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Psychosomatics 46:291-301, August 2005
© 2005 The Academy of Psychosomatic Medicine

Review

Acute Akathisia Associated With Quetiapine Use

Glenn Catalano, M.D., John W. Grace, M.D., Maria C. Catalano, D.O., Miguel J. Morales, M.D., and Laura M. Cruse, M.D.

Received Aug. 6, 2004; accepted Oct. 26, 2004. From the Department of Psychiatry and Behavioral Medicine and the Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Fla.; James A. Haley Veterans’ Hospital, Tampa, Fla.; and the Department of Psychiatry, University of Florida College of Medicine, Gainesville, Fla. Address correspondence and reprint requests to Dr. Catalano, University of South Florida Psychiatry Center, 3515 East Fletcher Ave., Tampa, FL 33613; gcatalan{at}hsc.usf.edu (e-mail).


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 Case Reports
 DISCUSSION
 REFERENCES
 
Because of their better side-effect profile, atypical antipsychotic agents have replaced conventional antipsychotic agents as the first-line treatment for schizophrenia. Although atypical agents are less likely to be associated with extrapyramidal symptoms, such symptoms sometimes do occur in patients treated with atypical agents. The authors report the cases of two patients who developed akathisia after treatment with quetiapine for insomnia, consider previously reported cases of akathisia induced by atypical antipsychotic agents, discuss other medications that can induce similar symptoms, discuss treatments for akathisia, and examine issues in the use of quetiapine as a soporific agent.

Key Words: Quetiapine • Akathisia • Movement Disorders • Atypical Antipsychotic Agents • Extrapyramidal Symptoms

  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
Case Reports
 DISCUSSION
 REFERENCES
 
Quetiapine is a psychotropic agent that was introduced in the United States in 1997. Currently, it is approved for the treatment of schizophrenia and acute bipolar mania. It is a dibenzothiazepine derivative that was produced by altering the structure of the clozapine molecule.1 It has low to moderate affinity for the dopamine D1 and D2 receptors and for the serotonin 5-HT1A and 5-HT2A receptors and moderate to high affinity for the {alpha}1- and {alpha}2-adrenergic receptors.1 It is also an antagonist of the histamine H1 receptor.2 Like other atypical antipsychotic agents, quetiapine has greater relative affinity for 5-HT2A receptors than for D2 receptors.1

We report the cases of two patients who developed severe akathisia after the initiation of a low-dose quetiapine regimen for the treatment of insomnia. The discussion of these cases is presented in the form of a dialogue among the authors.


  Case Reports

 
TOP
 ABSTRACT
 INTRODUCTION
 Case Reports
DISCUSSION
 REFERENCES
 
Case 1
Ms. A was a 43-year-old woman admitted to the pain management service for treatment of pain from steroid-induced avascular necrosis of multiple joints. She had a history of major depression and an unspecified anxiety disorder. No history of psychotic symptoms was noted. Ms. A had been "mostly compliant" with her medication regimen, usually taking her prescribed medications on 6 of 7 days. She had been taking extended-release venlafaxine (150 mg/day) and lorazepam (0.5 mg q.i.d.) before admission and had almost full remission of her depressive and anxious symptoms. She had been taking a stable dose of venlafaxine for 2 years. Her anxiety symptoms included "generalized worry," palpitations, sweatiness, and a feeling that she was "losing control." No muscular symptoms had ever been noted, and the patient had always been able to sleep well. For the most part, these symptoms were all under good control on admission.

Her past medical history was significant for a prior history of steroid-dependent asthma and steroid-induced avascular necrosis. Currently, her only medication other than those described previously was diphenhydramine on an as-needed basis for allergies. She had no history of thyroid illness. Ms. A had never been treated with any dopamine-blocking agents. Her vitamin B12 and folate levels on admission were within normal limits.

On admission, the patient began a 5-day tapering-dose regimen of methadone, hydroxyzine, and acetaminophen. Ms. A tolerated the taper well, and 6 days after admission, 20 mg of tiagabine nightly was added to her regimen. This addition was tolerated well, and 2 days later the tiagabine dose was increased to 4 mg nightly. The day after the tiagabine dose was increased, Ms. A began taking 25 mg of quetiapine at bedtime for insomnia. No psychotic symptoms were noted at that or any other time during the patient’s hospitalization. The dose of quetiapine was increased to 50 mg the next night. On the next day and subsequent days, the patient complained of "extreme anxiety," with a need to "walk around" because her legs had "so much energy." She noted that her "skin was crawling" and that she was "shaking all day." Ms. A stated that, although the quetiapine did help induce sleep, she was awakened nightly because she had to walk to "get the nervous energy out of my legs." The patient also described an inability to get comfortable when she attempted to go back to sleep. Ms. A also described constant hand wringing from "nervous energy," which occurred so often that her hands were becoming chapped.

