Affiliations
Department of Pharmacy Practice, Campbell University School of Pharmacy and Health Sciences, Buies Creek, North Carolina, and Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina
Given name(s)
Andrew J.
Family name
Muzyk
Degrees
PharmD

Quetiapine for the Treatment of Delirium

Article Type
Article
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Quetiapine for the treatment of delirium
Author(s)
Stefanie B. Hawkins, PharmD
Mason Bucklin, PharmD
Andrew J. Muzyk, PharmD

Delirium is an acute fluctuation in mental status that includes symptoms of inattention, disorganized thinking, and altered level of consciousness occurring over a short time period.[1] Prevalence of delirium ranges from 10% to 30% in the hospitalized medically ill and ranges from 40% to 60% in intensive care unit (ICU) patients who are not receiving mechanical ventilation.[2, 3] Patients experience delirium more often if they are of older age; have dementia, cancer, or acquired immune deficiency syndrome; have undergone surgery; are terminally ill; or have received multiple psychoactive medications, particularly benzodiazepines or opioids.[3, 4, 5, 6, 7] Delirium is associated with high rates of morbidity and mortality,[8] with patients more likely to develop complications such as pneumonia, decubitus ulcers, and long‐term cognitive deficits.[9, 10, 11, 12] These complications, in turn, lead to longer hospital stays and increased costs of care.[13, 14] Currently, there are no antipsychotics approved by the US Food and Drug Administration for the treatment of delirium.

Both the 2002 American Society of Critical Care Medicine[12] and the 2004 American Psychiatric Association guidelines[15] on delirium recommend haloperidol as the antipsychotic of choice due to its potent tranquilizing effect, lack of active metabolites, and limited anticholinergic and sedating side effects. However, when given intravenously or at high cumulative doses (generally >35 mg/day), haloperidol has been shown to cause QT interval prolongation potentially leading to torsades de pointes and sudden cardiac death.[15] Recent research in delirium treatment has focused on the second‐generation antipsychotics, and these studies have reported positive findings,[16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29] although no significant differences have been found compared to haloperidol.[16, 17, 18, 22, 23, 24] Systematic reviews have also failed to show a significant difference in efficacy or safety between second‐generation and first‐generation antipsychotics and unfortunately report a number of limitations including poor study designs, small sample sizes, lack of a placebo control group, exclusion of ICU patients, and weak primary outcomes.[8, 30, 31, 32] Attempting to correct for a number of these limitations, recent research with quetiapine has reported promising results in 2 controlled studies.[19, 20]

Quetiapine is a second‐generation antipsychotic with a very low affinity for dopamine receptors and a very high affinity for serotonin receptors.[33, 34] Additionally, quetiapine has a high affinity for histamine and 1‐adrenergic receptors, but a very low affinity for M1 muscarinic receptors.[34] This mechanism of action may allow quetiapine to effectively treat delirium and provide sedation without causing significant extrapyramidal side effects associated with potent dopamine receptor antagonism or precipitating delirium through muscarinic receptor antagonism. Quetiapine has a rapid absorption and a short half‐life (36 hours), giving it a quick onset of action and a fast elimination from the body.[35] Unlike haloperidol, it is only available in oral dosage forms, but can be crushed to administer via enteral tube. Common reported adverse effects include somnolence, hypotension, and dizziness. Although quetiapine has been shown to prolong QTc, Harrigan et al. reported a mean increase in QTc from baseline of 5.7 msec; there was no significant effect on this change in the presence of a metabolic inhibitor, ketoconazole.[36] The mean change in QTc from baseline with quetiapine was lower than the change reported with oral haloperidol, 5.7 msec compared to 7.1 msec, respectively. No statistical comparison was performed between these 2 drugs on this measure. Quetiapine does carry a black box warning for increased mortality in elderly patients with dementia‐related psychosis.[35] However, this risk has also been found with first‐generation antipsychotics.[37, 38, 39] A recent study found this risk of sudden cardiac death extended to adult users of both first‐ and second‐generation antipsychotics.[40] In contrast, Elie et al. found no increased risk of mortality in elderly patients with delirium receiving antipsychoticsover 90% were prescribed either haloperidol or risperidonein their nested case‐controlled study.[41] Quetiapine has demonstrated some benefit with limited side effects in studies utilizing antipsychotics for the treatment of delirium. The purpose of this review was to evaluate the role of quetiapine for the treatment of delirium.

LITERATURE REVIEW

We performed an English‐language literature search of MEDLINE and Embase databases to identify journal articles published between January 1960 and December 2012. Keywords included quetiapine, second‐generation antipsychotic, atypical antipsychotic, delirium, and agitation. The search was limited to English‐language articles and adult subjects (>18 years). Based on our review of abstracts, we included both controlled and noncontrolled trials as long as treatment of delirium was the primary focus. We eliminated case reports, foreign language articles, and poster presentations. We identified 8 trials[19, 20, 24, 25, 26, 27, 28, 29] that included 2 double‐blind, randomized, placebo‐controlled trials, which are described in the text below.[19, 20] Six other trials, 5 open‐label[25, 26, 27, 28, 29] and 1 retrospective cohort,[24] are described in Table 1.

Descriptions of One Retrospective Cohort and Five Open‐Label Trials
Study Study Design No. of Patients Included in Analyses Patient Type Treatment Baseline Delirium Scores Quetiapine Dose (mg/day) (MeanSD) Efficacy Measures Results Side Effects

  • NOTE: Abbreviations: A, amisulpride; BID, twice a day; CDT, Clock Drawing Test; CGI‐s, Clinical Global Impression Scale‐Severity; DRS, Delirium Rating Scale; DRS‐J, Delirium Rating ScaleJapanese version; DRS‐R‐98, Delirium Rating Scale‐Revised‐Severity 98; EPS, extrapyramidal symptoms; H, haloperidol; IV, intravenous; MMSE, Mini‐Mental State Exam; NR, not reported; OL, open label; Q, quetiapine; RC, retrospective cohort; SD, standard deviation.

Schwartz et al. (2000)[24] RC 22 General hospital Quetiapine or haloperidol flexible dose DRS score 20.9 Q; 18.5 H 211.4 Q; 3.4 H >50% improvement in DRS scores 10/11 in each treatment group had >50% improvement in DRS scores EPS 2/11 H and 0/11 Q; mild‐to‐moderate sedation 0/11 H and 2/11 Q
Pae et al. (2004)[25] OL 22 Neurosurgery and orthopedic surgery and oncology Flexible dose quetiapine DRS‐R‐98 21.83.2 and CGI‐s 4.90.8 127.172.2 DRS‐R‐98 and CGI‐s score reduction DRS‐R‐98 9.33.8 (P<0.0001) and CGI‐s 2.11.1 (P<0.0001) reduction from baseline; 19/22 (86.3%) and 17/22 (77.3%) showed >50% score reduction for DRS‐R‐98 and CGI‐s, respectively EPS none; sedation requiring discontinuation 2; mild sedation 3; serious side effects none
Maneeton et al. (2007)[26] OL 17 General hospital Quetiapine 25100 mg/day in 1 or 2 divided doses DRS 24.53.2 and CGI‐s 4.90.9 45.728.7 50% reduction in DRS scores 15/17 (88.2%) had 50% reduction in DRS score; all DRS and CGI‐s scores on days 17 of the 7‐day treatment course were significantly lower than baseline scores EPS tremor 2; hypotension 2; daytime sleepiness 13; nightmare 3; dry mouth 2; nausea 1
Kim et al. (2003)[27] OL 12 (all male and age 64 years) General hospital Quetiapine 25 mg BID and increased by 25 mg every 2 days until patient maximally stabilized DRS 18.256.05; MMSE 14.505.90; CGI‐s 3.000.43; CDT 3.25 2.77 93.7523.31 Reduction in DRS, MMSE, CGI‐s, or CDT scores All scores were statistically significantly improved from baseline; DRS at end of study 0.631.21 (P=0.03) No dropouts due to side effects; EPS none; sedation 2; vivid dreams 1
Sasaki et al. (2003)[28] OL 12 General hospital Quetiapine started at 25 or 50 mg/day and titrated to maximal clinical effect DRS‐J 18.14.2 44.931.0 Remission was DRS‐J score <12 (cutoff for delirium) and resolution of delirium symptoms Remission occurred in all patients; mean DRS‐J score was reduced to 9.31.6 after remission No statistically significant change from baseline in EPS; no excessive daytime sedation, anticholinergic effects, vital sign, or lab parameter changes
Lee et al. (2005)[29] OL 31 Neurosurgery and orthopedic surgery, internal medicine, neurology and rehabilitation medicine Flexible dose quetiapine or amisulpride DRS‐R‐98 10.14.1 Q and 10.54.1 A 11385.5 Q; 156.497.5 A Reduction in DRS‐R‐98 score DRS‐R‐98 scores significantly reduced from baseline in both groups with 3.52.6 Q (P=0.001) and 3.51.4 A (P=0.000); no difference between groups (P=0.842); 12 (80%) Q and 13 (81.3%) A had >50% reduction in DRS‐R‐98 score No serious side effects; dropouts 5 Q and 4 A; oversedation 1 Q and 1 A; patient withdrawal 2 Q and 1 A; no statistical differences in total sleep time P=0.767 or quality of sleep P=0.984

Randomized Controlled Trials

Tahir et al. published a double‐blind, randomized, placebo‐controlled trial examining the efficacy and tolerability of quetiapine in the treatment of delirium.[19] Inclusion criteria were a Diagnostic and Statistical Manual of Mental Disorders‐IV diagnosis of delirium and a Delirium Rating Scale Revised 98 (DRS‐R‐98) total score of at least 15, indicating the presence of delirium. Subjects were excluded for major preexisting cognitive deficits, alcohol withdrawal, preexisting psychosis, substance dependence, inability to comply with the constraints of the trial, and concurrent medications that interact with quetiapine.

Forty‐two general medicine subjects were enrolled and randomized in the study with no difference in baseline characteristics. Patients received either placebo or quetiapine 25 mg once daily. Doses were titrated by 25 mg daily to a maximum daily dose of 175 mg in divided doses. The primary end point was DRS‐R‐98 total mean score assessed on days 1, 2, 3, 4, 7, and 10, with follow‐up assessment on day 30. Secondary outcome measures were Mini‐Mental State Examination (MMSE), the Brief Psychiatric Rating Scale, and the Clinical Global Improvement Scale. Tolerability was assessed using the Abnormal Involuntary Movements Scale and by clinical examination.

No differences in total mean DRS‐R‐98 score at individual time points reached statistical significance, but these scores improved more quickly in the quetiapine group than placebo. The secondary outcome of rate of delirium improvement on severity score did reach statistical significance; differences on mean severity scores were 0.8270.37 (P=0.026), suggesting that severity scores improved 82% more quickly than placebo. There were no significant differences between groups for any of the other secondary outcomes. Seven patients died within 30 days of entering the study (4 in the quetiapine group and 3 in the placebo group) due to serious medical conditions and not due to study medication as determined through clinical review. One patient withdrew from quetiapine due to sedation. Results of this study are limited by a small sample size, as it was underpowered to detect a statistically significant difference in the primary outcome. Other limitations include subjects who were older, with mean age of 84 years, which may have prevented titration of quetiapine, and subjects with minor cognitive deficits were included, which may have reduced the impact of treatment on the study outcomes. Additionally, strict criteria for exclusion kept those patients most likely to develop delirium from being included, limiting the studies external validity. Finally, the use of DRS‐R‐98 mean total and severity scores is subject to error as outliers in the mean could potentially skew the results.

Devlin et al. investigated the efficacy and safety of quetiapine for ICU delirium in critically ill patients in a double‐blind, randomized, placebo‐controlled trial.[20] Inclusion criteria were an Intensive Care Delirium Screening Checklist Score (ICDSC) >4, which indicates the presence of delirium, an order for as‐needed haloperidol, and tolerating enteral nutrition. Patients were excluded if they had a complicating neurologic condition, current treatment with dexmedetomidine or with medications that interact with quetiapine, baseline QTc interval >500, pregnancy, or poor prognosis. Thirty‐six critically ill subjects were randomized with no significant differences in baseline characteristics including exposure to fentanyl, haloperidol, and benzodiazepines, and in particular, midazolam. If the subject received at least 1 dose of as‐needed haloperidol in the previous 24 hours, then either placebo or quetiapine was given. Quetiapine was initiated at 50 mg every 12 hours and titrated up by 50 mg every 12 hours to a maximum dose of 200 mg every 12 hours. Patients could receive intravenous haloperidol, 1 to 10 mg up to every 2 hours as needed. The primary outcome was time to first resolution of delirium defined as time from administration of the first dose of study drug until an ICDSC <3 was first detected, indicating an absence of delirium. Secondary outcomes were total hours in delirium, total hours spent deeply sedated (Sedation‐Agitation Scale [SAS] <2) or agitated (SAS >5), episodes of subject‐initiated device removal, use of haloperidol therapy including total dose in milligrams, number of doses and number of days of therapy, the use of sedatives (converted to midazolam equivalents) and analgesics, duration of study‐drug administration, average daily and maximum study‐drug dose, length of mechanical ventilation, duration of both ICU and hospital stay, hospital mortality, and disposition of subjects after hospital discharge. Safety measures were total number of adverse and serious adverse events, episodes of somnolence, incidence of extrapyramidal symptoms, and episodes of QTc interval prolongation.

