3 14 patients had benefit 46,47
Clonazepam Double blind clonazepam (N=7) vs placebo (N=7) controlled study 7 1 All patients in the clonazepam group had significant improvement of akathisia and 4 of the 7 patients in the placebo cohort subsequently treated in an open trial of clonazepam obtained marked benefit 46,47,78
Double blind clonazepam (N=6) vs placebo (N=6) controlled study 12 0.5–2.5 71% improvement in rating scales in clonazepam treated patients 78
Double blind clonazepam (N=8) vs trihexyphenidyl or promethazine (N=6) 8 1.5 All patients in the clonazepam treated cohort demonstrated improvement 78
Open studies (2) 31 0.5–3 Significant improvement in akathisia 46,47, 78
Case report co-administered baclofen (15mg) 1 1.5 Marked improvement in subjective and objective symptoms 78
Midazolam Double blind midazolam (N=28) vs diphenhydramine (N=28; 20mg) metoclopramide-induced akathisia parallel study 28 2 iv Midazolam improved symptoms within 15 min while diphenhydramine took 60 min 52

Double blind midazolam (N=75) vs diphenhydramine (N=75; 20mg) & placebo (N=75) prophylactic metoclopramide-induced akathisia trial 75 1.5 iv Midazolam reduced the risk of akathisia while diphenhydramine and placebo did not 55
Serotonin 2a agonists
Cyproheptadine Double blind cyproheptadine (N=18) vs propranolol (N=12; 80mg) study 18 16 Equivalent improvement between both treatments 79
Open study 17 16 All patients demonstrated improvement 80
Ritanserin Single blind trial 10 13.5 Effective treatment in 8 of 10 patients 81
Mianserin Double blind mianserin (N=15) placebo (N=15) controlled study 15 15 Objective and subjective improvement 82
Double blind mianserin (N=20) vs placebo (N=17) & vitamin B6 (N=23; 1200mg/day) controlled study 20 15 Only subjective improvements reported in treatment groups 83
Mirtazapine Double blind mirtazapine (N=13) vs placebo (N=13) controlled study 13 15 7 of 13 patients responded to treatment with 5 of them reporting complete resolution of symptoms 84
Double blind mirtazapine (N=30) vs propranolol (N=30; 80mg) & placebo (N=30) controlled trial 30 15 13 mirtazapine and 9 propranolol treated patients improved 85

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Apr 27, 2017 | Posted by in NEUROLOGY | Comments Off on Acute akathisia
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