Ms. A had only two medication changes after starting to take quetiapine. First, celecoxib (100 mg twice daily) was added to her regimen 4 days after she started taking quetiapine. Also, she was given as-needed doses of lorazepam (1 mg) for "anxiety and restlessness." After 4 days of a "severe need to move," a psychiatry consultation was requested for Ms. A to evaluate possible "new onset anxiety." The consultants diagnosed neuroleptic-induced akathisia, and quetiapine was discontinued. Zaleplon was started for insomnia, and the as-needed doses of lorazepam were continued for 48 hours. The patient noted significant improvement in her akathisia by the next morning. When Ms. A was discharged, her medications included extended-release venlafaxine (150 mg/day), lorazepam (0.5 mg q.i.d. and 1 mg as needed for akathisia), celecoxib (100 mg b.i.d.), and tiagabine (4 mg nightly). She was contacted 3 days after discharge and again 1 week after discharge, and she reported a full resolution of akathisia symptoms.

Case 2
Ms. B was a 27-year-old woman who was admitted to the pain management service for treatment of intractable headaches. She had a long history of major depression and endorsed multiple neurovegetative symptoms, including depressed mood, feelings of guilt, poor energy, decreased concentration, and fluctuating appetite with weight gain. The patient also described experiencing panic attacks, with episodes once per week. The episodes lasted up to 30 minutes and at different times included palpitations, sweating, tremors, shortness of breath, nausea, dizziness, paresthesia, chills, hot flashes, and fear of losing control. These symptoms were of moderate intensity at the time of the patient’s admission.

Her past medical history was significant only for a prior history of migraine headaches. Ms. B had never been treated with any dopamine-blocking agents. The only medication that she was currently taking was an oral contraceptive, which she had been taking for more than 5 years. At admission her thyroid-stimulating hormone, B12, and folate levels were within normal limits, and the results of a CBC and complete metabolic panel were within normal limits.

On admission, the patient began taking 25 mg of quetiapine at bedtime to aid her insomnia. After one dose she complained of developing severe "body anxiety." She described a feeling of inner restlessness and a need to continue moving. Staff noted that she was continually pacing, which they had not noted before she received quetiapine. Ms. B was unable to sleep through the night and woke up several times each night to perform "bicycling movements" to relieve the tension in her legs. She noted that she was nervous because of how "squirmy" she had become. Ms. B described this episode as being completely different from anything she had previously experienced.

After Ms. B had these symptoms for 2 days, the primary care team prescribed alprazolam (0.25 mg b.i.d.) and topiramate (25 mg q.a.m. and 50 mg q.h.s.). The alprazolam was intended to help with the patient’s "nerves" as well as to aid in alleviating her headaches. The topiramate was started to further address the patient’s headaches. The patient’s need to move and inner restlessness did not improve. Three days later, the psychiatric service was consulted to evaluate "new onset anxiety."

The consultants diagnosed neuroleptic-induced akathisia and discontinued the quetiapine. Topiramate was continued, and escitalopram (10 mg/day) was begun to address the patient’s mood. The next day, she reported that her need to move was greatly reduced, and the symptoms disappeared completely by 36 hours after the final dose of quetiapine. At the time of discharge, 4 days after the initial consultation, Ms. B had not again experienced any feeling consistent with akathisia.


  DISCUSSION

 
TOP
 ABSTRACT
 INTRODUCTION
 Case Reports
 DISCUSSION
REFERENCES
 
Dr. Glenn Catalano: How is quetiapine absorbed and metabolized?

Dr. Grace: Quetiapine is rapidly absorbed after oral administration and reaches peak plasma concentrations 90 minutes after administration.2 Its half-life is roughly 6 hours.2 It is primarily metabolized in the liver and is a substrate of the cytochrome P450 3A4 isoenzyme.3 Therefore, blood concentrations of quetiapine may be greatly influenced by the concomitant use of cytochrome P450 3A4 isoenzyme inhibitors (such as nefazodone and fluvoxamine) or inducers (such as carbamazepine).

Dr. Maria Catalano: What are some of the common side effects of quetiapine?