The time to first resolution of delirium was shorter with quetiapine compared to placebo (median [interquartile range]: 1.0 [0.53.0] vs 4.5 days [2.0‐7.0]; P=0.001). Resolution of delirium occurred at least once in all quetiapine patients and in 78% of placebo patients (P=0.05). Statistical significance with quetiapine was reached on the following secondary end points: time spent in delirium (36 [1287] vs 120 hours [60195], P=0.006); shorter duration of study drug (102 [84168] vs 186 hours [108228], P=0.04); lower daily study drug dose (110 [88191] vs 210 mg [116293], P=0.01); less upregulation of the study medication dose (200 [100313] vs 375 mg [25400], P=0.02); fewer hours of agitation (6 [038] vs 36 hours [1166], P=0.02); shorter duration of haloperidol therapy (3 [24] vs 4 days [38], P=0.05); and fewer days of fentanyl (0 [03] vs 4 days [19], P=0.03). There were no significant differences between groups for any other secondary outcomes. As‐needed haloperidol use in the quetiapine versus the placebo group was lower but not statistically significant (1.9 vs 4.3 mg per day; P=0.26). Two main limitations were a small sample size and strict exclusion criteria. Additionally, the primary end point of time to first resolution of delirium may be interpreted as a less rigorous measure, because there is no standard definition for delirium resolution, and delirium is a condition that waxes and wanes on its own.

A post hoc analysis by Devlin et al. was conducted on the above study to compare duration and time to first resolution of 10 delirium symptoms in 29 patients.[21] Symptoms included agitation, decreased level of consciousness, inattention, disorientation, hallucinations/delusions, hyperactivity, hypoactivity, inappropriate speech or mood, sleep/wake cycle disturbance, and symptom fluctuation. Only symptom fluctuation (P=0.009), time to first resolution of symptom fluctuation (P=0.004), time with inattention (47 vs 78 hours, P=0.025), and time with symptom fluctuation (47 vs 89 hours; P =0.04) reached statistical significance with quetiapine compared to placebo. However, quetiapine subjects had a longer time to resolution of agitation (3 vs 1 day, P=0.04) and hyperactivity (5 vs 1 day, P<0.04). The authors attribute these findings to the higher use of as‐needed haloperidol in the placebo group (1.9 vs 4.3 mg per day, P=0.26). These results may also be due to a limitation in the study design, which self‐selected for agitation delirium by requiring the use of as‐needed haloperidol as inclusion criteria, as symptoms of agitation would be more likely to receive as‐needed haloperidol doses. In addition, subjects were allowed to receive 1 to 10 mg of haloperidol up to every 2 hours as needed, but there is no discussion of controlling total daily haloperidol dose in each group in the study. Although 1.9 versus 4.3 mg per day is neither statistically nor likely clinically significant, haloperidol is a treatment for delirium, so the study design would be stronger if quetiapine could be directly compared to an equivalent daily dose of haloperidol or if both groups received the same daily dose of haloperidol. Study results are also limited by the nature of a post hoc analysis, missing documentation for individual delirium symptoms, symptoms of delirium not being well characterized and subjective, and delay in enrollment of subjects.

Noncontrolled Trials

Six additional trials are included in the table of this review including 5 open label trials and 1 retrospective cohort study.[24, 25, 26, 27, 28, 29] Schwartz and Masand[24] and Lee et al.[29] compared the efficacy of quetiapine to haloperidol and amisulpride, a second‐generation antipsychotic unavailable in the United States, respectively. In a retrospective cohort of 22 general hospital patients, Schwartz and Masand found quetiapine (average dose, 211.4 mg/day) was as efficacious as haloperidol (average dose, 3.4 mg/day) in improving delirium rating scale (DRS) scores by more than 50% in 10/11 subjects in each group. Lee et al. also found quetiapine (average dose, 113.0 mg/day) to be equally efficacious to amisulpride (156.4 mg/day) in statistically significantly improving DRS‐R‐98 scores in 31 neurosurgery, orthopedic surgery, internal medicine, neurology, and rehabilitation medicine patients. Four open‐label studies tested the efficacy of flexible doses of quetiapine in a total of 63 general hospital, neurosurgery, orthopedic surgery, and oncology patients.[25, 26, 27, 28] Pae et al.,[25] Maneeton et al.,[26] and Kim et al.[27] found that quetiapine statistically significantly reduced DRS‐R‐98, Clinical Global Impression Scale‐Severity, DRS, MMSE, and Clock Drawing Test scores from baseline. Sasaki et al.[28] found all 12 general hospital patients in their study reached remission with an average daily quetiapine dose of 44.9 mg/day. Although these studies have a limited level of evidence due to their small sample sizes, study designs, and heterogeneous subjects, they do still suggest that quetiapine may effectively treat delirium in various patient populations.

DISCUSSION

Although the role of quetiapine for the treatment of delirium continues to develop, the studies evaluated here suggest that quetiapine may be effective and safe for this usage. Resolution of delirium from baseline was shown in all studies. Quetiapine resolved symptoms of delirium more quickly than placebo and had equal efficacy to other antipsychotics, haloperidol and amisulpride. Quetiapine may be most useful for patients with symptom fluctuation as opposed to agitation and hyperactivity or in those patients who may not tolerate haloperidol well. Both randomized control and open‐label trials found a low incidence of adverse effects with quetiapine. There were fewer incidences of QT prolongation and extrapyramidal symptoms, but higher a rate of somnolence with quetiapine compared to other antipsychotics in these trials. However, none of these differences in adverse effects reached statistical significance.

Drawing definitive conclusions about the efficacy of quetiapine in the treatment of delirium is difficult due to multiple study limitations. First, the body of literature is small, with only 2 randomized controlled trials, both of which had limitations. Tahir et al.[19] was underpowered and found no statistically significant difference in the primary end point, DRS‐R‐98 total mean score. Devlin et al.[20] tested the primary end point of time to first resolution of delirium, which may be interpreted as a less rigorous measure because there is no standard definition for delirium resolution. Furthermore, both randomized controlled and observational trials tested the efficacy of quetiapine using different tests, making comparison between these trials difficult. All studies included in this review were carried out in small patient populations, with the largest trial having 42 subjects, and had highly restrictive exclusion criteria limiting the generalizability of the study population to the general hospital population. Although most of the patients included in these studies are general hospital populations, Devlin et al. was performed in critically ill patients, which creates the additional limitation of having heterogeneous study populations. Last, superiority of any 1 antipsychotic is not possible given that none of these studies have done a head‐to‐head comparison of quetiapine with another atypical antipsychotic.

Given the comparable efficacy and safety of antipsychotics, cost is a relevant factor in treatment decisions. Haloperidol is supplied as either a suspension for injection or a tablet. One vial of 5 mg/mL haloperidol is $8.32. Haloperidol 5 mg tablets are approximately $0.29 each, whereas 25 mg tablets of quetiapine are approximately $3.53 each. However, these prices are for consumers and will vary depending on institutional contracts.[42]

CONCLUSION

Quetiapine appears to be an effective and safe agent for the treatment of delirium in both general medicine and ICU patients. Superiority of quetiapine over other antipsychotics for hospital‐associated delirium has not been shown due to limitations in quality and quantity of data. Large, randomized, double‐blind, active control studies with longer study durations are needed to elucidate the efficacy and niche of quetiapine in the treatment of delirium.

Acknowledgment

Disclosure: Nothing to report.

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References
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  2. American Psychiatric Association. Practice guideline for the treatment of patients with delirium. Am J Psychiatry. 1999;156:1–20.
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  20. Devlin JW, Roberts RJ, Fong JJ, et al. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double‐blind, placebo‐controlled pilot study. Crit Care Med. 2010;38:419–427.
  21. Devlin JW, Skrobik Y, Riker RR, et al. Impact of quetiapine on resolution of individual delirium symptoms in critically ill patients with delirium: a post‐hoc analysis of a double‐blind, randomized, placebo‐controlled study. Critical Care. 2011;15:R215.
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jhm2019.pdf
Issue
Journal of Hospital Medicine - 8(4)
Page Number
215-220
Sections
Reviews
Author(s)
Stefanie B. Hawkins, PharmD
Mason Bucklin, PharmD
Andrew J. Muzyk, PharmD
Author(s)
Stefanie B. Hawkins, PharmD
Mason Bucklin, PharmD
Andrew J. Muzyk, PharmD
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Supplementary Information (1)
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jhm2019.pdf
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Delirium is an acute fluctuation in mental status that includes symptoms of inattention, disorganized thinking, and altered level of consciousness occurring over a short time period.[1] Prevalence of delirium ranges from 10% to 30% in the hospitalized medically ill and ranges from 40% to 60% in intensive care unit (ICU) patients who are not receiving mechanical ventilation.[2, 3] Patients experience delirium more often if they are of older age; have dementia, cancer, or acquired immune deficiency syndrome; have undergone surgery; are terminally ill; or have received multiple psychoactive medications, particularly benzodiazepines or opioids.[3, 4, 5, 6, 7] Delirium is associated with high rates of morbidity and mortality,[8] with patients more likely to develop complications such as pneumonia, decubitus ulcers, and long‐term cognitive deficits.[9, 10, 11, 12] These complications, in turn, lead to longer hospital stays and increased costs of care.[13, 14] Currently, there are no antipsychotics approved by the US Food and Drug Administration for the treatment of delirium.

Both the 2002 American Society of Critical Care Medicine[12] and the 2004 American Psychiatric Association guidelines[15] on delirium recommend haloperidol as the antipsychotic of choice due to its potent tranquilizing effect, lack of active metabolites, and limited anticholinergic and sedating side effects. However, when given intravenously or at high cumulative doses (generally >35 mg/day), haloperidol has been shown to cause QT interval prolongation potentially leading to torsades de pointes and sudden cardiac death.[15] Recent research in delirium treatment has focused on the second‐generation antipsychotics, and these studies have reported positive findings,[16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29] although no significant differences have been found compared to haloperidol.[16, 17, 18, 22, 23, 24] Systematic reviews have also failed to show a significant difference in efficacy or safety between second‐generation and first‐generation antipsychotics and unfortunately report a number of limitations including poor study designs, small sample sizes, lack of a placebo control group, exclusion of ICU patients, and weak primary outcomes.[8, 30, 31, 32] Attempting to correct for a number of these limitations, recent research with quetiapine has reported promising results in 2 controlled studies.[19, 20]

Quetiapine is a second‐generation antipsychotic with a very low affinity for dopamine receptors and a very high affinity for serotonin receptors.[33, 34] Additionally, quetiapine has a high affinity for histamine and 1‐adrenergic receptors, but a very low affinity for M1 muscarinic receptors.[34] This mechanism of action may allow quetiapine to effectively treat delirium and provide sedation without causing significant extrapyramidal side effects associated with potent dopamine receptor antagonism or precipitating delirium through muscarinic receptor antagonism. Quetiapine has a rapid absorption and a short half‐life (36 hours), giving it a quick onset of action and a fast elimination from the body.[35] Unlike haloperidol, it is only available in oral dosage forms, but can be crushed to administer via enteral tube. Common reported adverse effects include somnolence, hypotension, and dizziness. Although quetiapine has been shown to prolong QTc, Harrigan et al. reported a mean increase in QTc from baseline of 5.7 msec; there was no significant effect on this change in the presence of a metabolic inhibitor, ketoconazole.[36] The mean change in QTc from baseline with quetiapine was lower than the change reported with oral haloperidol, 5.7 msec compared to 7.1 msec, respectively. No statistical comparison was performed between these 2 drugs on this measure. Quetiapine does carry a black box warning for increased mortality in elderly patients with dementia‐related psychosis.[35] However, this risk has also been found with first‐generation antipsychotics.[37, 38, 39] A recent study found this risk of sudden cardiac death extended to adult users of both first‐ and second‐generation antipsychotics.[40] In contrast, Elie et al. found no increased risk of mortality in elderly patients with delirium receiving antipsychoticsover 90% were prescribed either haloperidol or risperidonein their nested case‐controlled study.[41] Quetiapine has demonstrated some benefit with limited side effects in studies utilizing antipsychotics for the treatment of delirium. The purpose of this review was to evaluate the role of quetiapine for the treatment of delirium.

