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CASE Anxiety in the ICU
Mr. B, age 42, an African American man, is admitted to the inpatient medical unit for surgical treatment of peritoneal carcinomatosis with pelvic exenteration. He has a history of metastatic rectal cancer, chronic pain, and hypertension, but no psychiatric history. Mr. B’s postsurgical hospital stay is complicated by treatment-resistant tachycardia and hypertension, and he requires a lengthy stay in the ICU. In the ICU, Mr. B reports having visual hallucinations where he sees an individual placing a drug in his IV line. Additionally, he reports severe anxiety related to this experience. His anxiety and visual hallucinations are treated with coadministration of IV lorazepam, diphenhydramine, and haloperidol. These medications resolve the hallucinations, but his anxiety worsens and he becomes restless. He receives additional doses of IV haloperidol administered in 5 mg increments and reaching a cumulative 12-hour dose of 50 mg. Mr. B continues to report anxiety, so the psychiatry consultation-liaison (C-L) service is called.
[polldaddy:9970907]
The authors’ observations
Determining the cause of Mr. B’s anxiety is challenging because of his prolonged medical course, com
From a medical perspective, in a post-surgical patient treated in the ICU, the consulting practitioner must pay particular attention to delirium. ICU delirium is common—one report indicated that it occurs in 32.3% of ICU patients1—and frequently confused with psychiatric morbidity.2 Identifying delirium as the cause of impairment is important because delirium has potentially modifiable underlying etiologies. Symptomatically, delirium presents as impairment and fluctuation in attention, awareness, and at least one other cognitive domain, with a clear indication that the impairment occurred over a short period of time and represents a departure from baseline.3 In Mr. B’s case, these symptoms have not been excluded and should be considered by the C-L psychiatrists.
In addition to delirium, the C-L team must consider psychiatric comorbidity. Mr. B has no psychiatric history and a sudden first occurrence of hallucinations; therefore, it is unlikely that he has developed a primary psychotic disorder. Because he reported his symptoms had been present only for several days, he would not meet criteria for schizophrenia, which according to DSM-5 criteria require at least 1 month of ≥2 symptoms (including delusions, hallucinations, disorganized speech, disorganized behavior, or negative symptoms) and 6 months of declining function.3 However, although it is improbable, the C-L team must consider a primary psychotic illness, particularly given the potential devastating consequence of being misdiagnosed and mismanaged for an alternative illness. Unlike psychotic disorders, anxiety disorders are significantly more prevalent in the U.S. general population than primary psychotic disorders.4 Furthermore, the prevalence of anxiety disorders increases in the ICU setting; one study found that up to 61% of ICU patients setting experience “anxiety features.”5 Therefore, anxiety disorders and stress disorders should be considered in ICU patients who exhibit psychiatric symptoms.
Clinicians also should consider medication-induced adverse effects. In the ICU, patients are frequently managed on multiple medications, which increase their risk of developing adverse effects and adverse reactions.6 One potential consequence of polypharmacy is delirium, which remains a relevant potential diagnosis for Mr. B.7 Alternative consequences vary by medication and their respective pharmacodynamics. We take into consideration Mr. B’s exposure to high doses of the high-potency antipsychotic agent, haloperidol. Exposure to haloperidol can result in extrapyramidal symptoms, including akathisia,8,9,10 and the rare, but potentially fatal, NMS.11 These reactions can often be distinguished by taking a thorough history and a physical evaluation. In the case of akathisia, the clinician should look for medication exposure, titration, or taper. Most commonly, akathisia occurs secondary to antipsychotic exposure,12 followed by the onset of a combination of subjective symptoms, such as restlessness, anxiety, and irritability, and an objective symptom of increased motor activity.3 NMS, on the other hand, is distinguished by symptoms that include hyperthermia (>38ºC), diaphoresis, severe rigidity, urinary incontinence, vital instability, alterations in mental health status, and elevations in creatine kinase greater than 4-fold the upper limit, usually in the setting of treatment with antipsychotics.3 Nearly all cases of NMS occur within the first 30 days of antipsychotic exposure.3 While, overtly, NMS may appear to be less subtle than akathisia, clinicians should still be weary to rule out this admittedly rare, though potentially lethal diagnosis, especially in an ICU patient, where the diagnosis can be muddied by medical comorbidities that may mask the syndrome.
Continue to: EVALUATION Focus on akathisia
EVALUATION Focus on akathisia
On interview by the C-L team, Mr. B is visibly restless, moving all 4 extremities. He reports increased anxiety and irritability over the past 2 to 3 days. Mr. B states that he is aware of his increased motor movements and can briefly suppress them. However, after several seconds, he again begins spontaneously fidgeting, moving all 4 extremities and shifting from side to side in bed, saying, “I just feel anxious.” He denies having visual hallucinations, and says that the previous hallucinations had spontaneously presented and remitted after surgery. He denies the use of psychotropics for mental illness, prior similar symptoms to this presentation, a family history of mental illness, recent illicit substance use, or excessive alcohol use prior to presentation. This history is corroborated by collateral information from his brother, who was present in the ICU. On physical examination, Mr. B is afebrile and his vital signs are within normal limits. He does not have muscular rigidity or neck dystonia. His laboratory values, including complete blood count, electrolytes, liver function tests, and creatine phosphokinase, are within normal limits.
His medication administration record includes 46 standing agents, 16 “as-needed” agents, and 8 infusions. Several of the standing agents had psychotropic properties; however, the most salient were several opioids, ketamine, midazolam, lorazepam, dexamethasone, haloperidol, and olanzapine.
[polldaddy:9970908]
The authors’ observations
We determined that the most likely diagnosis for Mr. B’s symptoms was medication-induced akathisia secondary to haloperidol. Akathisia, coined by Haskovec in 1901,12,13 is from Greek, meaning an “inability to sit.”12 DSM-5 describes 2 forms of akathisia: medication-induced acute akathisia, and tardive akathisia.3 In the literature, others have described additional classifications, including chronic akathisia, withdrawal akathisia, and pseudoakathisia (Table 13,14-17). In Mr. B’s case, given his sudden development of symptoms and their direct chronologic relationship to antipsychotic treatment, and his combined subjective and objective symptoms, we believed that Mr. B’s symptoms were consistent with medication-induced acute akathisia (MIA). The identification and treatment of this clinical entity is important for several reasons, including reducing patient morbidity and maximizing patient comfort. Additionally, because akathisia has been associated with poor medication adherence, increased agitation/aggression, increased suicidality, and the eventual development of tardive dyskinesia,18 it is a relevant prognostic consideration when deciding to treat a patient with antipsychotics.
Pathophysiologically, we have yet to fully shed light on the exact underpinnings of akathisia. Much of our present knowledge stems from patient response to pharmacologic agents. While dopamine blockade has been linked to akathisia, the exact mechanism is not completely understood. Previous theories linking nigrostriatal pathways have been expanded to include mesocortical and mesolimbic considerations.12,17,18 Similarly surmised from medication effects, the transmitters y-aminobutyric acid, serotonin/5-hydroxytryptamine (5-HT), norepinephrine, and acetylcholine also have been linked to this syndrome, though as of yet, exact gross pathophysiologic mechanisms have not been fully elucidated.12 More recently, Stahl and Loonen19 described a novel mechanism by which they link the shell of the nucleus accumbens to akathisia. In their report, they indicate that the potential reduction in dopaminergic activity, secondary to antipsychotic administration, can result in compensatory noradrenergic activation of the locus coeruleus.19 The increased noradrenergic activity results in the downstream activation of the shell of the nucleus accumbens.19 The activation of the nucleus accumbens shell, which has been linked to unconditioned feeding and fear behavior, can then result in a cascade of effects that would phenotypically present as the syndrome we recognize to be akathisia.19
Numerous etiologies have been linked to MIA. Of these, high-potency antipsychotics are believed to remain the greatest risk factor for akathisia,18 although atypical antipsychotics, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors, have been linked to the disorder.18,19
Continue to: Regarding antipsychotics...