Dr. Grace: Side effects of quetiapine include somnolence, postural hypotension, and dizziness.2 These effects are usually transient, and they can be minimized by adopting a more gradual upward dose titration schedule. Quetiapine has also been associated with elevations of serum cholesterol and triglycerides levels and with weight gain and hypothyroidism.2 It had been associated with the development of cataracts in studies of dogs, but no causal relationship has been established.4 It has not been associated with the development of hyperprolactinemia, cardiac conduction difficulties, or agranulocytosis.2 Compared with conventional neuroleptic agents, quetiapine is associated with a much lower risk for tardive dyskinesia, neuroleptic malignant syndrome, and extrapyramidal symptoms (including akathisia).2 Still, there have been some reports of quetiapine-induced akathisia in patients.2

Dr. Glenn Catalano: We should begin by asking, what is akathisia?

Dr. Morales: Akathisia literally means "no sitting down".5 It is a condition characterized by subjective feelings of restlessness and objective signs of restlessness.2 It is often associated with treatment with conventional antipsychotic agents. Symptoms include feelings of anxiousness, inability to relax, pacing, rocking movements, and jitteriness.2 The patient may rock from foot to foot while standing and make shuffling movements or stamp his or her legs and feet while seated. The patient may also complain of being able to feel his or her muscles quiver.6 The increased motor activity represents the patient’s attempt to relieve feelings of inner restlessness.5,7 Akathisia appears rapidly, and onset tends to coincide with the maximum drug concentration in the blood.8 Although symptoms are most commonly seen in the extremities, there are reports of akathisia occurring in the abdomen9 and in the respiratory muscles.10 As many as 90% of younger patients taking typical antipsychotics develop akathisia at some time during treatment.8 The incidence of akathisia associated with antipsychotics decreases with age; it occurs in only 15% of patients over age 65 years.8

In its acute form, akathisia is considered one of the extrapyramidal symptoms, which also include parkinsonian syndrome and acute dystonia.1 In its chronic form, akathisia is termed tardive akathisia.11 Frequently, akathisia is unrecognized or is mislabeled as either agitation or an increased level of psychotic decompensation.2 If akathisia is mistaken for worsening psychosis, the patient’s antipsychotic dose may be increased, resulting in a worsening of akathisia.12 Akathisia is severely disturbing to patients and often has multiple untoward effects. One article described several cases of akathisia that led to medication noncompliance and subsequent hospitalization.5 The presence and severity of acute extrapyramidal symptoms have been identified as major factors influencing treatment compliance.6,7 A case in which akathisia may have contributed to a patient’s suicide has been reported,13 and a link between akathisia and suicide has been proposed.14 It has also been postulated that akathisia may affect a patient’s financial condition by making it difficult for the person to find employment.15,16

Dr. Glenn Catalano: Were there any other possible causes of akathisia in these cases?

Dr. Cruse: In the first case there were a number of possibilities. Ms. A had been taking lorazepam and venlafaxine before admission and began taking tiagabine, quetiapine, celecoxib, and as-needed doses of lorazepam after admission. At the time of admission she was received a tapering cocktail of methadone, hydroxyzine, and acetaminophen. It is unlikely that the venlafaxine or lorazepam was the cause of the akathisia, as she had been taking stable doses of these medications for years without developing akathisia. Tiagabine was added to her regimen during the hospitalization, but it was not likely to have caused the akathisia because it resolved while Ms. A was still taking tiagabine. Celecoxib as a cause was also ruled out, as the akathisia began 2 days before this medication was initiated. Finally, the tapering methadone, hydroxyzine, and acetaminophen cocktail was not the likely culprit, as the taper was completed almost 6 days before the akathisia developed. Thus quetiapine was the most likely cause. Ms. A developed akathisia the day after her dose of quetiapine was increased to 50 mg, and her symptoms improved the day after it was discontinued.

Dr. Morales: In the second case, there were fewer variables regarding the development of akathisia. The only medication Ms. B was taking before admission was her oral contraceptive agent. After admission, the only medication that was started was quetiapine (25 mg nightly) to help with insomnia. Akathisia developed the morning after the first dose. The only other medications added to the patient’s regimen were topiramate, alprazolam, and escitalopram, but all were instituted days after the akathisia began. Once the quetiapine was discontinued, symptoms deceased by the next day and completely resolved within 36 hours. This temporal sequence makes quetiapine the most likely cause of Ms. B’s symptoms.

Dr. Maria Catalano: Have there been any previous reports of quetiapine-induced akathisia?