LITERATURE REVIEW

We performed an English‐language literature search of MEDLINE and Embase databases to identify journal articles published between January 1960 and December 2012. Keywords included quetiapine, second‐generation antipsychotic, atypical antipsychotic, delirium, and agitation. The search was limited to English‐language articles and adult subjects (>18 years). Based on our review of abstracts, we included both controlled and noncontrolled trials as long as treatment of delirium was the primary focus. We eliminated case reports, foreign language articles, and poster presentations. We identified 8 trials[19, 20, 24, 25, 26, 27, 28, 29] that included 2 double‐blind, randomized, placebo‐controlled trials, which are described in the text below.[19, 20] Six other trials, 5 open‐label[25, 26, 27, 28, 29] and 1 retrospective cohort,[24] are described in Table 1.

Descriptions of One Retrospective Cohort and Five Open‐Label Trials
Study Study Design No. of Patients Included in Analyses Patient Type Treatment Baseline Delirium Scores Quetiapine Dose (mg/day) (MeanSD) Efficacy Measures Results Side Effects

  • NOTE: Abbreviations: A, amisulpride; BID, twice a day; CDT, Clock Drawing Test; CGI‐s, Clinical Global Impression Scale‐Severity; DRS, Delirium Rating Scale; DRS‐J, Delirium Rating ScaleJapanese version; DRS‐R‐98, Delirium Rating Scale‐Revised‐Severity 98; EPS, extrapyramidal symptoms; H, haloperidol; IV, intravenous; MMSE, Mini‐Mental State Exam; NR, not reported; OL, open label; Q, quetiapine; RC, retrospective cohort; SD, standard deviation.

Schwartz et al. (2000)[24] RC 22 General hospital Quetiapine or haloperidol flexible dose DRS score 20.9 Q; 18.5 H 211.4 Q; 3.4 H >50% improvement in DRS scores 10/11 in each treatment group had >50% improvement in DRS scores EPS 2/11 H and 0/11 Q; mild‐to‐moderate sedation 0/11 H and 2/11 Q
Pae et al. (2004)[25] OL 22 Neurosurgery and orthopedic surgery and oncology Flexible dose quetiapine DRS‐R‐98 21.83.2 and CGI‐s 4.90.8 127.172.2 DRS‐R‐98 and CGI‐s score reduction DRS‐R‐98 9.33.8 (P<0.0001) and CGI‐s 2.11.1 (P<0.0001) reduction from baseline; 19/22 (86.3%) and 17/22 (77.3%) showed >50% score reduction for DRS‐R‐98 and CGI‐s, respectively EPS none; sedation requiring discontinuation 2; mild sedation 3; serious side effects none
Maneeton et al. (2007)[26] OL 17 General hospital Quetiapine 25100 mg/day in 1 or 2 divided doses DRS 24.53.2 and CGI‐s 4.90.9 45.728.7 50% reduction in DRS scores 15/17 (88.2%) had 50% reduction in DRS score; all DRS and CGI‐s scores on days 17 of the 7‐day treatment course were significantly lower than baseline scores EPS tremor 2; hypotension 2; daytime sleepiness 13; nightmare 3; dry mouth 2; nausea 1
Kim et al. (2003)[27] OL 12 (all male and age 64 years) General hospital Quetiapine 25 mg BID and increased by 25 mg every 2 days until patient maximally stabilized DRS 18.256.05; MMSE 14.505.90; CGI‐s 3.000.43; CDT 3.25 2.77 93.7523.31 Reduction in DRS, MMSE, CGI‐s, or CDT scores All scores were statistically significantly improved from baseline; DRS at end of study 0.631.21 (P=0.03) No dropouts due to side effects; EPS none; sedation 2; vivid dreams 1
Sasaki et al. (2003)[28] OL 12 General hospital Quetiapine started at 25 or 50 mg/day and titrated to maximal clinical effect DRS‐J 18.14.2 44.931.0 Remission was DRS‐J score <12 (cutoff for delirium) and resolution of delirium symptoms Remission occurred in all patients; mean DRS‐J score was reduced to 9.31.6 after remission No statistically significant change from baseline in EPS; no excessive daytime sedation, anticholinergic effects, vital sign, or lab parameter changes
Lee et al. (2005)[29] OL 31 Neurosurgery and orthopedic surgery, internal medicine, neurology and rehabilitation medicine Flexible dose quetiapine or amisulpride DRS‐R‐98 10.14.1 Q and 10.54.1 A 11385.5 Q; 156.497.5 A Reduction in DRS‐R‐98 score DRS‐R‐98 scores significantly reduced from baseline in both groups with 3.52.6 Q (P=0.001) and 3.51.4 A (P=0.000); no difference between groups (P=0.842); 12 (80%) Q and 13 (81.3%) A had >50% reduction in DRS‐R‐98 score No serious side effects; dropouts 5 Q and 4 A; oversedation 1 Q and 1 A; patient withdrawal 2 Q and 1 A; no statistical differences in total sleep time P=0.767 or quality of sleep P=0.984

Randomized Controlled Trials

Tahir et al. published a double‐blind, randomized, placebo‐controlled trial examining the efficacy and tolerability of quetiapine in the treatment of delirium.[19] Inclusion criteria were a Diagnostic and Statistical Manual of Mental Disorders‐IV diagnosis of delirium and a Delirium Rating Scale Revised 98 (DRS‐R‐98) total score of at least 15, indicating the presence of delirium. Subjects were excluded for major preexisting cognitive deficits, alcohol withdrawal, preexisting psychosis, substance dependence, inability to comply with the constraints of the trial, and concurrent medications that interact with quetiapine.

Forty‐two general medicine subjects were enrolled and randomized in the study with no difference in baseline characteristics. Patients received either placebo or quetiapine 25 mg once daily. Doses were titrated by 25 mg daily to a maximum daily dose of 175 mg in divided doses. The primary end point was DRS‐R‐98 total mean score assessed on days 1, 2, 3, 4, 7, and 10, with follow‐up assessment on day 30. Secondary outcome measures were Mini‐Mental State Examination (MMSE), the Brief Psychiatric Rating Scale, and the Clinical Global Improvement Scale. Tolerability was assessed using the Abnormal Involuntary Movements Scale and by clinical examination.

No differences in total mean DRS‐R‐98 score at individual time points reached statistical significance, but these scores improved more quickly in the quetiapine group than placebo. The secondary outcome of rate of delirium improvement on severity score did reach statistical significance; differences on mean severity scores were 0.8270.37 (P=0.026), suggesting that severity scores improved 82% more quickly than placebo. There were no significant differences between groups for any of the other secondary outcomes. Seven patients died within 30 days of entering the study (4 in the quetiapine group and 3 in the placebo group) due to serious medical conditions and not due to study medication as determined through clinical review. One patient withdrew from quetiapine due to sedation. Results of this study are limited by a small sample size, as it was underpowered to detect a statistically significant difference in the primary outcome. Other limitations include subjects who were older, with mean age of 84 years, which may have prevented titration of quetiapine, and subjects with minor cognitive deficits were included, which may have reduced the impact of treatment on the study outcomes. Additionally, strict criteria for exclusion kept those patients most likely to develop delirium from being included, limiting the studies external validity. Finally, the use of DRS‐R‐98 mean total and severity scores is subject to error as outliers in the mean could potentially skew the results.

Devlin et al. investigated the efficacy and safety of quetiapine for ICU delirium in critically ill patients in a double‐blind, randomized, placebo‐controlled trial.[20] Inclusion criteria were an Intensive Care Delirium Screening Checklist Score (ICDSC) >4, which indicates the presence of delirium, an order for as‐needed haloperidol, and tolerating enteral nutrition. Patients were excluded if they had a complicating neurologic condition, current treatment with dexmedetomidine or with medications that interact with quetiapine, baseline QTc interval >500, pregnancy, or poor prognosis. Thirty‐six critically ill subjects were randomized with no significant differences in baseline characteristics including exposure to fentanyl, haloperidol, and benzodiazepines, and in particular, midazolam. If the subject received at least 1 dose of as‐needed haloperidol in the previous 24 hours, then either placebo or quetiapine was given. Quetiapine was initiated at 50 mg every 12 hours and titrated up by 50 mg every 12 hours to a maximum dose of 200 mg every 12 hours. Patients could receive intravenous haloperidol, 1 to 10 mg up to every 2 hours as needed. The primary outcome was time to first resolution of delirium defined as time from administration of the first dose of study drug until an ICDSC <3 was first detected, indicating an absence of delirium. Secondary outcomes were total hours in delirium, total hours spent deeply sedated (Sedation‐Agitation Scale [SAS] <2) or agitated (SAS >5), episodes of subject‐initiated device removal, use of haloperidol therapy including total dose in milligrams, number of doses and number of days of therapy, the use of sedatives (converted to midazolam equivalents) and analgesics, duration of study‐drug administration, average daily and maximum study‐drug dose, length of mechanical ventilation, duration of both ICU and hospital stay, hospital mortality, and disposition of subjects after hospital discharge. Safety measures were total number of adverse and serious adverse events, episodes of somnolence, incidence of extrapyramidal symptoms, and episodes of QTc interval prolongation.

The time to first resolution of delirium was shorter with quetiapine compared to placebo (median [interquartile range]: 1.0 [0.53.0] vs 4.5 days [2.0‐7.0]; P=0.001). Resolution of delirium occurred at least once in all quetiapine patients and in 78% of placebo patients (P=0.05). Statistical significance with quetiapine was reached on the following secondary end points: time spent in delirium (36 [1287] vs 120 hours [60195], P=0.006); shorter duration of study drug (102 [84168] vs 186 hours [108228], P=0.04); lower daily study drug dose (110 [88191] vs 210 mg [116293], P=0.01); less upregulation of the study medication dose (200 [100313] vs 375 mg [25400], P=0.02); fewer hours of agitation (6 [038] vs 36 hours [1166], P=0.02); shorter duration of haloperidol therapy (3 [24] vs 4 days [38], P=0.05); and fewer days of fentanyl (0 [03] vs 4 days [19], P=0.03). There were no significant differences between groups for any other secondary outcomes. As‐needed haloperidol use in the quetiapine versus the placebo group was lower but not statistically significant (1.9 vs 4.3 mg per day; P=0.26). Two main limitations were a small sample size and strict exclusion criteria. Additionally, the primary end point of time to first resolution of delirium may be interpreted as a less rigorous measure, because there is no standard definition for delirium resolution, and delirium is a condition that waxes and wanes on its own.

A post hoc analysis by Devlin et al. was conducted on the above study to compare duration and time to first resolution of 10 delirium symptoms in 29 patients.[21] Symptoms included agitation, decreased level of consciousness, inattention, disorientation, hallucinations/delusions, hyperactivity, hypoactivity, inappropriate speech or mood, sleep/wake cycle disturbance, and symptom fluctuation. Only symptom fluctuation (P=0.009), time to first resolution of symptom fluctuation (P=0.004), time with inattention (47 vs 78 hours, P=0.025), and time with symptom fluctuation (47 vs 89 hours; P =0.04) reached statistical significance with quetiapine compared to placebo. However, quetiapine subjects had a longer time to resolution of agitation (3 vs 1 day, P=0.04) and hyperactivity (5 vs 1 day, P<0.04). The authors attribute these findings to the higher use of as‐needed haloperidol in the placebo group (1.9 vs 4.3 mg per day, P=0.26). These results may also be due to a limitation in the study design, which self‐selected for agitation delirium by requiring the use of as‐needed haloperidol as inclusion criteria, as symptoms of agitation would be more likely to receive as‐needed haloperidol doses. In addition, subjects were allowed to receive 1 to 10 mg of haloperidol up to every 2 hours as needed, but there is no discussion of controlling total daily haloperidol dose in each group in the study. Although 1.9 versus 4.3 mg per day is neither statistically nor likely clinically significant, haloperidol is a treatment for delirium, so the study design would be stronger if quetiapine could be directly compared to an equivalent daily dose of haloperidol or if both groups received the same daily dose of haloperidol. Study results are also limited by the nature of a post hoc analysis, missing documentation for individual delirium symptoms, symptoms of delirium not being well characterized and subjective, and delay in enrollment of subjects.