Regarding antipsychotics, risk factors for akathisia include drug potency, dose, and rapidity of titration.20 All of these factors were relevant in our patient’s case. Risk across antipsychotic classes is not well understood; few head-to-head studies have comparing antipsychotics. However, general estimates suggest a 15% to 40% prevalence in patients exposed to typical antipsychotics, as compared with 0% to 12% exposed to atypical antipsychotics.8 The literature-reported difference in risk, as well as our patient’s comparative difference in exposure to large doses of haloperidol (50 mg) as compared with 1 dose of olanzapine (5 mg), led us to believe his akathisia developed primarily due to his exposure to haloperidol. Conclusively linking his symptoms to haloperidol alone, however, is not possible, and we did consider that olanzapine may in fact have had some effect in worsening Mr. B’s akathisia.
[polldaddy:9970909]
The authors’ observations
While there are reports on the efficacy of various agents in the treatment of akathisia, the most commonly evaluated agents are propranolol, anticholinergics, and benzodiazepines.17, 21
Propranolol is a nonselective beta-adrenergic blocker with numerous indications.17 Despite a 2004 Cochrane Review indicating that there is no evidence in support of central acting beta-blockers for treating akathisia,22 propranolol is not yet recognized as an appropriate treatment.17 The reason for this discrepancy is likely due to the Cochrane Review’s restrictive inclusion criteria, which prevented the analysis of much of the literature.22 In fact, several reports cite evidence for the treatment efficacy of propranolol17 and, to date, some reports continue to advocate for its use as a first-line agent in the treatment of akathisia. Admittedly, besides the Cochrane Review,22 other reports have found propranolol to be ineffective for treating akathisia,23 although these tend to be limited by their population size and generalizability.
As with propranolol, a 2006 Cochrane Review found “no reliable evidence to support or refute” using anticholinergic agents in the treatment of akathisia.24 We suspect that the review’s findings were likely secondary to its strict inclusion criteria.24 In fact, several reports support using anticholinergic agents for treating akathisia.25 Here we focus on benztropine and diphenhydramine.
Two reviews—Blaisdell26 (1994) and Poyurovsky27 (2010)—suggest modest benefits from benztropine, primarily in patients with comorbid Parkinson’s disease. Despite these benefits, head-to-head trials seem to either point to the superiority of propranolol or to no difference between these agents for treating akathisia.28,29 In a review, we only found 1 trial demonstrating benztropine’s superiority over propranolol,23 but this trial was constrained by its small population (6 patients). Therefore, the data suggest that, when indicated, clinicians should lean towards using propranolol for treating akathisia.
Continue to: Diphenhydramine, a first-generation antihistamine...
Diphenhydramine, a first-generation antihistamine with antimuscarinic properties, has been studied for its efficacy in treating metoclopramide-induced akathisia in the emergency setting.30 There are several reports on the efficacy of this agent, including a large randomized study involving 281 patients that found it effective for preventing metoclopramide-induced akathisia.30 Another head-to-head trial reported the benefit of the diphenhydramine vs midazolam.31 Both agents were efficacious for treating akathisia; however, midazolam had a more rapid onset. Despite these positive reports, double-blind trials have found diphenhydramine to be ineffective,17 which suggests propranolol should be the first-line agent, assuming it is not contraindicated.
Benzodiazepines have also been found to be efficacious for treating akathisia. A 1999 Cochrane Review included 2 randomized controlled trials that assessed the efficacy of clonazepam vs placebo for treating akathisia.32 It found evidence of benefit for clonazepam, but questioned the generalizability of these studies.32 This review did not include several other reports that suggest benefits of other benzodiazepines for treating akathisia. Other than clonazepam, reports suggest benefit for diazepam, lorazepam, and midazolam for treating akathisia.17 Despite this evidence and the findings from this Cochrane Review, the literature does not appear to point to clear dominance of these agents over propranolol. Given the safety concerns when prescribing benzodiazepines, it would be prudent to utilize propranolol as a first-line agent for treating akathisia.
Finally, other reports have cited treatment efficacy linked to serotonin 2A receptor (5-HT2A) antagonists (mianserin, mirtazapine, and trazodone), clonidine, gabapentin, amantadine, and other agents.17 If treatment with propranolol is ineffective or contraindicated, clinicians should utilize their clinical judgement in deciding on the use of one agent over another.
OUTCOME Complete resolution
Haloperidol is discontinued and diphenhydramine, 50 mg IV, is administered. (Diphenhydramine was used instead of propranolol due to immediacy of availability.) Most of Mr. B’s signs and symptoms resolve on a repeat interview 3 hours later. He receives another dose of diphenhydramine, 25 mg IV, for persistent mild irritability. By Day 2 of follow-up, his symptoms completely resolve as measured on the Barnes Akathisia Scale33 (Table 2).
Continue to: Bottom Line
Bottom Line
Akathisia is an elusive adverse effect of antipsychotics and can be misdiagnosed as anxiety. Close consideration should be given to potential medical, psychiatric, and drug-related etiologies in patients who have a prolonged medical course, comorbidities, and exposure to multiple pharmacologic agents.
Related Resources
- Factor SA, Leffler JB, Murray CF. Drug-induced movement disorders: a clinical review. Medscape. http://www.medscape.org/viewarticle/586881.
- Marder S, Stroup TS. Pharmacotherapy for schizophrenia: side effect management. UpToDate. https://www.uptodate.com/contents/pharmacotherapy-for-schizophrenia-side-effect-management.
Drug Brand Names
Amantadine • Symmetrel
Benztropine • Cogentin
Clonazepam • Klonopin
Clonidine • Catapres
Dexamethasone • Decadron
Diazepam • Valium
Diphenhydramine • Benadryl
Gabapentin • Neurontin
Haloperidol • Haldol
Ketamine • Ketalar
Lorazepam • Ativan
Metoclopramide • Reglan
Mianserin • Tolvon
Midazolam • Versed
Mirtazapine • Remeron
Olanzapine • Zyprexa
Propranolol • Inderal
Rivastigmine • Exelon
Trazodone • Oleptro
1. Cavallazzi R, Saad M, Marik PE. Delirium in the ICU: an overview. Ann Intensive Care. 2012;2:49.
2. Farrell KR, Ganzini L. Misdiagnosing delirium as depression in medically ill elderly patients. Arch Intern Med. 1995;155(22):2459-2464.
3. Diagnostic and statistical manual of mental disorders, 5th ed. Washington, DC: American Psychiatric Association; 2013.
4. National Alliance on Mental Illness. Mental health by the numbers. https://www.nami.org/learn-more/mental-health-by-the-numbers. Accessed March 4, 2018.
5. Jacka MJ, Mitchell N, Perez-Parada J. Incidence and prevalence of anxiety, depression, and post-traumatic stress disorder among critical care patients, families, and practitioners. J Anest & Inten Care Med. 2016;1(1):55555. doi: 10.19080/JAICM.2016.01.555555.