Dr. Grace: There have been only a small number of prior reports. Wetzel et al.17 found that one of 12 patients (8.3%) treated with quetiapine developed "intermittent motor restlessness," but the researchers concluded that their preliminary observations found "virtually no extrapyramidal side effects." In a larger study by Small et al.,18 akathisia was seen in 4% of patients in a high-dose (mean of 360 mg/day) quetiapine group. Even with those findings, the researchers stated that there was "a minimal liability" for extrapyramidal symptoms with quetiapine. In a study of adolescents with psychotic illness, "agitation" was reported to be an "infrequent occurrence," meaning that it occurred in one or two of the 10 study patients.19

To my knowledge, only two cases of quetiapine-induced akathisia have been previously reported.20,21 The cases are similar, as the patients in both cases had Parkinson’s disease. In the first case, the patient developed akathisia while taking a quetiapine dose of 75 mg/day. This patient had both Parkinson’s disease and Lewy body dementia.21 In the other case, the patient was a 62-year-old man with Parkinson’s disease who developed akathisia after 2 days of treatment with 25 mg/day of quetiapine.20 Both of these patients developed akathisia while taking very low doses of quetiapine, but it has been noted that patients with Parkinson’s disease have a greater susceptibility to developing motor side effects from medications.20 That susceptibility may help explain the development of akathisia with such low doses in these cases.

Dr. Maria Catalano: How do you explain the development of akathisia at such low doses in the cases that you have described?

Dr. Cruse: Superficially, it is difficult to answer this question because the patients in these cases were treated with an atypical antipsychotic agent that is widely believed to have a lower extrapyramidal symptom burden.2 However, quetiapine is a dopamine-blocking agent and hence carries with it a risk of the development of extrapyramidal symptoms, including akathisia.

Dr. Glenn Catalano: What are the current theories regarding the cause of akathisia?

Dr. Grace: Previously accepted hypotheses suggest that neuroleptic-induced acute extrapyramidal symptoms are caused only by dopamine receptor blockade and the resulting cholinergic/dopaminergic imbalance in the striatum.22 However, antipsychotic-induced akathisia is now believed to be due to an inhibition of dopaminergic neurons that are located in the ventral tegmental area but have significant input from the noradrenergic and serotonergic systems.23 Parkinsonian symptoms are thought to be mediated by the dopaminergic neurons of the substantia nigra.23 Any medication that can decrease the release of dopamine and lead to a syndrome of dopamine deficiency in the ventral tegmental area can be expected to have akathisia as a side effect.23 However, it is possible for a medication to have a clinically significant influence in decreasing dopaminergic activity in the ventral tegmental area but not in the substantia nigra.23 Theoretically, in this scenario, the patient would develop akathisia without developing parkinsonian symptoms.

Dr. Glenn Catalano: Which medications are the most likely causative agents?

Dr. Morales: As we discuss later, akathisia can occur during treatment with many different types of medications. The antipsychotics, antidepressants, and sympathomimetics have all been implicated in the development of akathisia.2 However, the conventional antipsychotics are traditionally seen as the primary cause.2 The estimated incidence of akathisia in patients taking conventional antipsychotics varies widely, ranging from 20% to 75%.24 However, the most common estimate is around 20%.25 The risk for extrapyramidal symptoms varies among the conventional antipsychotics. Patients who take lower-potency agents, such as chlorpromazine and thioridazine, are thought to have a lower incidence of extrapyramidal symptoms, compared to patients who take higher-potency agents, such as haloperidol and fluphenazine.1,5

Dr. Glenn Catalano: What are the differences between the typical and atypical agents in regard to their chances of causing akathisia?

Dr. Grace: It is widely assumed that the atypical antipsychotic agents are much less likely to produce movement disorders than the conventional antipsychotic agents.2,7 Still, there have been reports of akathisia associated with all of the atypical antipsychotic agents.

Clozapine has been associated with both the development of and the treatment of akathisia. Some studies reported that use of clozapine decreases the severity of already present movement disorders,26,27 and others concluded that use of clozapine is associated with rates of akathisia similar to those associated with use of conventional antipsychotics.28,29 In clinical trials, there was a 3% incidence of akathisia in patients treated with clozapine.30 In patients taking clozapine who develop akathisia, the most commonly reported time frame for the appearance of akathisia is between 2 and 4 weeks after initiation of treatment.31

There is much discussion about how risperidone compares to the typical antipsychotic agents in regard to the induction of akathisia. There have been case reports of akathisia occurring during treatment with, and withdrawal from, risperidone.32,33 In a study of the prevalence of extrapyramidal side effects in patients taking clozapine, risperidone, or a conventional antipsychotic agent, the rate of extrapyramidal side effects in risperidone-treated patients (13%) was intermediate between the rate for clozapine-treated patients (7.3%) and the rate for patients receiving conventional antipsychotic agents (23.8%).34 This study used a mean risperidone dose of 4.7 mg/day. In a study comparing haloperidol (mean dose of 19.4 mg/day) and risperidone (mean dose of 7.5 mg/day), patients treated with risperidone were significantly less likely to have observable akathisia than those treated with haloperidol.35 Still, akathisia or parkinsonism was found to occur at a rate of 32% in a study of patients receiving 5–8 mg/day of risperidone.36 It is possible that the large difference in rates of akathisia reported in these studies was due to the difference in risperidone doses, and a review of the risperidone database found that akathisia scores were similar between patients receiving placebo and those receiving risperidone doses of 1–6 mg/day.37 High doses of risperidone (10–16 mg/day) have been associated with higher rates of extrapyramidal symptoms, compared with low doses (2–6 mg/day).38