Noncontrolled Trials

Six additional trials are included in the table of this review including 5 open label trials and 1 retrospective cohort study.[24, 25, 26, 27, 28, 29] Schwartz and Masand[24] and Lee et al.[29] compared the efficacy of quetiapine to haloperidol and amisulpride, a second‐generation antipsychotic unavailable in the United States, respectively. In a retrospective cohort of 22 general hospital patients, Schwartz and Masand found quetiapine (average dose, 211.4 mg/day) was as efficacious as haloperidol (average dose, 3.4 mg/day) in improving delirium rating scale (DRS) scores by more than 50% in 10/11 subjects in each group. Lee et al. also found quetiapine (average dose, 113.0 mg/day) to be equally efficacious to amisulpride (156.4 mg/day) in statistically significantly improving DRS‐R‐98 scores in 31 neurosurgery, orthopedic surgery, internal medicine, neurology, and rehabilitation medicine patients. Four open‐label studies tested the efficacy of flexible doses of quetiapine in a total of 63 general hospital, neurosurgery, orthopedic surgery, and oncology patients.[25, 26, 27, 28] Pae et al.,[25] Maneeton et al.,[26] and Kim et al.[27] found that quetiapine statistically significantly reduced DRS‐R‐98, Clinical Global Impression Scale‐Severity, DRS, MMSE, and Clock Drawing Test scores from baseline. Sasaki et al.[28] found all 12 general hospital patients in their study reached remission with an average daily quetiapine dose of 44.9 mg/day. Although these studies have a limited level of evidence due to their small sample sizes, study designs, and heterogeneous subjects, they do still suggest that quetiapine may effectively treat delirium in various patient populations.

DISCUSSION

Although the role of quetiapine for the treatment of delirium continues to develop, the studies evaluated here suggest that quetiapine may be effective and safe for this usage. Resolution of delirium from baseline was shown in all studies. Quetiapine resolved symptoms of delirium more quickly than placebo and had equal efficacy to other antipsychotics, haloperidol and amisulpride. Quetiapine may be most useful for patients with symptom fluctuation as opposed to agitation and hyperactivity or in those patients who may not tolerate haloperidol well. Both randomized control and open‐label trials found a low incidence of adverse effects with quetiapine. There were fewer incidences of QT prolongation and extrapyramidal symptoms, but higher a rate of somnolence with quetiapine compared to other antipsychotics in these trials. However, none of these differences in adverse effects reached statistical significance.

Drawing definitive conclusions about the efficacy of quetiapine in the treatment of delirium is difficult due to multiple study limitations. First, the body of literature is small, with only 2 randomized controlled trials, both of which had limitations. Tahir et al.[19] was underpowered and found no statistically significant difference in the primary end point, DRS‐R‐98 total mean score. Devlin et al.[20] tested the primary end point of time to first resolution of delirium, which may be interpreted as a less rigorous measure because there is no standard definition for delirium resolution. Furthermore, both randomized controlled and observational trials tested the efficacy of quetiapine using different tests, making comparison between these trials difficult. All studies included in this review were carried out in small patient populations, with the largest trial having 42 subjects, and had highly restrictive exclusion criteria limiting the generalizability of the study population to the general hospital population. Although most of the patients included in these studies are general hospital populations, Devlin et al. was performed in critically ill patients, which creates the additional limitation of having heterogeneous study populations. Last, superiority of any 1 antipsychotic is not possible given that none of these studies have done a head‐to‐head comparison of quetiapine with another atypical antipsychotic.

Given the comparable efficacy and safety of antipsychotics, cost is a relevant factor in treatment decisions. Haloperidol is supplied as either a suspension for injection or a tablet. One vial of 5 mg/mL haloperidol is $8.32. Haloperidol 5 mg tablets are approximately $0.29 each, whereas 25 mg tablets of quetiapine are approximately $3.53 each. However, these prices are for consumers and will vary depending on institutional contracts.[42]

CONCLUSION

Quetiapine appears to be an effective and safe agent for the treatment of delirium in both general medicine and ICU patients. Superiority of quetiapine over other antipsychotics for hospital‐associated delirium has not been shown due to limitations in quality and quantity of data. Large, randomized, double‐blind, active control studies with longer study durations are needed to elucidate the efficacy and niche of quetiapine in the treatment of delirium.

Acknowledgment

Disclosure: Nothing to report.

Delirium is an acute fluctuation in mental status that includes symptoms of inattention, disorganized thinking, and altered level of consciousness occurring over a short time period.[1] Prevalence of delirium ranges from 10% to 30% in the hospitalized medically ill and ranges from 40% to 60% in intensive care unit (ICU) patients who are not receiving mechanical ventilation.[2, 3] Patients experience delirium more often if they are of older age; have dementia, cancer, or acquired immune deficiency syndrome; have undergone surgery; are terminally ill; or have received multiple psychoactive medications, particularly benzodiazepines or opioids.[3, 4, 5, 6, 7] Delirium is associated with high rates of morbidity and mortality,[8] with patients more likely to develop complications such as pneumonia, decubitus ulcers, and long‐term cognitive deficits.[9, 10, 11, 12] These complications, in turn, lead to longer hospital stays and increased costs of care.[13, 14] Currently, there are no antipsychotics approved by the US Food and Drug Administration for the treatment of delirium.

Both the 2002 American Society of Critical Care Medicine[12] and the 2004 American Psychiatric Association guidelines[15] on delirium recommend haloperidol as the antipsychotic of choice due to its potent tranquilizing effect, lack of active metabolites, and limited anticholinergic and sedating side effects. However, when given intravenously or at high cumulative doses (generally >35 mg/day), haloperidol has been shown to cause QT interval prolongation potentially leading to torsades de pointes and sudden cardiac death.[15] Recent research in delirium treatment has focused on the second‐generation antipsychotics, and these studies have reported positive findings,[16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29] although no significant differences have been found compared to haloperidol.[16, 17, 18, 22, 23, 24] Systematic reviews have also failed to show a significant difference in efficacy or safety between second‐generation and first‐generation antipsychotics and unfortunately report a number of limitations including poor study designs, small sample sizes, lack of a placebo control group, exclusion of ICU patients, and weak primary outcomes.[8, 30, 31, 32] Attempting to correct for a number of these limitations, recent research with quetiapine has reported promising results in 2 controlled studies.[19, 20]

Quetiapine is a second‐generation antipsychotic with a very low affinity for dopamine receptors and a very high affinity for serotonin receptors.[33, 34] Additionally, quetiapine has a high affinity for histamine and 1‐adrenergic receptors, but a very low affinity for M1 muscarinic receptors.[34] This mechanism of action may allow quetiapine to effectively treat delirium and provide sedation without causing significant extrapyramidal side effects associated with potent dopamine receptor antagonism or precipitating delirium through muscarinic receptor antagonism. Quetiapine has a rapid absorption and a short half‐life (36 hours), giving it a quick onset of action and a fast elimination from the body.[35] Unlike haloperidol, it is only available in oral dosage forms, but can be crushed to administer via enteral tube. Common reported adverse effects include somnolence, hypotension, and dizziness. Although quetiapine has been shown to prolong QTc, Harrigan et al. reported a mean increase in QTc from baseline of 5.7 msec; there was no significant effect on this change in the presence of a metabolic inhibitor, ketoconazole.[36] The mean change in QTc from baseline with quetiapine was lower than the change reported with oral haloperidol, 5.7 msec compared to 7.1 msec, respectively. No statistical comparison was performed between these 2 drugs on this measure. Quetiapine does carry a black box warning for increased mortality in elderly patients with dementia‐related psychosis.[35] However, this risk has also been found with first‐generation antipsychotics.[37, 38, 39] A recent study found this risk of sudden cardiac death extended to adult users of both first‐ and second‐generation antipsychotics.[40] In contrast, Elie et al. found no increased risk of mortality in elderly patients with delirium receiving antipsychoticsover 90% were prescribed either haloperidol or risperidonein their nested case‐controlled study.[41] Quetiapine has demonstrated some benefit with limited side effects in studies utilizing antipsychotics for the treatment of delirium. The purpose of this review was to evaluate the role of quetiapine for the treatment of delirium.

LITERATURE REVIEW

We performed an English‐language literature search of MEDLINE and Embase databases to identify journal articles published between January 1960 and December 2012. Keywords included quetiapine, second‐generation antipsychotic, atypical antipsychotic, delirium, and agitation. The search was limited to English‐language articles and adult subjects (>18 years). Based on our review of abstracts, we included both controlled and noncontrolled trials as long as treatment of delirium was the primary focus. We eliminated case reports, foreign language articles, and poster presentations. We identified 8 trials[19, 20, 24, 25, 26, 27, 28, 29] that included 2 double‐blind, randomized, placebo‐controlled trials, which are described in the text below.[19, 20] Six other trials, 5 open‐label[25, 26, 27, 28, 29] and 1 retrospective cohort,[24] are described in Table 1.

Descriptions of One Retrospective Cohort and Five Open‐Label Trials
Study Study Design No. of Patients Included in Analyses Patient Type Treatment Baseline Delirium Scores Quetiapine Dose (mg/day) (MeanSD) Efficacy Measures Results Side Effects

  • NOTE: Abbreviations: A, amisulpride; BID, twice a day; CDT, Clock Drawing Test; CGI‐s, Clinical Global Impression Scale‐Severity; DRS, Delirium Rating Scale; DRS‐J, Delirium Rating ScaleJapanese version; DRS‐R‐98, Delirium Rating Scale‐Revised‐Severity 98; EPS, extrapyramidal symptoms; H, haloperidol; IV, intravenous; MMSE, Mini‐Mental State Exam; NR, not reported; OL, open label; Q, quetiapine; RC, retrospective cohort; SD, standard deviation.

Schwartz et al. (2000)[24] RC 22 General hospital Quetiapine or haloperidol flexible dose DRS score 20.9 Q; 18.5 H 211.4 Q; 3.4 H >50% improvement in DRS scores 10/11 in each treatment group had >50% improvement in DRS scores EPS 2/11 H and 0/11 Q; mild‐to‐moderate sedation 0/11 H and 2/11 Q
Pae et al. (2004)[25] OL 22 Neurosurgery and orthopedic surgery and oncology Flexible dose quetiapine DRS‐R‐98 21.83.2 and CGI‐s 4.90.8 127.172.2 DRS‐R‐98 and CGI‐s score reduction DRS‐R‐98 9.33.8 (P<0.0001) and CGI‐s 2.11.1 (P<0.0001) reduction from baseline; 19/22 (86.3%) and 17/22 (77.3%) showed >50% score reduction for DRS‐R‐98 and CGI‐s, respectively EPS none; sedation requiring discontinuation 2; mild sedation 3; serious side effects none
Maneeton et al. (2007)[26] OL 17 General hospital Quetiapine 25100 mg/day in 1 or 2 divided doses DRS 24.53.2 and CGI‐s 4.90.9 45.728.7 50% reduction in DRS scores 15/17 (88.2%) had 50% reduction in DRS score; all DRS and CGI‐s scores on days 17 of the 7‐day treatment course were significantly lower than baseline scores EPS tremor 2; hypotension 2; daytime sleepiness 13; nightmare 3; dry mouth 2; nausea 1
Kim et al. (2003)[27] OL 12 (all male and age 64 years) General hospital Quetiapine 25 mg BID and increased by 25 mg every 2 days until patient maximally stabilized DRS 18.256.05; MMSE 14.505.90; CGI‐s 3.000.43; CDT 3.25 2.77 93.7523.31 Reduction in DRS, MMSE, CGI‐s, or CDT scores All scores were statistically significantly improved from baseline; DRS at end of study 0.631.21 (P=0.03) No dropouts due to side effects; EPS none; sedation 2; vivid dreams 1
Sasaki et al. (2003)[28] OL 12 General hospital Quetiapine started at 25 or 50 mg/day and titrated to maximal clinical effect DRS‐J 18.14.2 44.931.0 Remission was DRS‐J score <12 (cutoff for delirium) and resolution of delirium symptoms Remission occurred in all patients; mean DRS‐J score was reduced to 9.31.6 after remission No statistically significant change from baseline in EPS; no excessive daytime sedation, anticholinergic effects, vital sign, or lab parameter changes
Lee et al. (2005)[29] OL 31 Neurosurgery and orthopedic surgery, internal medicine, neurology and rehabilitation medicine Flexible dose quetiapine or amisulpride DRS‐R‐98 10.14.1 Q and 10.54.1 A 11385.5 Q; 156.497.5 A Reduction in DRS‐R‐98 score DRS‐R‐98 scores significantly reduced from baseline in both groups with 3.52.6 Q (P=0.001) and 3.51.4 A (P=0.000); no difference between groups (P=0.842); 12 (80%) Q and 13 (81.3%) A had >50% reduction in DRS‐R‐98 score No serious side effects; dropouts 5 Q and 4 A; oversedation 1 Q and 1 A; patient withdrawal 2 Q and 1 A; no statistical differences in total sleep time P=0.767 or quality of sleep P=0.984

Randomized Controlled Trials

Tahir et al. published a double‐blind, randomized, placebo‐controlled trial examining the efficacy and tolerability of quetiapine in the treatment of delirium.[19] Inclusion criteria were a Diagnostic and Statistical Manual of Mental Disorders‐IV diagnosis of delirium and a Delirium Rating Scale Revised 98 (DRS‐R‐98) total score of at least 15, indicating the presence of delirium. Subjects were excluded for major preexisting cognitive deficits, alcohol withdrawal, preexisting psychosis, substance dependence, inability to comply with the constraints of the trial, and concurrent medications that interact with quetiapine.