6. Reis AM, Cassiani SH. Adverse drug events in an intensive care unit of a university hospital. Eur J Clin Pharmacol. 2011;67(6):625-632.
7. Garpestad E, Devlin JW. Polypharmacy and delirium in critically ill older adults: recognition and prevention. Clin Geriatr Med. 2017;33(2):189-203.
8. Caroff SN, Hurford I, Lybrand J, et al. Movement disorders induced by antipsychotic drugs: implications of the CATIE schizophrenia trial. Neurol Clin. 2011;29(1):127-148.
9. Van Putten T, Marder SR. Toward a more reliable diagnosis of akathisia. Arch Gen Psychiatry. 1986;43(10):1015-1016.
10. Penders TM, Agarwal S, Rohaidy R. Persistent akathisia masquerading as agitated depression after use of ziprasidone in the treatment of bipolar depression. Neuropsychiatr Dis Treat. 2013;9:463-465.
11. Naganuma H, Fujii I. Incidence and risk factors in neuroleptic malignant syndrome. Acta Psychiatr Scand. 1994;90(6):424-426.
12. Forcen FE, Matsoukas K, Alici Y. Antipsychotic-induced akathisia in delirium: a systematic review. Palliat Support Care. 2016;14(1):77-84.
13. Brune M, Sachdev, PS. Ladislav Haskovec and 100 years of akathisia. American Journal of Psychiatry. 2002;159(5):727-727.
14. Havaki-Kontaxaki BJ, Kontaxakis VP, Christodoulou GN. Prevalence and characteristics of patients with pseudoakathisia. Eur Neuropsychopharmacol. 2000;10(5):333-336.
15. Lang AE. Withdrawal akathisia: case reports and a proposed classification of chronic akathisia. Mov Disord. 1994;9(2):188-192.
16. Sachdev P. The epidemiology of drug-induced akathisia: Part II. Chronic, tardive, and withdrawal akathisias. Schizophr Bull. 1995;21(3):451-461.
17. Kern DS, Lang AE. Acute akathisia. In: Friedman JH, ed. Medication-induced movement disorders. Cambridge, United Kingdom: Cambridge University Press; 2015:12-24.
18. Adler LA, Angrist B, Reiter S, et al. Neuroleptic-induced akathisia: a review. Psychopharmacology (Berl). 1989;97(1):1-11.
19. Stahl SM, Loonen AJM. The mechanism of drug-induced akathisia. CNS Spectr. 2011;16(1):7-10.
20. Sachdev P, Kruk J. Clinical characteristics and predisposing factors in acute drug-induced akathisia. Arch Gen Psychiatry. 1994;51(12):963-974.
21. Laoutidis ZG, Luckhaus C. 5-HT2A receptor antagonists for the treatment of neuroleptic-induced akathisia: a systematic review and meta-analysis. Int J Neuropsychopharmacol. 2014;17(5):823-832.
22. Lima AR, Bacalcthuk J, Barnes TR, et al. Central action beta-blockers versus placebo for neuroleptic-induced acute akathisia. Cochrane Database Syst Rev. 2004;(4):CD001946.
23. Sachdev P, Loneragan C. Intravenous benztropine and propranolol challenges in acute neuroleptic-induced akathisia. Clin Neuropharmacol. 1993;16(4):324-331.
24. Lima AR, Weiser KV, Bacaltchuk J, et al. Anticholinergics for neuroleptic-induced acute akathisia. Cochrane Database Syst Rev. 2004;(1):CD003727.
25. Fleischhacker WW, Roth SD, Kane JM. The pharmacologic treatment of neuroleptic-induced akathisia. J Clin Psychopharmacol. 1990;10(1):12-21.
26. Blaisdell GD. Akathisia: a comprehensive review and treatment summary. Pharmacopsychiatry. 1994;27(4):139-146.
27. Poyurovsky M. Acute antipsychotic-induced akathisia revisited. Br J Psychiatry. 2010;196(2):89-91.
28. Adler LA, Reiter S, Corwin J, et al. Neuroleptic-induced akathisia: propranolol versus benztropine. Biol Psychiatry. 1988;23(2):211-213.
29. Adler LA, Peselow E, Rosenthal M, et al. A controlled comparison of the effects of propranolol, benztropine, and placebo on akathisia: an interim analysis. Psychopharmacol Bull. 1993;29(2):283-286.
30. Bender B, Friedman B, Davitt M, et al. 118: metoclopramide in the emergency department: a randomized factorial design study to determine the influence of dose and diphenhydramine on akathisia. Ann of Emerg Med. 2008;52(4):S78.
31. Parlak I, Erdur B, Parlak M, et al. Midazolam vs. diphenhydramine for the treatment of metoclopramide-induced akathisia: a randomized controlled trial. Acad Emerg Med. 2007;14(8):715-721.
32. Lima AR, Soares-Weiser K, Bacaltchuk J, et al. Benzodiazepines for neuroleptic-induced acute akathisia. Cochrane Database Syst Rev. 1999;(4):CD001950.
33. Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154(5):672-676..
CASE Anxiety in the ICU
Mr. B, age 42, an African American man, is admitted to the inpatient medical unit for surgical treatment of peritoneal carcinomatosis with pelvic exenteration. He has a history of metastatic rectal cancer, chronic pain, and hypertension, but no psychiatric history. Mr. B’s postsurgical hospital stay is complicated by treatment-resistant tachycardia and hypertension, and he requires a lengthy stay in the ICU. In the ICU, Mr. B reports having visual hallucinations where he sees an individual placing a drug in his IV line. Additionally, he reports severe anxiety related to this experience. His anxiety and visual hallucinations are treated with coadministration of IV lorazepam, diphenhydramine, and haloperidol. These medications resolve the hallucinations, but his anxiety worsens and he becomes restless. He receives additional doses of IV haloperidol administered in 5 mg increments and reaching a cumulative 12-hour dose of 50 mg. Mr. B continues to report anxiety, so the psychiatry consultation-liaison (C-L) service is called.
[polldaddy:9970907]
The authors’ observations
Determining the cause of Mr. B’s anxiety is challenging because of his prolonged medical course, com
From a medical perspective, in a post-surgical patient treated in the ICU, the consulting practitioner must pay particular attention to delirium. ICU delirium is common—one report indicated that it occurs in 32.3% of ICU patients1—and frequently confused with psychiatric morbidity.2 Identifying delirium as the cause of impairment is important because delirium has potentially modifiable underlying etiologies. Symptomatically, delirium presents as impairment and fluctuation in attention, awareness, and at least one other cognitive domain, with a clear indication that the impairment occurred over a short period of time and represents a departure from baseline.3 In Mr. B’s case, these symptoms have not been excluded and should be considered by the C-L psychiatrists.
In addition to delirium, the C-L team must consider psychiatric comorbidity. Mr. B has no psychiatric history and a sudden first occurrence of hallucinations; therefore, it is unlikely that he has developed a primary psychotic disorder. Because he reported his symptoms had been present only for several days, he would not meet criteria for schizophrenia, which according to DSM-5 criteria require at least 1 month of ≥2 symptoms (including delusions, hallucinations, disorganized speech, disorganized behavior, or negative symptoms) and 6 months of declining function.3 However, although it is improbable, the C-L team must consider a primary psychotic illness, particularly given the potential devastating consequence of being misdiagnosed and mismanaged for an alternative illness. Unlike psychotic disorders, anxiety disorders are significantly more prevalent in the U.S. general population than primary psychotic disorders.4 Furthermore, the prevalence of anxiety disorders increases in the ICU setting; one study found that up to 61% of ICU patients setting experience “anxiety features.”5 Therefore, anxiety disorders and stress disorders should be considered in ICU patients who exhibit psychiatric symptoms.