There have been some case reports of olanzapine-induced akathisia as well.6 In these cases, the patients developed symptoms while taking therapeutic doses of olanzapine (15–25 mg/day). During a dose-finding study for olanzapine, the most commonly reported extrapyramidal side effect was akathisia, with an incidence of 6.4%.39

Akathisia has been noted as a side effect of aripiprazole treatment. In a 4-week, double-blind, placebo-controlled study of aripiprazole (20–30 mg/day), 20% of patients developed akathisia.40 In regard to ziprasidone, a study testing its effectiveness in treating schizoaffective disorder at therapeutic doses (40–160 mg/day) found that between 5% and 17% of patients developed akathisia.41 Finally, in a study looking at the long-term safety of amisulpride, 8% of patients were noted to have akathisia after 12 months of treatment with the medication.42

Although the data from the studies we reviewed here suggest that the atypical antipsychotic agents have rates of akathisia similar to those of conventional agents, one must remember that the majority of patients who entered he atypical antipsychotic clinical trials had previously been treated with traditional neuroleptics. Therefore, it is possible that the extrapyramidal symptoms may have persisted from prior conventional antipsychotic use.43 Also, in a study of 230 patients whose symptoms had been stabilized for more than 6 months while they were taking antipsychotic medications, the akathisia scores of patients taking any of the atypical antipsychotics tested (clozapine, risperidone, olanzapine, and quetiapine) were lower than those of patients taking conventional agents.44

Dr. Maria Catalano: Has akathisia been reported with other psychiatric medications?

Dr. Grace: Numerous psychiatric medications have been reported to induce akathisia. It is increasingly being identified in patients treated with antidepressants,12 and it has been proposed that the antidepressants may produce akathisia "fairly frequently".23 They may induce the self-destructive and aggressive impulses often seen with akathisia as well.45 Of the antidepressants, the selective serotonin reuptake inhibitors (SSRIs) are more commonly associated with extrapyramidal symptoms than are the traditional tricyclic antidepressants.22

All of the SSRIs have been reported to induce akathisia. Fluoxetine has been identified as the SSRI most likely to induce extrapyramidal symptoms.22 The estimated incidence of fluoxetine-induced akathisia is between 9.8% and 25%.23 There have been numerous case reports describing fluoxetine-induced akathisia.23,46 However, these cases were not associated with signs or symptoms of dystonia or parkinsonism.23

There have been multiple case reports of sertraline-induced akathisia.47–49 In the majority of these cases, the patient developed akathisia very close to the time that the sertraline dose was administered, usually within 2 hours of taking the dose.47 Paroxetine use has also been associated with akathisia.14 In a chart review, Baldassano et al.14 estimated the incidence of paroxetine-induced akathisia to be 4%. There have been reports of fluvoxamine-induced akathisia as well.50,51 During the clinical trials for other SSRIs, akathisia or jitteriness was observed in patients taking citalopram and escitalopram.30

Other antidepressants besides the SSRIs may also induce akathisia. The tricyclic antidepressants have been associated with a "jitteriness syndrome".52 This syndrome is thought to be identical to the akathisia produced by fluoxetine.53 There have been multiple case reports of akathisia induced by nortriptyline,53 imipramine,54 and desipramine.54 A review by Vandel et al.55 discussed cases of akathisia induced by the tricyclic antidepressants, as well as cases induced by amitriptyline, doxepin, and clomipramine.

Other medications that have been implicated in causing akathisia include nefazodone,56 trazodone,54 and tranylcypromine.54 Development of akathisia was noted in the clinical trials of bupropion, venlafaxine, and mirtazapine.30 A case report described a patient treated with 900 mg/day of lithium who developed akathisia and severe parkinsonism.57 The antidepressant amoxapine has been noted to cause akathisia in multiple cases.58–60 However, the mechanism in these cases may be similar to that in cases of antipsychotic-induced akathisia, as amoxapine has a chemical structure similar to the antipsychotic loxapine.52

Dr. Maria Catalano: Is there any difference between the mechanisms of antidepressant-induced akathisia and of antipsychotic-induced akathisia?