Forty‐two general medicine subjects were enrolled and randomized in the study with no difference in baseline characteristics. Patients received either placebo or quetiapine 25 mg once daily. Doses were titrated by 25 mg daily to a maximum daily dose of 175 mg in divided doses. The primary end point was DRS‐R‐98 total mean score assessed on days 1, 2, 3, 4, 7, and 10, with follow‐up assessment on day 30. Secondary outcome measures were Mini‐Mental State Examination (MMSE), the Brief Psychiatric Rating Scale, and the Clinical Global Improvement Scale. Tolerability was assessed using the Abnormal Involuntary Movements Scale and by clinical examination.

No differences in total mean DRS‐R‐98 score at individual time points reached statistical significance, but these scores improved more quickly in the quetiapine group than placebo. The secondary outcome of rate of delirium improvement on severity score did reach statistical significance; differences on mean severity scores were 0.8270.37 (P=0.026), suggesting that severity scores improved 82% more quickly than placebo. There were no significant differences between groups for any of the other secondary outcomes. Seven patients died within 30 days of entering the study (4 in the quetiapine group and 3 in the placebo group) due to serious medical conditions and not due to study medication as determined through clinical review. One patient withdrew from quetiapine due to sedation. Results of this study are limited by a small sample size, as it was underpowered to detect a statistically significant difference in the primary outcome. Other limitations include subjects who were older, with mean age of 84 years, which may have prevented titration of quetiapine, and subjects with minor cognitive deficits were included, which may have reduced the impact of treatment on the study outcomes. Additionally, strict criteria for exclusion kept those patients most likely to develop delirium from being included, limiting the studies external validity. Finally, the use of DRS‐R‐98 mean total and severity scores is subject to error as outliers in the mean could potentially skew the results.

Devlin et al. investigated the efficacy and safety of quetiapine for ICU delirium in critically ill patients in a double‐blind, randomized, placebo‐controlled trial.[20] Inclusion criteria were an Intensive Care Delirium Screening Checklist Score (ICDSC) >4, which indicates the presence of delirium, an order for as‐needed haloperidol, and tolerating enteral nutrition. Patients were excluded if they had a complicating neurologic condition, current treatment with dexmedetomidine or with medications that interact with quetiapine, baseline QTc interval >500, pregnancy, or poor prognosis. Thirty‐six critically ill subjects were randomized with no significant differences in baseline characteristics including exposure to fentanyl, haloperidol, and benzodiazepines, and in particular, midazolam. If the subject received at least 1 dose of as‐needed haloperidol in the previous 24 hours, then either placebo or quetiapine was given. Quetiapine was initiated at 50 mg every 12 hours and titrated up by 50 mg every 12 hours to a maximum dose of 200 mg every 12 hours. Patients could receive intravenous haloperidol, 1 to 10 mg up to every 2 hours as needed. The primary outcome was time to first resolution of delirium defined as time from administration of the first dose of study drug until an ICDSC <3 was first detected, indicating an absence of delirium. Secondary outcomes were total hours in delirium, total hours spent deeply sedated (Sedation‐Agitation Scale [SAS] <2) or agitated (SAS >5), episodes of subject‐initiated device removal, use of haloperidol therapy including total dose in milligrams, number of doses and number of days of therapy, the use of sedatives (converted to midazolam equivalents) and analgesics, duration of study‐drug administration, average daily and maximum study‐drug dose, length of mechanical ventilation, duration of both ICU and hospital stay, hospital mortality, and disposition of subjects after hospital discharge. Safety measures were total number of adverse and serious adverse events, episodes of somnolence, incidence of extrapyramidal symptoms, and episodes of QTc interval prolongation.

The time to first resolution of delirium was shorter with quetiapine compared to placebo (median [interquartile range]: 1.0 [0.53.0] vs 4.5 days [2.0‐7.0]; P=0.001). Resolution of delirium occurred at least once in all quetiapine patients and in 78% of placebo patients (P=0.05). Statistical significance with quetiapine was reached on the following secondary end points: time spent in delirium (36 [1287] vs 120 hours [60195], P=0.006); shorter duration of study drug (102 [84168] vs 186 hours [108228], P=0.04); lower daily study drug dose (110 [88191] vs 210 mg [116293], P=0.01); less upregulation of the study medication dose (200 [100313] vs 375 mg [25400], P=0.02); fewer hours of agitation (6 [038] vs 36 hours [1166], P=0.02); shorter duration of haloperidol therapy (3 [24] vs 4 days [38], P=0.05); and fewer days of fentanyl (0 [03] vs 4 days [19], P=0.03). There were no significant differences between groups for any other secondary outcomes. As‐needed haloperidol use in the quetiapine versus the placebo group was lower but not statistically significant (1.9 vs 4.3 mg per day; P=0.26). Two main limitations were a small sample size and strict exclusion criteria. Additionally, the primary end point of time to first resolution of delirium may be interpreted as a less rigorous measure, because there is no standard definition for delirium resolution, and delirium is a condition that waxes and wanes on its own.

A post hoc analysis by Devlin et al. was conducted on the above study to compare duration and time to first resolution of 10 delirium symptoms in 29 patients.[21] Symptoms included agitation, decreased level of consciousness, inattention, disorientation, hallucinations/delusions, hyperactivity, hypoactivity, inappropriate speech or mood, sleep/wake cycle disturbance, and symptom fluctuation. Only symptom fluctuation (P=0.009), time to first resolution of symptom fluctuation (P=0.004), time with inattention (47 vs 78 hours, P=0.025), and time with symptom fluctuation (47 vs 89 hours; P =0.04) reached statistical significance with quetiapine compared to placebo. However, quetiapine subjects had a longer time to resolution of agitation (3 vs 1 day, P=0.04) and hyperactivity (5 vs 1 day, P<0.04). The authors attribute these findings to the higher use of as‐needed haloperidol in the placebo group (1.9 vs 4.3 mg per day, P=0.26). These results may also be due to a limitation in the study design, which self‐selected for agitation delirium by requiring the use of as‐needed haloperidol as inclusion criteria, as symptoms of agitation would be more likely to receive as‐needed haloperidol doses. In addition, subjects were allowed to receive 1 to 10 mg of haloperidol up to every 2 hours as needed, but there is no discussion of controlling total daily haloperidol dose in each group in the study. Although 1.9 versus 4.3 mg per day is neither statistically nor likely clinically significant, haloperidol is a treatment for delirium, so the study design would be stronger if quetiapine could be directly compared to an equivalent daily dose of haloperidol or if both groups received the same daily dose of haloperidol. Study results are also limited by the nature of a post hoc analysis, missing documentation for individual delirium symptoms, symptoms of delirium not being well characterized and subjective, and delay in enrollment of subjects.

Noncontrolled Trials

Six additional trials are included in the table of this review including 5 open label trials and 1 retrospective cohort study.[24, 25, 26, 27, 28, 29] Schwartz and Masand[24] and Lee et al.[29] compared the efficacy of quetiapine to haloperidol and amisulpride, a second‐generation antipsychotic unavailable in the United States, respectively. In a retrospective cohort of 22 general hospital patients, Schwartz and Masand found quetiapine (average dose, 211.4 mg/day) was as efficacious as haloperidol (average dose, 3.4 mg/day) in improving delirium rating scale (DRS) scores by more than 50% in 10/11 subjects in each group. Lee et al. also found quetiapine (average dose, 113.0 mg/day) to be equally efficacious to amisulpride (156.4 mg/day) in statistically significantly improving DRS‐R‐98 scores in 31 neurosurgery, orthopedic surgery, internal medicine, neurology, and rehabilitation medicine patients. Four open‐label studies tested the efficacy of flexible doses of quetiapine in a total of 63 general hospital, neurosurgery, orthopedic surgery, and oncology patients.[25, 26, 27, 28] Pae et al.,[25] Maneeton et al.,[26] and Kim et al.[27] found that quetiapine statistically significantly reduced DRS‐R‐98, Clinical Global Impression Scale‐Severity, DRS, MMSE, and Clock Drawing Test scores from baseline. Sasaki et al.[28] found all 12 general hospital patients in their study reached remission with an average daily quetiapine dose of 44.9 mg/day. Although these studies have a limited level of evidence due to their small sample sizes, study designs, and heterogeneous subjects, they do still suggest that quetiapine may effectively treat delirium in various patient populations.

DISCUSSION

Although the role of quetiapine for the treatment of delirium continues to develop, the studies evaluated here suggest that quetiapine may be effective and safe for this usage. Resolution of delirium from baseline was shown in all studies. Quetiapine resolved symptoms of delirium more quickly than placebo and had equal efficacy to other antipsychotics, haloperidol and amisulpride. Quetiapine may be most useful for patients with symptom fluctuation as opposed to agitation and hyperactivity or in those patients who may not tolerate haloperidol well. Both randomized control and open‐label trials found a low incidence of adverse effects with quetiapine. There were fewer incidences of QT prolongation and extrapyramidal symptoms, but higher a rate of somnolence with quetiapine compared to other antipsychotics in these trials. However, none of these differences in adverse effects reached statistical significance.

Drawing definitive conclusions about the efficacy of quetiapine in the treatment of delirium is difficult due to multiple study limitations. First, the body of literature is small, with only 2 randomized controlled trials, both of which had limitations. Tahir et al.[19] was underpowered and found no statistically significant difference in the primary end point, DRS‐R‐98 total mean score. Devlin et al.[20] tested the primary end point of time to first resolution of delirium, which may be interpreted as a less rigorous measure because there is no standard definition for delirium resolution. Furthermore, both randomized controlled and observational trials tested the efficacy of quetiapine using different tests, making comparison between these trials difficult. All studies included in this review were carried out in small patient populations, with the largest trial having 42 subjects, and had highly restrictive exclusion criteria limiting the generalizability of the study population to the general hospital population. Although most of the patients included in these studies are general hospital populations, Devlin et al. was performed in critically ill patients, which creates the additional limitation of having heterogeneous study populations. Last, superiority of any 1 antipsychotic is not possible given that none of these studies have done a head‐to‐head comparison of quetiapine with another atypical antipsychotic.

Given the comparable efficacy and safety of antipsychotics, cost is a relevant factor in treatment decisions. Haloperidol is supplied as either a suspension for injection or a tablet. One vial of 5 mg/mL haloperidol is $8.32. Haloperidol 5 mg tablets are approximately $0.29 each, whereas 25 mg tablets of quetiapine are approximately $3.53 each. However, these prices are for consumers and will vary depending on institutional contracts.[42]

CONCLUSION

Quetiapine appears to be an effective and safe agent for the treatment of delirium in both general medicine and ICU patients. Superiority of quetiapine over other antipsychotics for hospital‐associated delirium has not been shown due to limitations in quality and quantity of data. Large, randomized, double‐blind, active control studies with longer study durations are needed to elucidate the efficacy and niche of quetiapine in the treatment of delirium.

Acknowledgment

Disclosure: Nothing to report.