Clinicians also should consider medication-induced adverse effects. In the ICU, patients are frequently managed on multiple medications, which increase their risk of developing adverse effects and adverse reactions.6 One potential consequence of polypharmacy is delirium, which remains a relevant potential diagnosis for Mr. B.7 Alternative consequences vary by medication and their respective pharmacodynamics. We take into consideration Mr. B’s exposure to high doses of the high-potency antipsychotic agent, haloperidol. Exposure to haloperidol can result in extrapyramidal symptoms, including akathisia,8,9,10 and the rare, but potentially fatal, NMS.11 These reactions can often be distinguished by taking a thorough history and a physical evaluation. In the case of akathisia, the clinician should look for medication exposure, titration, or taper. Most commonly, akathisia occurs secondary to antipsychotic exposure,12 followed by the onset of a combination of subjective symptoms, such as restlessness, anxiety, and irritability, and an objective symptom of increased motor activity.3 NMS, on the other hand, is distinguished by symptoms that include hyperthermia (>38ºC), diaphoresis, severe rigidity, urinary incontinence, vital instability, alterations in mental health status, and elevations in creatine kinase greater than 4-fold the upper limit, usually in the setting of treatment with antipsychotics.3 Nearly all cases of NMS occur within the first 30 days of antipsychotic exposure.3 While, overtly, NMS may appear to be less subtle than akathisia, clinicians should still be weary to rule out this admittedly rare, though potentially lethal diagnosis, especially in an ICU patient, where the diagnosis can be muddied by medical comorbidities that may mask the syndrome.
Continue to: EVALUATION Focus on akathisia
EVALUATION Focus on akathisia
On interview by the C-L team, Mr. B is visibly restless, moving all 4 extremities. He reports increased anxiety and irritability over the past 2 to 3 days. Mr. B states that he is aware of his increased motor movements and can briefly suppress them. However, after several seconds, he again begins spontaneously fidgeting, moving all 4 extremities and shifting from side to side in bed, saying, “I just feel anxious.” He denies having visual hallucinations, and says that the previous hallucinations had spontaneously presented and remitted after surgery. He denies the use of psychotropics for mental illness, prior similar symptoms to this presentation, a family history of mental illness, recent illicit substance use, or excessive alcohol use prior to presentation. This history is corroborated by collateral information from his brother, who was present in the ICU. On physical examination, Mr. B is afebrile and his vital signs are within normal limits. He does not have muscular rigidity or neck dystonia. His laboratory values, including complete blood count, electrolytes, liver function tests, and creatine phosphokinase, are within normal limits.
His medication administration record includes 46 standing agents, 16 “as-needed” agents, and 8 infusions. Several of the standing agents had psychotropic properties; however, the most salient were several opioids, ketamine, midazolam, lorazepam, dexamethasone, haloperidol, and olanzapine.
[polldaddy:9970908]
The authors’ observations
We determined that the most likely diagnosis for Mr. B’s symptoms was medication-induced akathisia secondary to haloperidol. Akathisia, coined by Haskovec in 1901,12,13 is from Greek, meaning an “inability to sit.”12 DSM-5 describes 2 forms of akathisia: medication-induced acute akathisia, and tardive akathisia.3 In the literature, others have described additional classifications, including chronic akathisia, withdrawal akathisia, and pseudoakathisia (Table 13,14-17). In Mr. B’s case, given his sudden development of symptoms and their direct chronologic relationship to antipsychotic treatment, and his combined subjective and objective symptoms, we believed that Mr. B’s symptoms were consistent with medication-induced acute akathisia (MIA). The identification and treatment of this clinical entity is important for several reasons, including reducing patient morbidity and maximizing patient comfort. Additionally, because akathisia has been associated with poor medication adherence, increased agitation/aggression, increased suicidality, and the eventual development of tardive dyskinesia,18 it is a relevant prognostic consideration when deciding to treat a patient with antipsychotics.
Pathophysiologically, we have yet to fully shed light on the exact underpinnings of akathisia. Much of our present knowledge stems from patient response to pharmacologic agents. While dopamine blockade has been linked to akathisia, the exact mechanism is not completely understood. Previous theories linking nigrostriatal pathways have been expanded to include mesocortical and mesolimbic considerations.12,17,18 Similarly surmised from medication effects, the transmitters y-aminobutyric acid, serotonin/5-hydroxytryptamine (5-HT), norepinephrine, and acetylcholine also have been linked to this syndrome, though as of yet, exact gross pathophysiologic mechanisms have not been fully elucidated.12 More recently, Stahl and Loonen19 described a novel mechanism by which they link the shell of the nucleus accumbens to akathisia. In their report, they indicate that the potential reduction in dopaminergic activity, secondary to antipsychotic administration, can result in compensatory noradrenergic activation of the locus coeruleus.19 The increased noradrenergic activity results in the downstream activation of the shell of the nucleus accumbens.19 The activation of the nucleus accumbens shell, which has been linked to unconditioned feeding and fear behavior, can then result in a cascade of effects that would phenotypically present as the syndrome we recognize to be akathisia.19
Numerous etiologies have been linked to MIA. Of these, high-potency antipsychotics are believed to remain the greatest risk factor for akathisia,18 although atypical antipsychotics, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors, have been linked to the disorder.18,19
Continue to: Regarding antipsychotics...
Regarding antipsychotics, risk factors for akathisia include drug potency, dose, and rapidity of titration.20 All of these factors were relevant in our patient’s case. Risk across antipsychotic classes is not well understood; few head-to-head studies have comparing antipsychotics. However, general estimates suggest a 15% to 40% prevalence in patients exposed to typical antipsychotics, as compared with 0% to 12% exposed to atypical antipsychotics.8 The literature-reported difference in risk, as well as our patient’s comparative difference in exposure to large doses of haloperidol (50 mg) as compared with 1 dose of olanzapine (5 mg), led us to believe his akathisia developed primarily due to his exposure to haloperidol. Conclusively linking his symptoms to haloperidol alone, however, is not possible, and we did consider that olanzapine may in fact have had some effect in worsening Mr. B’s akathisia.
[polldaddy:9970909]
The authors’ observations
While there are reports on the efficacy of various agents in the treatment of akathisia, the most commonly evaluated agents are propranolol, anticholinergics, and benzodiazepines.17, 21
Propranolol is a nonselective beta-adrenergic blocker with numerous indications.17 Despite a 2004 Cochrane Review indicating that there is no evidence in support of central acting beta-blockers for treating akathisia,22 propranolol is not yet recognized as an appropriate treatment.17 The reason for this discrepancy is likely due to the Cochrane Review’s restrictive inclusion criteria, which prevented the analysis of much of the literature.22 In fact, several reports cite evidence for the treatment efficacy of propranolol17 and, to date, some reports continue to advocate for its use as a first-line agent in the treatment of akathisia. Admittedly, besides the Cochrane Review,22 other reports have found propranolol to be ineffective for treating akathisia,23 although these tend to be limited by their population size and generalizability.
As with propranolol, a 2006 Cochrane Review found “no reliable evidence to support or refute” using anticholinergic agents in the treatment of akathisia.24 We suspect that the review’s findings were likely secondary to its strict inclusion criteria.24 In fact, several reports support using anticholinergic agents for treating akathisia.25 Here we focus on benztropine and diphenhydramine.