Dr. Cruse: In the final common pathway, probably not. The end result of treatment with antidepressants and antipsychotics is likely a decrease in dopaminergic activity in the ventral tegmental area, which leads to akathisia. The ventral tegmental area and the substantia nigra are both known to have noradrenergic inputs that are inhibitory in nature.23 Therefore, any medication that is able to enhance noradrenergic neurotransmission will inhibit dopaminergic activity in the ventral tegmental area, with akathisia a possible outcome.23

Antidepressants that affect serotonin neurotransmission have been noted to decrease dopaminergic activity as well. Dopaminergic neurons in both the ventral tegmental area and substantia nigra have both been found to receive inhibitory serotonergic input from the midbrain raphe nuclei.61 Electrophysiological responses of striatal neuronal activity after stimulation of the dorsal raphe consistently demonstrate an inhibitory effect of serotonin.22 Therefore, serotonergic medications can cause a decrease in dopaminergic activity in the ventral tegmental area, which may lead to clinically significant akathisia as well.23

Dr. Maria Catalano: Has akathisia been associated with medications that are more commonly associated with the treatment of nonpsychiatric conditions?

Dr. Cruse: Akathisia has been reported with a number of medications that are more commonly used in other fields of medicine. Cases have been reported after the administration of antiemetic or prokinetic medications with D2 antagonist activity.62 These agents include promethazine, prochlorperazine, and metoclopramide.62 Patients treated with trimethobenzamide have been noted to develop extrapyramidal symptoms.30 The anesthetic agent droperidol, which, like haloperidol, is a butyrophenone, has also been found to induce akathisia.5 Other medications that have been reported to induce akathisia include steroids, some bronchodilators, and interferon.63

Dr. Maria Catalano: Are there any risk factors for the development of akathisia?

Dr. Morales: There are multiple factors that have been postulated to increase a patient’s risk of developing akathisia. First, a history of organic brain disease has been associated with the development of this side effect.6 A patient’s risk of developing akathisia may also be increased if the patient has ever been treated with a high-potency conventional antipsychotic agent.6 The concomitant use of antidepressants and neuroleptics can increase a patient’s akathisia risk.64 Patients infected with HIV have been noted to be at increased risk of developing extrapyramidal symptoms.65 Although in general extrapyramidal symptoms are equally likely to occur in both sexes and all age groups,1 akathisia occurs more commonly in middle-aged female patients.2

Dr. Glenn Catalano: Are there any treatments for akathisia?

Dr. Grace: It is important to realize that medications are not always the first choice in the treatment of akathisia. In fact, no single medication has been definitely proven to treat it well.50 If a patient taking conventional antipsychotics develops akathisia, a recommended first action is to reduce the dose.8 If that change is not effective, or if it is not clinically prudent, then the patient’s medication could be switched to an atypical antipsychotic agent.8 A considerable period of time may be required for akathisia to remit, because of the high level of lipid solubility of neuroleptic agents, which gives them a long half-life in the brain.5

Many agents have been used in the attempt to treat akathisia, but none have distinguished themselves through rigorous study as being the most effective agent. Most articles are either case reports or reports of open-label studies. Few placebo-controlled studies have been completed. Most literature on this issue centers around the use of ß-adrenergic blocking agents, anticholinergic agents, the atypical antipsychotic agent clozapine, and the benzodiazepines. There have also been a few other reports of less commonly used regimens as well.

Currently, the ß-adrenergic blocking agents, such as propranolol, have emerged as a top choice to treat akathisia. They have been studied extensively, and the "weight of evidence" points toward propranolol as being useful in treatment of akathisia.66 In a series of cases of antidepressant-related akathisia, Zubenko et al.54 noted that propranolol "appeared to be superior to either the anticholinergic agent or the benzodiazepine" to treat the akathisia. Case reports have described the effective use of propranolol to treat akathisia induced by conventional antipsychotics, atypical antipsychotics,67 tricyclic antidepressants,53 and SSRIs.68 Sachdev69 suggested that doses of propranolol as low as 60 mg/day are sufficient to reduce the restlessness associated with akathisia. Still, care must be exercised when using propranolol in elderly patients. If the patient is taking an antipsychotic medication with {alpha}1 blockade (such as all of the currently available atypical antipsychotic agents), the addition of ß blockade could result in a decrease in peripheral vascular resistance and cardiac decompensation.8