References
  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: APA; 1994.
  2. American Psychiatric Association. Practice guideline for the treatment of patients with delirium. Am J Psychiatry. 1999;156:1–20.
  3. Hipp DM, Ely EW. Pharmacological and nonpharmacological management of delirium in critically ill patients. Neurotherapeutics. 2012;9:158–175.
  4. Stiefel F, Holland J. Delirium in cancer patients. Int Psychogeriatr. 1991;3:333–336.
  5. Perry S. Organic mental disorders caused by HIV: update on early‐diagnosis and treatment. Am J Psychiatry. 1990;147:696–710.
  6. Tune LE. Post‐operative delirium. Int Psychogeriatr. 1991;3:325–332.
  7. Massie MJ, Holland J, Glass E. Delirium in terminally ill cancer patients. Am J Psychiatry. 1983;140:1048–1050.
  8. Seitz DP, Sudeep SG, Zyl LT. Antipsychotics in the treatment of delirium: a systematic review. J Clin Psychiatry. 2007;68:11–21.
  9. Inouye S, Horowitz R, Tinetti M, et al. Acute confusional states in the hospitalized elderly: incidence, risk factors and complications [abstract]. Clin Res. 1989;37:524A.
  10. Cole MG, Primeau FJ. Prognosis of delirium in elderly hospital patients. CMAJ. 1993;149:41–46.
  11. Koizumi J, Shiraishi H, Suzuki T. Duration of delirium shortened by the correction of electrolyte imbalance. Jpn J Psychiatry Neurol. 1988;42:81–88.
  12. Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002;30:119–141.
  13. Thomason JW, Shintani A, Peterson JF, Pun BT, Jackson JC, Ely EW. Intensive care unit delirium is an independent predictor of longer hospital stay: a prospective analysis of 261 non‐ventilated patients. Crit Care. 2005;9:R375–R381.
  14. Milbrandt EB, Deppen S, Harrison PL, et al. Costs associated with delirium in mechanically ventilated patients. Crit Care Med. 2004;32:955–962.
  15. Cook IA: Guideline Watch: Practice Guideline for the Treatment of Patients With Delirium. Arlington, VA:American Psychiatric Association, 2004. Available at: http://www.psych.org/psych_pract/treatg/pg/prac_guide.cfm. Accessed March 5, 2012.
  16. Han C, Kim YK. A double‐blind trial of risperdone and haloperidol for the treatment of delirium. Psychosomatics. 2004;45:297–301.
  17. Skrobik YK, Bergeron N, Dumont M, Gottfried SB. Olanzapine vs haloperidol: treating delirium in a critical care setting. Intensive Care Med. 2004;30:444–449.
  18. Girard TD, Pandharipande PP, Carson SS, et al. Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo‐controlled trial. Crit Care Med. 2010;38:428–437.
  19. Tahir TA, Eeles E, Karapareddy V, et al. A randomized controlled trial of quetiapine versus placebo in the treatment of delirium. Psychosom Res. 2010;69:485–490.
  20. Devlin JW, Roberts RJ, Fong JJ, et al. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double‐blind, placebo‐controlled pilot study. Crit Care Med. 2010;38:419–427.
  21. Devlin JW, Skrobik Y, Riker RR, et al. Impact of quetiapine on resolution of individual delirium symptoms in critically ill patients with delirium: a post‐hoc analysis of a double‐blind, randomized, placebo‐controlled study. Critical Care. 2011;15:R215.
  22. Sipahimalani A, Masand PS. Olanzapine in the treatment of delirium. Psychosomatics. 1998;39:422–430.
  23. Grover S, Kumar V, Chakrabarti S. Comparative efficacy study of haloperidol, olanzapine and risperidone in delirium. J Psychosom Res. 2011;71:277–281.
  24. Schwartz TL, Masand P. Treatment of delirium with quetiapine. J Clin Psychiatry. 2000;2:10–12.
  25. Pae CU, Lee SJ, Lee CU, Lee C, Paik IH. A pilot trial of quetiapine for the treatment of patients with delirium. Hum Psychopharmacol Clin Exp. 2004;19:125–127.
  26. Maneeton B, Maneeton N, Srisurapanont M. An open‐label study of quetiapine for delirium. J Med Assoc Thai. 2007;10:2158–2163.
  27. Kim KY, Bader GM, Kotlyar V, Gropper D. Treatment of delirium in older adults with quetiapine. J Geriatr Psychiatry Neurol. 2003;16:29–31.
  28. Sasaki Y, Matsuyama T, Inoue S, et al. A prospective, open‐label, flexible‐dose study of quetiapine in the treatment of delirium. J Clin Psychiatry. 2003;64:1316–1321.
  29. Lee KU, Won WY, Lee HK, et al. Amisulpride versus quetiapine for the treatment of delirium: a randomized, open prospective study. Int Clin Psychopharmacol. 2005;20:311–314.
  30. Campbell N, Boustani MA, Ayub A, et al. Pharmacological management of delirium in hospitalized adults‐a systematic evidence review. J Gen Intern Med. 2009;24:848–853.
  31. Lacasse H, Perreault MM, Williamson DR. Systematic review of antipsychotics for the treatment of hospital‐associated delirium in medically or surgically ill patients. Ann Pharmacother. 2006;40:1966–1973.
  32. Rea RS, Battistone S, Fong JJ, Devlin JW. Atypical antipsychotics versus haloperidol for treatment of delirium in acutely ill patients. Pharmacotherapy. 2007;27:588–594.
  33. Cole MG, Primeau FJ, Elie LM. Delirium: prevention, treatment, and outcome studies. J Geriatr Psychiatry Neurol. 1998;11:126–137.
  34. Saller CF, Salama AI. Seroquel: biochemical profile of a potential atypical antipsychotic. Psychopharmacology. 1993;112:285–292.
  35. Seroquel [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; December 2011.
  36. Harrigan EP, Miceli JJ, Anziano R, et al. A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition. J Clin Psychopharmacol. 2004;24:62–69.
  37. Kales HC, Valenstein M, Kim HM, et al. Mortality risk in patients with dementia treated with antipsychotics versus other psychiatric medications. Am J Psychiatry. 2007;164:1568–1576.
  38. Gill S, Bronskill SE, Normand SL, et al. Antipsychotic drug use and mortality in older adults with dementia. Ann Intern Med. 2007;146:775–786.
  39. Wang PS, Schneeweis S, Avorn J, et al. Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med. 2005;353:2335–2341.
  40. Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med. 2009;360:225–235.
  41. Elie M, Boss K, Cole MG, McCusker J, Belzile E, Ciampi A. A retrospective, exploratory, secondary analysis of the association between antipsychotic use and mortality in elderly patients with delirium. Int Psychogeriatr. 2009;21(3):588–592.
  42. Walgreens Co. Price your drugs Available at: http://www.walgreens.com/pharmacy/psc/drugpricing/psc_drug_pricing.jsp. Accessed December 17, 2012.
References
  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: APA; 1994.
  2. American Psychiatric Association. Practice guideline for the treatment of patients with delirium. Am J Psychiatry. 1999;156:1–20.
  3. Hipp DM, Ely EW. Pharmacological and nonpharmacological management of delirium in critically ill patients. Neurotherapeutics. 2012;9:158–175.
  4. Stiefel F, Holland J. Delirium in cancer patients. Int Psychogeriatr. 1991;3:333–336.
  5. Perry S. Organic mental disorders caused by HIV: update on early‐diagnosis and treatment. Am J Psychiatry. 1990;147:696–710.
  6. Tune LE. Post‐operative delirium. Int Psychogeriatr. 1991;3:325–332.
  7. Massie MJ, Holland J, Glass E. Delirium in terminally ill cancer patients. Am J Psychiatry. 1983;140:1048–1050.
  8. Seitz DP, Sudeep SG, Zyl LT. Antipsychotics in the treatment of delirium: a systematic review. J Clin Psychiatry. 2007;68:11–21.
  9. Inouye S, Horowitz R, Tinetti M, et al. Acute confusional states in the hospitalized elderly: incidence, risk factors and complications [abstract]. Clin Res. 1989;37:524A.
  10. Cole MG, Primeau FJ. Prognosis of delirium in elderly hospital patients. CMAJ. 1993;149:41–46.
  11. Koizumi J, Shiraishi H, Suzuki T. Duration of delirium shortened by the correction of electrolyte imbalance. Jpn J Psychiatry Neurol. 1988;42:81–88.
  12. Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002;30:119–141.
  13. Thomason JW, Shintani A, Peterson JF, Pun BT, Jackson JC, Ely EW. Intensive care unit delirium is an independent predictor of longer hospital stay: a prospective analysis of 261 non‐ventilated patients. Crit Care. 2005;9:R375–R381.
  14. Milbrandt EB, Deppen S, Harrison PL, et al. Costs associated with delirium in mechanically ventilated patients. Crit Care Med. 2004;32:955–962.
  15. Cook IA: Guideline Watch: Practice Guideline for the Treatment of Patients With Delirium. Arlington, VA:American Psychiatric Association, 2004. Available at: http://www.psych.org/psych_pract/treatg/pg/prac_guide.cfm. Accessed March 5, 2012.
  16. Han C, Kim YK. A double‐blind trial of risperdone and haloperidol for the treatment of delirium. Psychosomatics. 2004;45:297–301.
  17. Skrobik YK, Bergeron N, Dumont M, Gottfried SB. Olanzapine vs haloperidol: treating delirium in a critical care setting. Intensive Care Med. 2004;30:444–449.
  18. Girard TD, Pandharipande PP, Carson SS, et al. Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo‐controlled trial. Crit Care Med. 2010;38:428–437.
  19. Tahir TA, Eeles E, Karapareddy V, et al. A randomized controlled trial of quetiapine versus placebo in the treatment of delirium. Psychosom Res. 2010;69:485–490.
  20. Devlin JW, Roberts RJ, Fong JJ, et al. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double‐blind, placebo‐controlled pilot study. Crit Care Med. 2010;38:419–427.
  21. Devlin JW, Skrobik Y, Riker RR, et al. Impact of quetiapine on resolution of individual delirium symptoms in critically ill patients with delirium: a post‐hoc analysis of a double‐blind, randomized, placebo‐controlled study. Critical Care. 2011;15:R215.
  22. Sipahimalani A, Masand PS. Olanzapine in the treatment of delirium. Psychosomatics. 1998;39:422–430.
  23. Grover S, Kumar V, Chakrabarti S. Comparative efficacy study of haloperidol, olanzapine and risperidone in delirium. J Psychosom Res. 2011;71:277–281.
  24. Schwartz TL, Masand P. Treatment of delirium with quetiapine. J Clin Psychiatry. 2000;2:10–12.
  25. Pae CU, Lee SJ, Lee CU, Lee C, Paik IH. A pilot trial of quetiapine for the treatment of patients with delirium. Hum Psychopharmacol Clin Exp. 2004;19:125–127.
  26. Maneeton B, Maneeton N, Srisurapanont M. An open‐label study of quetiapine for delirium. J Med Assoc Thai. 2007;10:2158–2163.
  27. Kim KY, Bader GM, Kotlyar V, Gropper D. Treatment of delirium in older adults with quetiapine. J Geriatr Psychiatry Neurol. 2003;16:29–31.
  28. Sasaki Y, Matsuyama T, Inoue S, et al. A prospective, open‐label, flexible‐dose study of quetiapine in the treatment of delirium. J Clin Psychiatry. 2003;64:1316–1321.
  29. Lee KU, Won WY, Lee HK, et al. Amisulpride versus quetiapine for the treatment of delirium: a randomized, open prospective study. Int Clin Psychopharmacol. 2005;20:311–314.
  30. Campbell N, Boustani MA, Ayub A, et al. Pharmacological management of delirium in hospitalized adults‐a systematic evidence review. J Gen Intern Med. 2009;24:848–853.
  31. Lacasse H, Perreault MM, Williamson DR. Systematic review of antipsychotics for the treatment of hospital‐associated delirium in medically or surgically ill patients. Ann Pharmacother. 2006;40:1966–1973.
  32. Rea RS, Battistone S, Fong JJ, Devlin JW. Atypical antipsychotics versus haloperidol for treatment of delirium in acutely ill patients. Pharmacotherapy. 2007;27:588–594.
  33. Cole MG, Primeau FJ, Elie LM. Delirium: prevention, treatment, and outcome studies. J Geriatr Psychiatry Neurol. 1998;11:126–137.
  34. Saller CF, Salama AI. Seroquel: biochemical profile of a potential atypical antipsychotic. Psychopharmacology. 1993;112:285–292.
  35. Seroquel [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; December 2011.
  36. Harrigan EP, Miceli JJ, Anziano R, et al. A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition. J Clin Psychopharmacol. 2004;24:62–69.
  37. Kales HC, Valenstein M, Kim HM, et al. Mortality risk in patients with dementia treated with antipsychotics versus other psychiatric medications. Am J Psychiatry. 2007;164:1568–1576.
  38. Gill S, Bronskill SE, Normand SL, et al. Antipsychotic drug use and mortality in older adults with dementia. Ann Intern Med. 2007;146:775–786.
  39. Wang PS, Schneeweis S, Avorn J, et al. Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med. 2005;353:2335–2341.
  40. Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med. 2009;360:225–235.
  41. Elie M, Boss K, Cole MG, McCusker J, Belzile E, Ciampi A. A retrospective, exploratory, secondary analysis of the association between antipsychotic use and mortality in elderly patients with delirium. Int Psychogeriatr. 2009;21(3):588–592.
  42. Walgreens Co. Price your drugs Available at: http://www.walgreens.com/pharmacy/psc/drugpricing/psc_drug_pricing.jsp. Accessed December 17, 2012.
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Quetiapine for the treatment of delirium
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Do beta blockers cause depression?