Two reviews—Blaisdell26 (1994) and Poyurovsky27 (2010)—suggest modest benefits from benztropine, primarily in patients with comorbid Parkinson’s disease. Despite these benefits, head-to-head trials seem to either point to the superiority of propranolol or to no difference between these agents for treating akathisia.28,29 In a review, we only found 1 trial demonstrating benztropine’s superiority over propranolol,23 but this trial was constrained by its small population (6 patients). Therefore, the data suggest that, when indicated, clinicians should lean towards using propranolol for treating akathisia.
Continue to: Diphenhydramine, a first-generation antihistamine...
Diphenhydramine, a first-generation antihistamine with antimuscarinic properties, has been studied for its efficacy in treating metoclopramide-induced akathisia in the emergency setting.30 There are several reports on the efficacy of this agent, including a large randomized study involving 281 patients that found it effective for preventing metoclopramide-induced akathisia.30 Another head-to-head trial reported the benefit of the diphenhydramine vs midazolam.31 Both agents were efficacious for treating akathisia; however, midazolam had a more rapid onset. Despite these positive reports, double-blind trials have found diphenhydramine to be ineffective,17 which suggests propranolol should be the first-line agent, assuming it is not contraindicated.
Benzodiazepines have also been found to be efficacious for treating akathisia. A 1999 Cochrane Review included 2 randomized controlled trials that assessed the efficacy of clonazepam vs placebo for treating akathisia.32 It found evidence of benefit for clonazepam, but questioned the generalizability of these studies.32 This review did not include several other reports that suggest benefits of other benzodiazepines for treating akathisia. Other than clonazepam, reports suggest benefit for diazepam, lorazepam, and midazolam for treating akathisia.17 Despite this evidence and the findings from this Cochrane Review, the literature does not appear to point to clear dominance of these agents over propranolol. Given the safety concerns when prescribing benzodiazepines, it would be prudent to utilize propranolol as a first-line agent for treating akathisia.
Finally, other reports have cited treatment efficacy linked to serotonin 2A receptor (5-HT2A) antagonists (mianserin, mirtazapine, and trazodone), clonidine, gabapentin, amantadine, and other agents.17 If treatment with propranolol is ineffective or contraindicated, clinicians should utilize their clinical judgement in deciding on the use of one agent over another.
OUTCOME Complete resolution
Haloperidol is discontinued and diphenhydramine, 50 mg IV, is administered. (Diphenhydramine was used instead of propranolol due to immediacy of availability.) Most of Mr. B’s signs and symptoms resolve on a repeat interview 3 hours later. He receives another dose of diphenhydramine, 25 mg IV, for persistent mild irritability. By Day 2 of follow-up, his symptoms completely resolve as measured on the Barnes Akathisia Scale33 (Table 2).
Continue to: Bottom Line
Bottom Line
Akathisia is an elusive adverse effect of antipsychotics and can be misdiagnosed as anxiety. Close consideration should be given to potential medical, psychiatric, and drug-related etiologies in patients who have a prolonged medical course, comorbidities, and exposure to multiple pharmacologic agents.
Related Resources
- Factor SA, Leffler JB, Murray CF. Drug-induced movement disorders: a clinical review. Medscape. http://www.medscape.org/viewarticle/586881.
- Marder S, Stroup TS. Pharmacotherapy for schizophrenia: side effect management. UpToDate. https://www.uptodate.com/contents/pharmacotherapy-for-schizophrenia-side-effect-management.
Drug Brand Names
Amantadine • Symmetrel
Benztropine • Cogentin
Clonazepam • Klonopin
Clonidine • Catapres
Dexamethasone • Decadron
Diazepam • Valium
Diphenhydramine • Benadryl
Gabapentin • Neurontin
Haloperidol • Haldol
Ketamine • Ketalar
Lorazepam • Ativan
Metoclopramide • Reglan
Mianserin • Tolvon
Midazolam • Versed
Mirtazapine • Remeron
Olanzapine • Zyprexa
Propranolol • Inderal
Rivastigmine • Exelon
Trazodone • Oleptro
CASE Anxiety in the ICU
Mr. B, age 42, an African American man, is admitted to the inpatient medical unit for surgical treatment of peritoneal carcinomatosis with pelvic exenteration. He has a history of metastatic rectal cancer, chronic pain, and hypertension, but no psychiatric history. Mr. B’s postsurgical hospital stay is complicated by treatment-resistant tachycardia and hypertension, and he requires a lengthy stay in the ICU. In the ICU, Mr. B reports having visual hallucinations where he sees an individual placing a drug in his IV line. Additionally, he reports severe anxiety related to this experience. His anxiety and visual hallucinations are treated with coadministration of IV lorazepam, diphenhydramine, and haloperidol. These medications resolve the hallucinations, but his anxiety worsens and he becomes restless. He receives additional doses of IV haloperidol administered in 5 mg increments and reaching a cumulative 12-hour dose of 50 mg. Mr. B continues to report anxiety, so the psychiatry consultation-liaison (C-L) service is called.
[polldaddy:9970907]
The authors’ observations
Determining the cause of Mr. B’s anxiety is challenging because of his prolonged medical course, com
From a medical perspective, in a post-surgical patient treated in the ICU, the consulting practitioner must pay particular attention to delirium. ICU delirium is common—one report indicated that it occurs in 32.3% of ICU patients1—and frequently confused with psychiatric morbidity.2 Identifying delirium as the cause of impairment is important because delirium has potentially modifiable underlying etiologies. Symptomatically, delirium presents as impairment and fluctuation in attention, awareness, and at least one other cognitive domain, with a clear indication that the impairment occurred over a short period of time and represents a departure from baseline.3 In Mr. B’s case, these symptoms have not been excluded and should be considered by the C-L psychiatrists.
In addition to delirium, the C-L team must consider psychiatric comorbidity. Mr. B has no psychiatric history and a sudden first occurrence of hallucinations; therefore, it is unlikely that he has developed a primary psychotic disorder. Because he reported his symptoms had been present only for several days, he would not meet criteria for schizophrenia, which according to DSM-5 criteria require at least 1 month of ≥2 symptoms (including delusions, hallucinations, disorganized speech, disorganized behavior, or negative symptoms) and 6 months of declining function.3 However, although it is improbable, the C-L team must consider a primary psychotic illness, particularly given the potential devastating consequence of being misdiagnosed and mismanaged for an alternative illness. Unlike psychotic disorders, anxiety disorders are significantly more prevalent in the U.S. general population than primary psychotic disorders.4 Furthermore, the prevalence of anxiety disorders increases in the ICU setting; one study found that up to 61% of ICU patients setting experience “anxiety features.”5 Therefore, anxiety disorders and stress disorders should be considered in ICU patients who exhibit psychiatric symptoms.