The anticholinergic agents and antihistamines (such as diphenhydramine and cyproheptadine) have long been used to treat akathisia.2 Case reports have identified benztropine and trihexiphenidyl as being very effective for the treatment of this side effect.45 Procyclidine and biperiden have been reported to be useful in the treatment of akathisia.5,70 One study found that a 5-mg dose of biperiden delivered intravenously relieved akathisia significantly faster than when it was administered intramuscularly.70 The mean onset of action was 1.6 minutes for intravenous biperiden and 30.5 minutes for intramuscular biperiden. Akathisia was completely ameliorated by biperiden in all of the study patients. It has been suggested that anticholinergic agents for treatment of akathisia may have their most robust effects in younger patients.66 Diphenhydramine (25 mg t.i.d.) is often effective in the treatment of akathisia.2,5 A double-blind study comparing cyproheptadine and propranolol found that cyproheptadine was as effective as propranolol for the treatment of neuroleptic-induced akathisia.71 The doses were 16 mg/day for cyproheptadine and 80 mg/day for propranolol. Amantadine is another agent that has been investigated for use in treating akathisia. In a case series describing four patients with akathisia who were treated with amantadine, the patients initially did well, but tolerance to the effects of amantadine developed within a week in each case.72

The efficacy of clozapine to treat neuroleptic-induced akathisia has been examined in a few studies. In a review of the literature, Factor and Friedman73 noted that clozapine had been used to treat akathisia in patients with Parkinson’s disease and that the "evidence is compelling enough" to recommend a trial of clozapine in Parkinson’s disease patients with akathisia for whom more standard treatments have failed. A retrospective chart review of 172 patients with Parkinson’s disease who were treated with clozapine was undertaken by Trosch et al.74 They noted that akathisia associated with Parkinson’s disease "consistently and dramatically" improved during clozapine treatment. These results were obtained with a mean clozapine dose of 31.4 mg/day. Still, not all researchers agree on the use of clozapine to treat akathisia, noting that a well-designed, placebo-controlled study is needed before it can be concluded that clozapine is an effective treatment for akathisia.75

Benzodiazepines are commonly used to treat akathisia. In 1973, Donlan76 reported on 13 patients who developed akathisia while being treated with conventional neuroleptic agents. After treatment with diazepam (5 mg t.i.d.), 10 of the 13 patients reported either "marked" or "moderate" improvement in their akathisia. Although lorazepam, clonazepam, and diazepam have all been reported to have some efficacy in treating akathisia, few scientifically rigorous studies have been done.66 Clinicians who prescribe benzodiazepines to treat akathisia should take extreme care to avoid causing oversedation, especially if the patient is also being treated with a sedating antipsychotic agent.8

Some research has pointed to a possible serotonergic mechanism for akathisia,61,66,77 and agents with 5-HT2A receptor antagonism have been investigated as possible treatments for akathisia. Poyurovsky et al. have done much work in this area. In their first study, which had an open-label design, patients with akathisia who were treated with the 5-HT2A/5-HT2C antagonist mianserin (15 mg/day) showed improvement in their symptoms.77 Another study compared mianserin (15 mg/day) with placebo in the treatment of akathisia.78 Patients treated with mianserin for 5 days displayed a significant improvement in akathisia, compared to patients who received placebo. Finally, Poyurovsky and Weizman79 reported on a case in which mirtazapine was used to treat neuroleptic-induced akathisia. Treatment with mirtazapine (15 mg/day) resulted in a complete amelioration of the akathisia. Mianserin is structurally related to mirtazapine, which is also known as 6-aza-mianserin.52 Therefore, one might expect that the two agents would have similar effects on akathisia.

Many other treatments of akathisia have been reported in the literature. Caspi and Levine43 described a case of treatment-resistant akathisia that improved after ECT treatments. Shulman et al.80 described a case in which a patient with tardive dystonia and akathisia had a robust therapeutic response to botulinum toxin injections. The authors suggested that this result may have represented a distant effect of botulinum toxin on the CNS. In another case, the nootropic agent piracetam was used to treat a man who had developed akathisia and tardive dyskinesia after long-term treatment with haloperidol.81 With a dose of 24 g/day, the patients reported a "marked relief" of his symptoms. Finally, Sandyk82 reported the case of a man who developed akathisia after being treated with haloperidol. Clonazepam (0.5 mg t.i.d.) and baclofen (10 mg t.i.d.) were added to the patient’s regimen, and the akathisia abated.