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Display Headline
Do beta blockers cause depression?
Author(s)
Andrew J. Muzyk, PharmD

Dr. Muzyk is a clinical pharmacist, Duke University Medical Center, and Dr. Galiardi is assistant professor of psychiatry and behavioral sciences and assistant clinical professor of medicine, Duke University School of Medicine, Durham, NC.

Principal Source: van Melle JP, Verbeek DEP, van den Berg MP, et al. Beta-blockers and depression after myocardial infarction: a multicenter prospective study. J Am Coll Cardiol. 2006;48(11):2209-2214.

Practice Points

  • Although patients with cardiovascular disease are at increased risk for developing depression, there is no convincing evidence that adding beta blockers will further increase their risk.
  • Initiating beta-blocker therapy at the lowest possible dose and slowly titrating the dose over time could minimize adverse effects such as fatigue and sexual side effects.
  • If a patient taking beta blockers develops signs of major depression, carefully evaluate and treat symptoms with appropriate psychotherapy, psychotropics, and monitoring.

Beyond their well-known role for treating cardiovascular disease, beta adrenergic receptor antagonists—beta blockers—are used for a variety of medical conditions, including coronary artery disease, hypertension, migraines, and tremor. Their usefulness makes them 1 of the most commonly prescribed medication classes. Unfortunately, their increased use comes with increased reports of depression. Being able to sort fact from fiction will help guide your care for patients taking beta blockers who report new or worsening depressive symptoms.

Does research support a link?

First reported in the 1960s, beta blocker-induced depression was thought to result from the drugs’ antagonistic effect on norepinephrine at ß1 post-synaptic brain receptors. Prompted by case reports of a possible association between beta blockers and depression, 2 prescription database reviews found that patients taking beta blockers were more likely to receive a concurrent antidepressant prescription than patients prescribed other cardiovascular and diabetic medications.1,2 However, these reviews had major limitations, such as inadequately defined methods for defining depression and lack of control for potential confounding factors.

Mechanistically, peripheral effects of beta blockers on the heart and kidneys lead to decreased chronotropy and inotropy as well as lower blood pressure. These cardiovascular and hemodynamic changes could cause fatigue, decreased energy, and sexual dysfunction that may be interpreted as symptoms of new-onset depression.

Researchers found that beta-blocker use was not associated with depression in a case-control study examining 4,302 New Jersey Medicaid records.3 Also, because most patients in this study received propranolol, the authors were unable to confirm a long-held belief that highly lipophilic beta blockers (such as propranolol, metoprolol, and timolol) are more likely than hydrophilic beta blockers such as atenolol to produce depression.

A retrospective cohort study analyzed 381 patients from 2 myocardial infarction (MI) trials who had been assessed for depressive symptoms and severity.4 Researchers matched 254 subjects taking beta blockers during hospitalization for MI with 127 subjects not taking beta blockers. Patients in the study were well balanced on multiple baseline characteristics, including demographics, history of depression, and left ventricular ejection fraction, although those who did not take beta blockers had a significantly higher incidence of chronic obstructive pulmonary disease, digoxin use, and pre-MI beta-blocker use. Researchers assessed depressive symptoms using the Beck Depression Inventory (BDI) at baseline and 3, 6, and 12 months post-MI and identified patients with depression using a Composite International Diagnostic Interview. They found no statistically significant difference in BDI scores between beta-blockers users and nonusers at discharge and at 3, 6, and 12 months post-MI after accounting for potential confounding factors, including:

  • contraindications for beta-blocker use (other than history of depression)
  • indicators and risk factors for cardiac disease
  • baseline depressive symptoms
  • benzodiazepine use.

In fact, after controlling for baseline depression, researchers found that beta-blocker users demonstrated significantly lower BDI scores 3 months post-MI than nonusers. Based on these results, the authors concluded that clinicians should not be deterred from prescribing beta blockers because the drugs’ benefit in reducing morbidity and mortality in cardiovascular disease greatly outweighs the risk—if any—of new-onset depression associated with beta-blocker use.

Clinical Point

Studies show no significant difference in incidence of depression between patients who received beta blockers and those who did not

Two additional studies reported no significant difference in the incidence of depression between patients who received beta blockers and those who received other antihypertensives or placebo.5,6 Future studies assessing depression among subjects randomized to beta blockers vs placebo would be helpful, though withholding beta blockers in some cardiac conditions is not justifiable, and such studies may not be feasible.

Treatment for psychiatric patients

Evidence supports beta-blocker use in coronary artery disease and congestive heart failure. Although patients with these conditions are at increased risk for developing depression,7 there is little evidence that their risk will be further increased by adding beta blockers (Table),3-6 Although patients taking beta blockers report a higher incidence of fatigue and sexual side effects—which could be interpreted as related to depression—studies do not support an association between these medications and depression. As with any medication, initiate beta-blocker therapy with the lowest possible dose and titrate slowly to minimize side effects. Any patient who develops signs and symptoms of major depression should be thoroughly evaluated and treated with appropriate psychotherapy, psychotropics, and careful monitoring.

 

 

Table

Beta blockers and depression: Is there a link?

StudyMethodsResults
Bright et al, 19923Case-control study of 4,302 patients with new-onset depressionBeta-blocker use was not associated with depression after controlling for confounding factors, although depressed patients were more likely to receive beta blockers
van Melle et al, 20064A prospective study of post-myocardial infarction patients; 254 taking beta blockers, 127 controlsNo significant differences in depressive symptoms or incidence of depressive disorder between beta-blocker users and nonusers
Gerstman et al, 19965New users of propranolol (n=704) other beta blockers (n=587), angiotensin-converting enzyme inhibitors (n=976), calcium channel blockers (n=742), and diuretics (n=773)Depression occurred no more frequently among beta-blocker users than other subjects
Ko et al, 20026Quantitative review of randomized trials that tested beta blockers in myocardial infarction, heart failure, and hypertensionBeta-blocker therapy was not associated with a significant absolute annual increase in risk of depressive symptoms (6 per 1,000 patients; 95% confidence interval, -7 to 19)

Related resources

  • Rivelli S, Jiang W. Depression and ischemic heart disease: what have we learned from clinical trials? Curr Opin Cardiol. 2007;22(4):286-291.
  • National guideline clearinghouse. Secondary prevention of coronary artery disease. www.guideline.gov/summary/summary.aspx?doc_id=14585.

Drug brand names

  • Atenolol • Tenormin
  • Digoxin • Lanoxin
  • Metoprolol • Lopressor, Toprol-XL
  • Propranolol • Inderal
  • Timolol • Blocadren

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

References

1. Avorn J, Everitt D, Weiss S. Increased antidepressant use in patients prescribed beta-blockers. JAMA. 1986;256:357-360.

2. Thiessen B, Wallace S, Blackburn J, et al. Increased prescribing of antidepressants subsequent to beta-blocker therapy. Arch Intern Med. 1990;150:2286-2290.

3. Bright R, Everitt D. Beta-blockers and depression. Evidence against an association. JAMA. 1992;267(13):1783-1787.

4. van Melle JP, Verbeek DEP, van den Berg MP, et al. Beta-blockers and depression after myocardial infarction: a multicenter prospective study. J Am Coll Cardiol. 2006;48(11):2209-2214.

5. Gerstman B, Jolson HM, Bauer M, et al. The incidence of depression in new users of beta-blockers and selected antihypertensives. J Clin Epidemiol. 1996;49(7):809-815.

6. Ko D, Hebert P, Coffey C, et al. Beta-blockers therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA. 2002;288(3):351-357.

7. Pozuelo L, Tesar G, Zhang J, et al. Depression and heart disease: what do we know, and where are we headed? Cleve Clin J Med. 2009;76(1):59-70.

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Dr. Muzyk is a clinical pharmacist, Duke University Medical Center, and Dr. Galiardi is assistant professor of psychiatry and behavioral sciences and assistant clinical professor of medicine, Duke University School of Medicine, Durham, NC.

Principal Source: van Melle JP, Verbeek DEP, van den Berg MP, et al. Beta-blockers and depression after myocardial infarction: a multicenter prospective study. J Am Coll Cardiol. 2006;48(11):2209-2214.

Practice Points

  • Although patients with cardiovascular disease are at increased risk for developing depression, there is no convincing evidence that adding beta blockers will further increase their risk.
  • Initiating beta-blocker therapy at the lowest possible dose and slowly titrating the dose over time could minimize adverse effects such as fatigue and sexual side effects.
  • If a patient taking beta blockers develops signs of major depression, carefully evaluate and treat symptoms with appropriate psychotherapy, psychotropics, and monitoring.

Beyond their well-known role for treating cardiovascular disease, beta adrenergic receptor antagonists—beta blockers—are used for a variety of medical conditions, including coronary artery disease, hypertension, migraines, and tremor. Their usefulness makes them 1 of the most commonly prescribed medication classes. Unfortunately, their increased use comes with increased reports of depression. Being able to sort fact from fiction will help guide your care for patients taking beta blockers who report new or worsening depressive symptoms.

Does research support a link?

First reported in the 1960s, beta blocker-induced depression was thought to result from the drugs’ antagonistic effect on norepinephrine at ß1 post-synaptic brain receptors. Prompted by case reports of a possible association between beta blockers and depression, 2 prescription database reviews found that patients taking beta blockers were more likely to receive a concurrent antidepressant prescription than patients prescribed other cardiovascular and diabetic medications.1,2 However, these reviews had major limitations, such as inadequately defined methods for defining depression and lack of control for potential confounding factors.

Mechanistically, peripheral effects of beta blockers on the heart and kidneys lead to decreased chronotropy and inotropy as well as lower blood pressure. These cardiovascular and hemodynamic changes could cause fatigue, decreased energy, and sexual dysfunction that may be interpreted as symptoms of new-onset depression.

Researchers found that beta-blocker use was not associated with depression in a case-control study examining 4,302 New Jersey Medicaid records.3 Also, because most patients in this study received propranolol, the authors were unable to confirm a long-held belief that highly lipophilic beta blockers (such as propranolol, metoprolol, and timolol) are more likely than hydrophilic beta blockers such as atenolol to produce depression.

A retrospective cohort study analyzed 381 patients from 2 myocardial infarction (MI) trials who had been assessed for depressive symptoms and severity.4 Researchers matched 254 subjects taking beta blockers during hospitalization for MI with 127 subjects not taking beta blockers. Patients in the study were well balanced on multiple baseline characteristics, including demographics, history of depression, and left ventricular ejection fraction, although those who did not take beta blockers had a significantly higher incidence of chronic obstructive pulmonary disease, digoxin use, and pre-MI beta-blocker use. Researchers assessed depressive symptoms using the Beck Depression Inventory (BDI) at baseline and 3, 6, and 12 months post-MI and identified patients with depression using a Composite International Diagnostic Interview. They found no statistically significant difference in BDI scores between beta-blockers users and nonusers at discharge and at 3, 6, and 12 months post-MI after accounting for potential confounding factors, including:

  • contraindications for beta-blocker use (other than history of depression)
  • indicators and risk factors for cardiac disease
  • baseline depressive symptoms
  • benzodiazepine use.

In fact, after controlling for baseline depression, researchers found that beta-blocker users demonstrated significantly lower BDI scores 3 months post-MI than nonusers. Based on these results, the authors concluded that clinicians should not be deterred from prescribing beta blockers because the drugs’ benefit in reducing morbidity and mortality in cardiovascular disease greatly outweighs the risk—if any—of new-onset depression associated with beta-blocker use.

Clinical Point

Studies show no significant difference in incidence of depression between patients who received beta blockers and those who did not

Two additional studies reported no significant difference in the incidence of depression between patients who received beta blockers and those who received other antihypertensives or placebo.5,6 Future studies assessing depression among subjects randomized to beta blockers vs placebo would be helpful, though withholding beta blockers in some cardiac conditions is not justifiable, and such studies may not be feasible.