Clinicians also should consider medication-induced adverse effects. In the ICU, patients are frequently managed on multiple medications, which increase their risk of developing adverse effects and adverse reactions.6 One potential consequence of polypharmacy is delirium, which remains a relevant potential diagnosis for Mr. B.7 Alternative consequences vary by medication and their respective pharmacodynamics. We take into consideration Mr. B’s exposure to high doses of the high-potency antipsychotic agent, haloperidol. Exposure to haloperidol can result in extrapyramidal symptoms, including akathisia,8,9,10 and the rare, but potentially fatal, NMS.11 These reactions can often be distinguished by taking a thorough history and a physical evaluation. In the case of akathisia, the clinician should look for medication exposure, titration, or taper. Most commonly, akathisia occurs secondary to antipsychotic exposure,12 followed by the onset of a combination of subjective symptoms, such as restlessness, anxiety, and irritability, and an objective symptom of increased motor activity.3 NMS, on the other hand, is distinguished by symptoms that include hyperthermia (>38ºC), diaphoresis, severe rigidity, urinary incontinence, vital instability, alterations in mental health status, and elevations in creatine kinase greater than 4-fold the upper limit, usually in the setting of treatment with antipsychotics.3 Nearly all cases of NMS occur within the first 30 days of antipsychotic exposure.3 While, overtly, NMS may appear to be less subtle than akathisia, clinicians should still be weary to rule out this admittedly rare, though potentially lethal diagnosis, especially in an ICU patient, where the diagnosis can be muddied by medical comorbidities that may mask the syndrome.
Continue to: EVALUATION Focus on akathisia
EVALUATION Focus on akathisia
On interview by the C-L team, Mr. B is visibly restless, moving all 4 extremities. He reports increased anxiety and irritability over the past 2 to 3 days. Mr. B states that he is aware of his increased motor movements and can briefly suppress them. However, after several seconds, he again begins spontaneously fidgeting, moving all 4 extremities and shifting from side to side in bed, saying, “I just feel anxious.” He denies having visual hallucinations, and says that the previous hallucinations had spontaneously presented and remitted after surgery. He denies the use of psychotropics for mental illness, prior similar symptoms to this presentation, a family history of mental illness, recent illicit substance use, or excessive alcohol use prior to presentation. This history is corroborated by collateral information from his brother, who was present in the ICU. On physical examination, Mr. B is afebrile and his vital signs are within normal limits. He does not have muscular rigidity or neck dystonia. His laboratory values, including complete blood count, electrolytes, liver function tests, and creatine phosphokinase, are within normal limits.
His medication administration record includes 46 standing agents, 16 “as-needed” agents, and 8 infusions. Several of the standing agents had psychotropic properties; however, the most salient were several opioids, ketamine, midazolam, lorazepam, dexamethasone, haloperidol, and olanzapine.
[polldaddy:9970908]
The authors’ observations
We determined that the most likely diagnosis for Mr. B’s symptoms was medication-induced akathisia secondary to haloperidol. Akathisia, coined by Haskovec in 1901,12,13 is from Greek, meaning an “inability to sit.”12 DSM-5 describes 2 forms of akathisia: medication-induced acute akathisia, and tardive akathisia.3 In the literature, others have described additional classifications, including chronic akathisia, withdrawal akathisia, and pseudoakathisia (Table 13,14-17). In Mr. B’s case, given his sudden development of symptoms and their direct chronologic relationship to antipsychotic treatment, and his combined subjective and objective symptoms, we believed that Mr. B’s symptoms were consistent with medication-induced acute akathisia (MIA). The identification and treatment of this clinical entity is important for several reasons, including reducing patient morbidity and maximizing patient comfort. Additionally, because akathisia has been associated with poor medication adherence, increased agitation/aggression, increased suicidality, and the eventual development of tardive dyskinesia,18 it is a relevant prognostic consideration when deciding to treat a patient with antipsychotics.
Pathophysiologically, we have yet to fully shed light on the exact underpinnings of akathisia. Much of our present knowledge stems from patient response to pharmacologic agents. While dopamine blockade has been linked to akathisia, the exact mechanism is not completely understood. Previous theories linking nigrostriatal pathways have been expanded to include mesocortical and mesolimbic considerations.12,17,18 Similarly surmised from medication effects, the transmitters y-aminobutyric acid, serotonin/5-hydroxytryptamine (5-HT), norepinephrine, and acetylcholine also have been linked to this syndrome, though as of yet, exact gross pathophysiologic mechanisms have not been fully elucidated.12 More recently, Stahl and Loonen19 described a novel mechanism by which they link the shell of the nucleus accumbens to akathisia. In their report, they indicate that the potential reduction in dopaminergic activity, secondary to antipsychotic administration, can result in compensatory noradrenergic activation of the locus coeruleus.19 The increased noradrenergic activity results in the downstream activation of the shell of the nucleus accumbens.19 The activation of the nucleus accumbens shell, which has been linked to unconditioned feeding and fear behavior, can then result in a cascade of effects that would phenotypically present as the syndrome we recognize to be akathisia.19
Numerous etiologies have been linked to MIA. Of these, high-potency antipsychotics are believed to remain the greatest risk factor for akathisia,18 although atypical antipsychotics, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors, have been linked to the disorder.18,19
Continue to: Regarding antipsychotics...
Regarding antipsychotics, risk factors for akathisia include drug potency, dose, and rapidity of titration.20 All of these factors were relevant in our patient’s case. Risk across antipsychotic classes is not well understood; few head-to-head studies have comparing antipsychotics. However, general estimates suggest a 15% to 40% prevalence in patients exposed to typical antipsychotics, as compared with 0% to 12% exposed to atypical antipsychotics.8 The literature-reported difference in risk, as well as our patient’s comparative difference in exposure to large doses of haloperidol (50 mg) as compared with 1 dose of olanzapine (5 mg), led us to believe his akathisia developed primarily due to his exposure to haloperidol. Conclusively linking his symptoms to haloperidol alone, however, is not possible, and we did consider that olanzapine may in fact have had some effect in worsening Mr. B’s akathisia.
[polldaddy:9970909]
The authors’ observations
While there are reports on the efficacy of various agents in the treatment of akathisia, the most commonly evaluated agents are propranolol, anticholinergics, and benzodiazepines.17, 21
Propranolol is a nonselective beta-adrenergic blocker with numerous indications.17 Despite a 2004 Cochrane Review indicating that there is no evidence in support of central acting beta-blockers for treating akathisia,22 propranolol is not yet recognized as an appropriate treatment.17 The reason for this discrepancy is likely due to the Cochrane Review’s restrictive inclusion criteria, which prevented the analysis of much of the literature.22 In fact, several reports cite evidence for the treatment efficacy of propranolol17 and, to date, some reports continue to advocate for its use as a first-line agent in the treatment of akathisia. Admittedly, besides the Cochrane Review,22 other reports have found propranolol to be ineffective for treating akathisia,23 although these tend to be limited by their population size and generalizability.
As with propranolol, a 2006 Cochrane Review found “no reliable evidence to support or refute” using anticholinergic agents in the treatment of akathisia.24 We suspect that the review’s findings were likely secondary to its strict inclusion criteria.24 In fact, several reports support using anticholinergic agents for treating akathisia.25 Here we focus on benztropine and diphenhydramine.
Two reviews—Blaisdell26 (1994) and Poyurovsky27 (2010)—suggest modest benefits from benztropine, primarily in patients with comorbid Parkinson’s disease. Despite these benefits, head-to-head trials seem to either point to the superiority of propranolol or to no difference between these agents for treating akathisia.28,29 In a review, we only found 1 trial demonstrating benztropine’s superiority over propranolol,23 but this trial was constrained by its small population (6 patients). Therefore, the data suggest that, when indicated, clinicians should lean towards using propranolol for treating akathisia.
Continue to: Diphenhydramine, a first-generation antihistamine...