Although many different options exist for the treatment of akathisia, most authors have very similar recommendations. In 1981, Shen83 commented that akathisia "can be easily treated" by reducing the neuroleptic dose, changing to an antipsychotic agent with less propensity for causing extrapyramidal symptoms, and starting an antiparkinsonian agent immediately after extrapyramidal symptoms develop. In 1989, Lipinski et al.23 made similar recommendations for treating fluoxetine-induced akathisia, noting that dose reduction and the addition of substances that have been helpful in treating neuroleptic-induced akathisia (such as propranolol or benzodiazepines) "may have some value." In a 2001 review, Poyurovsky and Weizman61 divided their treatment algorithm into two parts: drug regimen modification and addition of antiakathisia agents. For drug regimen modification, the recommendations were dose reduction, followed by a switch to a low-potency antipsychotic agent and then to an atypical antipsychotic agent. If these changes did not improve the patient’s akathisia, the clinician could initiate a switch to clozapine. If these changes were not effective, it was recommended that propranolol (40–120 mg/day), mianserin (15–30 mg/day), ritanserin (5–20 mg/day), or cyproheptadine (8–16 mg/day) be considered for addition to the treatment regimen as first-line agents. If the patient had concurrent parkinsonism, then priority could be given to anticholinergic agents such as benztropine (1.5–8 mg/day), trihexyphenidyl (2–10 mg/day), or biperiden (4–12 mg/day). In patients with continued subjective distress, a benzodiazepine such as clonazepam (0.5 mg/day), lorazepam (2 mg/day), or diazepam (5–15 mg/day) could be added. Finally, if these medications were not effective, a trial of amantadine (100 mg/day) or clonidine (up to 0.150 mg/day) could be considered.

Dr. Glenn Catalano: The two cases described in this article occurred in a general hospital setting. What are the uses of the atypical antipsychotics in the general hospital?

Dr. Morales: Of course, the atypical antipsychotics are used to treat patients with bipolar disorder and schizophrenia who require hospitalization for medical reasons. Other psychiatric conditions for which the atypical antipsychotics have been used include the mood and anxiety disorders, obsessive-compulsive disorder, posttraumatic stress disorder, and borderline personality disorder.84 They have also been used in the treatment of general agitation,85,86 for psychosis and behavioral dyscontrol in dementia patients,87,88 for symptom control in delirium89,90 and even for sleep induction.91,92

Dr. Maria Catalano: In the cases presented here, why was quetiapine prescribed for the patients when there was no psychiatric indication?

Dr. Cruse: They were given quetiapine to help with insomnia.

Dr. Maria Catalano: Does quetiapine have approval from the United States Food and Drug Administration (FDA) for the treatment of insomnia, and are there any studies of the use of quetiapine for insomnia?

Dr. Cruse: Currently, quetiapine has no FDA indication for the treatment of insomnia. A search of the literature revealed no studies on the utility of quetiapine to treat insomnia. Much of the use of quetiapine as a soporific agent is based on the clinical knowledge that quetiapine is very sedating.2

Dr. Maria Catalano: On the basis of this information, can you make a recommendation regarding the use of quetiapine as a soporific agent?

Dr. Cruse: Certainly, on the basis of the side effects experienced by the patients in the two case reports, we would suggest that quetiapine and the other antipsychotics not be used as a first-line treatment of insomnia in the absence of other psychiatric indications for the use of these medications. Quetiapine has proven to be an effective agent in the treatment of schizophrenia and bipolar disorder, but one has to take into account that, although it is generally well tolerated, quetiapine has been associated with significant side effects such as hypotension, tardive dyskinesia, neuroleptic malignant syndrome, and akathisia.30 For those reasons, medications such as zaleplon and zolpidem would likely be better choices to treat a patient with insomnia.

Dr. Glenn Catalano: On the basis of your literature review, can you put these cases in perspective?

Dr. Grace: To my knowledge, these cases are the third and fourth case descriptions of quetiapine-induced akathisia to be reported in the literature.20,21 However, they are the first reported cases in patients without preexisting Parkinson’s disease. The patients in these cases were younger than those in the previously reported cases, and they had none of the commonly reported akathisia risk factors. Any practitioner who prescribes quetiapine must be aware that akathisia can occur even with extremely low doses.

Dr. Glenn Catalano: Akathisia is an extrapyramidal symptom that is very difficult to treat. In many cases, it has a subtle presentation and may often be misdiagnosed as a worsening of a patient’s primary psychiatric pathology. It is important for clinicians to be aware of this side effect, as it has been associated with poor treatment outcome and even an increase in suicide risk.2,14 Clinicians must be alert to the fact that akathisia can occur during treatment with agents that are not normally associated with extrapyramidal symptoms, such as the atypical antipsychotics. Therefore, care must be used when prescribing these medications, especially for "off-label" uses. Because of the side effects associated with quetiapine use, the lack of research on quetiapine’s efficacy as a soporific agent, and the availability of better studied medications for the treatment of insomnia, we feel that the risk-benefit analysis does not currently support the use of quetiapine as a treatment for insomnia.


  REFERENCES

 
TOP
 ABSTRACT
 INTRODUCTION
 Case Reports
 DISCUSSION
 REFERENCES
 

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