Diphenhydramine, a first-generation antihistamine with antimuscarinic properties, has been studied for its efficacy in treating metoclopramide-induced akathisia in the emergency setting.30 There are several reports on the efficacy of this agent, including a large randomized study involving 281 patients that found it effective for preventing metoclopramide-induced akathisia.30 Another head-to-head trial reported the benefit of the diphenhydramine vs midazolam.31 Both agents were efficacious for treating akathisia; however, midazolam had a more rapid onset. Despite these positive reports, double-blind trials have found diphenhydramine to be ineffective,17 which suggests propranolol should be the first-line agent, assuming it is not contraindicated.
Benzodiazepines have also been found to be efficacious for treating akathisia. A 1999 Cochrane Review included 2 randomized controlled trials that assessed the efficacy of clonazepam vs placebo for treating akathisia.32 It found evidence of benefit for clonazepam, but questioned the generalizability of these studies.32 This review did not include several other reports that suggest benefits of other benzodiazepines for treating akathisia. Other than clonazepam, reports suggest benefit for diazepam, lorazepam, and midazolam for treating akathisia.17 Despite this evidence and the findings from this Cochrane Review, the literature does not appear to point to clear dominance of these agents over propranolol. Given the safety concerns when prescribing benzodiazepines, it would be prudent to utilize propranolol as a first-line agent for treating akathisia.
Finally, other reports have cited treatment efficacy linked to serotonin 2A receptor (5-HT2A) antagonists (mianserin, mirtazapine, and trazodone), clonidine, gabapentin, amantadine, and other agents.17 If treatment with propranolol is ineffective or contraindicated, clinicians should utilize their clinical judgement in deciding on the use of one agent over another.
OUTCOME Complete resolution
Haloperidol is discontinued and diphenhydramine, 50 mg IV, is administered. (Diphenhydramine was used instead of propranolol due to immediacy of availability.) Most of Mr. B’s signs and symptoms resolve on a repeat interview 3 hours later. He receives another dose of diphenhydramine, 25 mg IV, for persistent mild irritability. By Day 2 of follow-up, his symptoms completely resolve as measured on the Barnes Akathisia Scale33 (Table 2).
Continue to: Bottom Line
Bottom Line
Akathisia is an elusive adverse effect of antipsychotics and can be misdiagnosed as anxiety. Close consideration should be given to potential medical, psychiatric, and drug-related etiologies in patients who have a prolonged medical course, comorbidities, and exposure to multiple pharmacologic agents.
Related Resources
- Factor SA, Leffler JB, Murray CF. Drug-induced movement disorders: a clinical review. Medscape. http://www.medscape.org/viewarticle/586881.
- Marder S, Stroup TS. Pharmacotherapy for schizophrenia: side effect management. UpToDate. https://www.uptodate.com/contents/pharmacotherapy-for-schizophrenia-side-effect-management.
Drug Brand Names
Amantadine • Symmetrel
Benztropine • Cogentin
Clonazepam • Klonopin
Clonidine • Catapres
Dexamethasone • Decadron
Diazepam • Valium
Diphenhydramine • Benadryl
Gabapentin • Neurontin
Haloperidol • Haldol
Ketamine • Ketalar
Lorazepam • Ativan
Metoclopramide • Reglan
Mianserin • Tolvon
Midazolam • Versed
Mirtazapine • Remeron
Olanzapine • Zyprexa
Propranolol • Inderal
Rivastigmine • Exelon
Trazodone • Oleptro
1. Cavallazzi R, Saad M, Marik PE. Delirium in the ICU: an overview. Ann Intensive Care. 2012;2:49.
2. Farrell KR, Ganzini L. Misdiagnosing delirium as depression in medically ill elderly patients. Arch Intern Med. 1995;155(22):2459-2464.
3. Diagnostic and statistical manual of mental disorders, 5th ed. Washington, DC: American Psychiatric Association; 2013.
4. National Alliance on Mental Illness. Mental health by the numbers. https://www.nami.org/learn-more/mental-health-by-the-numbers. Accessed March 4, 2018.
5. Jacka MJ, Mitchell N, Perez-Parada J. Incidence and prevalence of anxiety, depression, and post-traumatic stress disorder among critical care patients, families, and practitioners. J Anest & Inten Care Med. 2016;1(1):55555. doi: 10.19080/JAICM.2016.01.555555.
6. Reis AM, Cassiani SH. Adverse drug events in an intensive care unit of a university hospital. Eur J Clin Pharmacol. 2011;67(6):625-632.
7. Garpestad E, Devlin JW. Polypharmacy and delirium in critically ill older adults: recognition and prevention. Clin Geriatr Med. 2017;33(2):189-203.
8. Caroff SN, Hurford I, Lybrand J, et al. Movement disorders induced by antipsychotic drugs: implications of the CATIE schizophrenia trial. Neurol Clin. 2011;29(1):127-148.
9. Van Putten T, Marder SR. Toward a more reliable diagnosis of akathisia. Arch Gen Psychiatry. 1986;43(10):1015-1016.
10. Penders TM, Agarwal S, Rohaidy R. Persistent akathisia masquerading as agitated depression after use of ziprasidone in the treatment of bipolar depression. Neuropsychiatr Dis Treat. 2013;9:463-465.
11. Naganuma H, Fujii I. Incidence and risk factors in neuroleptic malignant syndrome. Acta Psychiatr Scand. 1994;90(6):424-426.
12. Forcen FE, Matsoukas K, Alici Y. Antipsychotic-induced akathisia in delirium: a systematic review. Palliat Support Care. 2016;14(1):77-84.
13. Brune M, Sachdev, PS. Ladislav Haskovec and 100 years of akathisia. American Journal of Psychiatry. 2002;159(5):727-727.
14. Havaki-Kontaxaki BJ, Kontaxakis VP, Christodoulou GN. Prevalence and characteristics of patients with pseudoakathisia. Eur Neuropsychopharmacol. 2000;10(5):333-336.
15. Lang AE. Withdrawal akathisia: case reports and a proposed classification of chronic akathisia. Mov Disord. 1994;9(2):188-192.
16. Sachdev P. The epidemiology of drug-induced akathisia: Part II. Chronic, tardive, and withdrawal akathisias. Schizophr Bull. 1995;21(3):451-461.
17. Kern DS, Lang AE. Acute akathisia. In: Friedman JH, ed. Medication-induced movement disorders. Cambridge, United Kingdom: Cambridge University Press; 2015:12-24.
18. Adler LA, Angrist B, Reiter S, et al. Neuroleptic-induced akathisia: a review. Psychopharmacology (Berl). 1989;97(1):1-11.
19. Stahl SM, Loonen AJM. The mechanism of drug-induced akathisia. CNS Spectr. 2011;16(1):7-10.
20. Sachdev P, Kruk J. Clinical characteristics and predisposing factors in acute drug-induced akathisia. Arch Gen Psychiatry. 1994;51(12):963-974.
21. Laoutidis ZG, Luckhaus C. 5-HT2A receptor antagonists for the treatment of neuroleptic-induced akathisia: a systematic review and meta-analysis. Int J Neuropsychopharmacol. 2014;17(5):823-832.
22. Lima AR, Bacalcthuk J, Barnes TR, et al. Central action beta-blockers versus placebo for neuroleptic-induced acute akathisia. Cochrane Database Syst Rev. 2004;(4):CD001946.
23. Sachdev P, Loneragan C. Intravenous benztropine and propranolol challenges in acute neuroleptic-induced akathisia. Clin Neuropharmacol. 1993;16(4):324-331.
24. Lima AR, Weiser KV, Bacaltchuk J, et al. Anticholinergics for neuroleptic-induced acute akathisia. Cochrane Database Syst Rev. 2004;(1):CD003727.
25. Fleischhacker WW, Roth SD, Kane JM. The pharmacologic treatment of neuroleptic-induced akathisia. J Clin Psychopharmacol. 1990;10(1):12-21.
26. Blaisdell GD. Akathisia: a comprehensive review and treatment summary. Pharmacopsychiatry. 1994;27(4):139-146.
27. Poyurovsky M. Acute antipsychotic-induced akathisia revisited. Br J Psychiatry. 2010;196(2):89-91.
28. Adler LA, Reiter S, Corwin J, et al. Neuroleptic-induced akathisia: propranolol versus benztropine. Biol Psychiatry. 1988;23(2):211-213.
29. Adler LA, Peselow E, Rosenthal M, et al. A controlled comparison of the effects of propranolol, benztropine, and placebo on akathisia: an interim analysis. Psychopharmacol Bull. 1993;29(2):283-286.
30. Bender B, Friedman B, Davitt M, et al. 118: metoclopramide in the emergency department: a randomized factorial design study to determine the influence of dose and diphenhydramine on akathisia. Ann of Emerg Med. 2008;52(4):S78.
31. Parlak I, Erdur B, Parlak M, et al. Midazolam vs. diphenhydramine for the treatment of metoclopramide-induced akathisia: a randomized controlled trial. Acad Emerg Med. 2007;14(8):715-721.
32. Lima AR, Soares-Weiser K, Bacaltchuk J, et al. Benzodiazepines for neuroleptic-induced acute akathisia. Cochrane Database Syst Rev. 1999;(4):CD001950.
33. Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154(5):672-676..
1. Cavallazzi R, Saad M, Marik PE. Delirium in the ICU: an overview. Ann Intensive Care. 2012;2:49.
2. Farrell KR, Ganzini L. Misdiagnosing delirium as depression in medically ill elderly patients. Arch Intern Med. 1995;155(22):2459-2464.
3. Diagnostic and statistical manual of mental disorders, 5th ed. Washington, DC: American Psychiatric Association; 2013.
4. National Alliance on Mental Illness. Mental health by the numbers. https://www.nami.org/learn-more/mental-health-by-the-numbers. Accessed March 4, 2018.
5. Jacka MJ, Mitchell N, Perez-Parada J. Incidence and prevalence of anxiety, depression, and post-traumatic stress disorder among critical care patients, families, and practitioners. J Anest & Inten Care Med. 2016;1(1):55555. doi: 10.19080/JAICM.2016.01.555555.
6. Reis AM, Cassiani SH. Adverse drug events in an intensive care unit of a university hospital. Eur J Clin Pharmacol. 2011;67(6):625-632.
7. Garpestad E, Devlin JW. Polypharmacy and delirium in critically ill older adults: recognition and prevention. Clin Geriatr Med. 2017;33(2):189-203.
8. Caroff SN, Hurford I, Lybrand J, et al. Movement disorders induced by antipsychotic drugs: implications of the CATIE schizophrenia trial. Neurol Clin. 2011;29(1):127-148.
9. Van Putten T, Marder SR. Toward a more reliable diagnosis of akathisia. Arch Gen Psychiatry. 1986;43(10):1015-1016.
10. Penders TM, Agarwal S, Rohaidy R. Persistent akathisia masquerading as agitated depression after use of ziprasidone in the treatment of bipolar depression. Neuropsychiatr Dis Treat. 2013;9:463-465.
11. Naganuma H, Fujii I. Incidence and risk factors in neuroleptic malignant syndrome. Acta Psychiatr Scand. 1994;90(6):424-426.
12. Forcen FE, Matsoukas K, Alici Y. Antipsychotic-induced akathisia in delirium: a systematic review. Palliat Support Care. 2016;14(1):77-84.
13. Brune M, Sachdev, PS. Ladislav Haskovec and 100 years of akathisia. American Journal of Psychiatry. 2002;159(5):727-727.
14. Havaki-Kontaxaki BJ, Kontaxakis VP, Christodoulou GN. Prevalence and characteristics of patients with pseudoakathisia. Eur Neuropsychopharmacol. 2000;10(5):333-336.
15. Lang AE. Withdrawal akathisia: case reports and a proposed classification of chronic akathisia. Mov Disord. 1994;9(2):188-192.
16. Sachdev P. The epidemiology of drug-induced akathisia: Part II. Chronic, tardive, and withdrawal akathisias. Schizophr Bull. 1995;21(3):451-461.
17. Kern DS, Lang AE. Acute akathisia. In: Friedman JH, ed. Medication-induced movement disorders. Cambridge, United Kingdom: Cambridge University Press; 2015:12-24.
18. Adler LA, Angrist B, Reiter S, et al. Neuroleptic-induced akathisia: a review. Psychopharmacology (Berl). 1989;97(1):1-11.
19. Stahl SM, Loonen AJM. The mechanism of drug-induced akathisia. CNS Spectr. 2011;16(1):7-10.
20. Sachdev P, Kruk J. Clinical characteristics and predisposing factors in acute drug-induced akathisia. Arch Gen Psychiatry. 1994;51(12):963-974.
21. Laoutidis ZG, Luckhaus C. 5-HT2A receptor antagonists for the treatment of neuroleptic-induced akathisia: a systematic review and meta-analysis. Int J Neuropsychopharmacol. 2014;17(5):823-832.
22. Lima AR, Bacalcthuk J, Barnes TR, et al. Central action beta-blockers versus placebo for neuroleptic-induced acute akathisia. Cochrane Database Syst Rev. 2004;(4):CD001946.
23. Sachdev P, Loneragan C. Intravenous benztropine and propranolol challenges in acute neuroleptic-induced akathisia. Clin Neuropharmacol. 1993;16(4):324-331.
24. Lima AR, Weiser KV, Bacaltchuk J, et al. Anticholinergics for neuroleptic-induced acute akathisia. Cochrane Database Syst Rev. 2004;(1):CD003727.
25. Fleischhacker WW, Roth SD, Kane JM. The pharmacologic treatment of neuroleptic-induced akathisia. J Clin Psychopharmacol. 1990;10(1):12-21.
26. Blaisdell GD. Akathisia: a comprehensive review and treatment summary. Pharmacopsychiatry. 1994;27(4):139-146.
27. Poyurovsky M. Acute antipsychotic-induced akathisia revisited. Br J Psychiatry. 2010;196(2):89-91.
28. Adler LA, Reiter S, Corwin J, et al. Neuroleptic-induced akathisia: propranolol versus benztropine. Biol Psychiatry. 1988;23(2):211-213.
29. Adler LA, Peselow E, Rosenthal M, et al. A controlled comparison of the effects of propranolol, benztropine, and placebo on akathisia: an interim analysis. Psychopharmacol Bull. 1993;29(2):283-286.
30. Bender B, Friedman B, Davitt M, et al. 118: metoclopramide in the emergency department: a randomized factorial design study to determine the influence of dose and diphenhydramine on akathisia. Ann of Emerg Med. 2008;52(4):S78.
31. Parlak I, Erdur B, Parlak M, et al. Midazolam vs. diphenhydramine for the treatment of metoclopramide-induced akathisia: a randomized controlled trial. Acad Emerg Med. 2007;14(8):715-721.
32. Lima AR, Soares-Weiser K, Bacaltchuk J, et al. Benzodiazepines for neuroleptic-induced acute akathisia. Cochrane Database Syst Rev. 1999;(4):CD001950.
33. Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154(5):672-676..