Treatment for psychiatric patients

Evidence supports beta-blocker use in coronary artery disease and congestive heart failure. Although patients with these conditions are at increased risk for developing depression,7 there is little evidence that their risk will be further increased by adding beta blockers (Table),3-6 Although patients taking beta blockers report a higher incidence of fatigue and sexual side effects—which could be interpreted as related to depression—studies do not support an association between these medications and depression. As with any medication, initiate beta-blocker therapy with the lowest possible dose and titrate slowly to minimize side effects. Any patient who develops signs and symptoms of major depression should be thoroughly evaluated and treated with appropriate psychotherapy, psychotropics, and careful monitoring.

 

 

Table

Beta blockers and depression: Is there a link?

StudyMethodsResults
Bright et al, 19923Case-control study of 4,302 patients with new-onset depressionBeta-blocker use was not associated with depression after controlling for confounding factors, although depressed patients were more likely to receive beta blockers
van Melle et al, 20064A prospective study of post-myocardial infarction patients; 254 taking beta blockers, 127 controlsNo significant differences in depressive symptoms or incidence of depressive disorder between beta-blocker users and nonusers
Gerstman et al, 19965New users of propranolol (n=704) other beta blockers (n=587), angiotensin-converting enzyme inhibitors (n=976), calcium channel blockers (n=742), and diuretics (n=773)Depression occurred no more frequently among beta-blocker users than other subjects
Ko et al, 20026Quantitative review of randomized trials that tested beta blockers in myocardial infarction, heart failure, and hypertensionBeta-blocker therapy was not associated with a significant absolute annual increase in risk of depressive symptoms (6 per 1,000 patients; 95% confidence interval, -7 to 19)

Related resources

  • Rivelli S, Jiang W. Depression and ischemic heart disease: what have we learned from clinical trials? Curr Opin Cardiol. 2007;22(4):286-291.
  • National guideline clearinghouse. Secondary prevention of coronary artery disease. www.guideline.gov/summary/summary.aspx?doc_id=14585.

Drug brand names

  • Atenolol • Tenormin
  • Digoxin • Lanoxin
  • Metoprolol • Lopressor, Toprol-XL
  • Propranolol • Inderal
  • Timolol • Blocadren

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Muzyk is a clinical pharmacist, Duke University Medical Center, and Dr. Galiardi is assistant professor of psychiatry and behavioral sciences and assistant clinical professor of medicine, Duke University School of Medicine, Durham, NC.

Principal Source: van Melle JP, Verbeek DEP, van den Berg MP, et al. Beta-blockers and depression after myocardial infarction: a multicenter prospective study. J Am Coll Cardiol. 2006;48(11):2209-2214.

Practice Points

  • Although patients with cardiovascular disease are at increased risk for developing depression, there is no convincing evidence that adding beta blockers will further increase their risk.
  • Initiating beta-blocker therapy at the lowest possible dose and slowly titrating the dose over time could minimize adverse effects such as fatigue and sexual side effects.
  • If a patient taking beta blockers develops signs of major depression, carefully evaluate and treat symptoms with appropriate psychotherapy, psychotropics, and monitoring.

Beyond their well-known role for treating cardiovascular disease, beta adrenergic receptor antagonists—beta blockers—are used for a variety of medical conditions, including coronary artery disease, hypertension, migraines, and tremor. Their usefulness makes them 1 of the most commonly prescribed medication classes. Unfortunately, their increased use comes with increased reports of depression. Being able to sort fact from fiction will help guide your care for patients taking beta blockers who report new or worsening depressive symptoms.

Does research support a link?

First reported in the 1960s, beta blocker-induced depression was thought to result from the drugs’ antagonistic effect on norepinephrine at ß1 post-synaptic brain receptors. Prompted by case reports of a possible association between beta blockers and depression, 2 prescription database reviews found that patients taking beta blockers were more likely to receive a concurrent antidepressant prescription than patients prescribed other cardiovascular and diabetic medications.1,2 However, these reviews had major limitations, such as inadequately defined methods for defining depression and lack of control for potential confounding factors.

Mechanistically, peripheral effects of beta blockers on the heart and kidneys lead to decreased chronotropy and inotropy as well as lower blood pressure. These cardiovascular and hemodynamic changes could cause fatigue, decreased energy, and sexual dysfunction that may be interpreted as symptoms of new-onset depression.

Researchers found that beta-blocker use was not associated with depression in a case-control study examining 4,302 New Jersey Medicaid records.3 Also, because most patients in this study received propranolol, the authors were unable to confirm a long-held belief that highly lipophilic beta blockers (such as propranolol, metoprolol, and timolol) are more likely than hydrophilic beta blockers such as atenolol to produce depression.

A retrospective cohort study analyzed 381 patients from 2 myocardial infarction (MI) trials who had been assessed for depressive symptoms and severity.4 Researchers matched 254 subjects taking beta blockers during hospitalization for MI with 127 subjects not taking beta blockers. Patients in the study were well balanced on multiple baseline characteristics, including demographics, history of depression, and left ventricular ejection fraction, although those who did not take beta blockers had a significantly higher incidence of chronic obstructive pulmonary disease, digoxin use, and pre-MI beta-blocker use. Researchers assessed depressive symptoms using the Beck Depression Inventory (BDI) at baseline and 3, 6, and 12 months post-MI and identified patients with depression using a Composite International Diagnostic Interview. They found no statistically significant difference in BDI scores between beta-blockers users and nonusers at discharge and at 3, 6, and 12 months post-MI after accounting for potential confounding factors, including:

  • contraindications for beta-blocker use (other than history of depression)
  • indicators and risk factors for cardiac disease
  • baseline depressive symptoms
  • benzodiazepine use.

In fact, after controlling for baseline depression, researchers found that beta-blocker users demonstrated significantly lower BDI scores 3 months post-MI than nonusers. Based on these results, the authors concluded that clinicians should not be deterred from prescribing beta blockers because the drugs’ benefit in reducing morbidity and mortality in cardiovascular disease greatly outweighs the risk—if any—of new-onset depression associated with beta-blocker use.

Clinical Point

Studies show no significant difference in incidence of depression between patients who received beta blockers and those who did not

Two additional studies reported no significant difference in the incidence of depression between patients who received beta blockers and those who received other antihypertensives or placebo.5,6 Future studies assessing depression among subjects randomized to beta blockers vs placebo would be helpful, though withholding beta blockers in some cardiac conditions is not justifiable, and such studies may not be feasible.

Treatment for psychiatric patients

Evidence supports beta-blocker use in coronary artery disease and congestive heart failure. Although patients with these conditions are at increased risk for developing depression,7 there is little evidence that their risk will be further increased by adding beta blockers (Table),3-6 Although patients taking beta blockers report a higher incidence of fatigue and sexual side effects—which could be interpreted as related to depression—studies do not support an association between these medications and depression. As with any medication, initiate beta-blocker therapy with the lowest possible dose and titrate slowly to minimize side effects. Any patient who develops signs and symptoms of major depression should be thoroughly evaluated and treated with appropriate psychotherapy, psychotropics, and careful monitoring.

 

 

Table

Beta blockers and depression: Is there a link?

StudyMethodsResults
Bright et al, 19923Case-control study of 4,302 patients with new-onset depressionBeta-blocker use was not associated with depression after controlling for confounding factors, although depressed patients were more likely to receive beta blockers
van Melle et al, 20064A prospective study of post-myocardial infarction patients; 254 taking beta blockers, 127 controlsNo significant differences in depressive symptoms or incidence of depressive disorder between beta-blocker users and nonusers
Gerstman et al, 19965New users of propranolol (n=704) other beta blockers (n=587), angiotensin-converting enzyme inhibitors (n=976), calcium channel blockers (n=742), and diuretics (n=773)Depression occurred no more frequently among beta-blocker users than other subjects
Ko et al, 20026Quantitative review of randomized trials that tested beta blockers in myocardial infarction, heart failure, and hypertensionBeta-blocker therapy was not associated with a significant absolute annual increase in risk of depressive symptoms (6 per 1,000 patients; 95% confidence interval, -7 to 19)

Related resources

  • Rivelli S, Jiang W. Depression and ischemic heart disease: what have we learned from clinical trials? Curr Opin Cardiol. 2007;22(4):286-291.
  • National guideline clearinghouse. Secondary prevention of coronary artery disease. www.guideline.gov/summary/summary.aspx?doc_id=14585.

Drug brand names

  • Atenolol • Tenormin
  • Digoxin • Lanoxin
  • Metoprolol • Lopressor, Toprol-XL
  • Propranolol • Inderal
  • Timolol • Blocadren

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

References

1. Avorn J, Everitt D, Weiss S. Increased antidepressant use in patients prescribed beta-blockers. JAMA. 1986;256:357-360.

2. Thiessen B, Wallace S, Blackburn J, et al. Increased prescribing of antidepressants subsequent to beta-blocker therapy. Arch Intern Med. 1990;150:2286-2290.

3. Bright R, Everitt D. Beta-blockers and depression. Evidence against an association. JAMA. 1992;267(13):1783-1787.

4. van Melle JP, Verbeek DEP, van den Berg MP, et al. Beta-blockers and depression after myocardial infarction: a multicenter prospective study. J Am Coll Cardiol. 2006;48(11):2209-2214.

5. Gerstman B, Jolson HM, Bauer M, et al. The incidence of depression in new users of beta-blockers and selected antihypertensives. J Clin Epidemiol. 1996;49(7):809-815.

6. Ko D, Hebert P, Coffey C, et al. Beta-blockers therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA. 2002;288(3):351-357.

7. Pozuelo L, Tesar G, Zhang J, et al. Depression and heart disease: what do we know, and where are we headed? Cleve Clin J Med. 2009;76(1):59-70.

References

1. Avorn J, Everitt D, Weiss S. Increased antidepressant use in patients prescribed beta-blockers. JAMA. 1986;256:357-360.

2. Thiessen B, Wallace S, Blackburn J, et al. Increased prescribing of antidepressants subsequent to beta-blocker therapy. Arch Intern Med. 1990;150:2286-2290.

3. Bright R, Everitt D. Beta-blockers and depression. Evidence against an association. JAMA. 1992;267(13):1783-1787.

4. van Melle JP, Verbeek DEP, van den Berg MP, et al. Beta-blockers and depression after myocardial infarction: a multicenter prospective study. J Am Coll Cardiol. 2006;48(11):2209-2214.

5. Gerstman B, Jolson HM, Bauer M, et al. The incidence of depression in new users of beta-blockers and selected antihypertensives. J Clin Epidemiol. 1996;49(7):809-815.

6. Ko D, Hebert P, Coffey C, et al. Beta-blockers therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA. 2002;288(3):351-357.

7. Pozuelo L, Tesar G, Zhang J, et al. Depression and heart disease: what do we know, and where are we headed? Cleve Clin J Med. 2009;76(1):59-70.

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Corticosteroid psychosis: Stop therapy or add psychotropics?

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Mrs. E, age 31, develops rapid, pressured speech and insomnia for 4 consecutive nights, but reports a normal energy level after receiving high-dose methylprednisolone for an acute flare of systemic lupus erythematosus (SLE).

Her medical history indicates an overlap syndrome between SLE and systemic sclerosis for the last 5 years, migraine headaches, and 4 spontaneous miscarriages, but she has no psychiatric history. Her family history is negative for psychiatric illness and positive for diabetes mellitus, hypertension, and coronary artery disease.

Mrs. E lives with her husband and 10-year-old son. She admits to multiple stressors, including her health problems and financial dificulties, which recently led to the family’s decision to move to her mother-in-law’s house. Mrs. E denies using illicit drugs, cigarettes, or alcohol.

Mrs. E is admitted to the hospital, and her corticosteroid dosage is reduced with a switch to prednisone, 60 mg/d. She is started on risperidone, 1 mg at bedtime, which is titrated without adverse effect. Her psychotic symptoms improve over 4 days, and she is discharged on prednisone, 60 mg/d, and risperidone, 0.5 mg in the morning and 2 mg at night.

After completing her corticosteroid course, Mrs. E experiences complete resolution of psychiatric symptoms and is tapered off risperidone after 6 months.

Corticosteroid use can cause a variety of psychiatric syndromes, including mania, psychosis, depression, and delirium. A meta-analysis reports severe psychotic reactions in 5.7% of patients taking corticosteroids and mild-to-moderate reactions in 28% of patients.1 Hypomania, mania, and psychosis are the most common psychiatric reactions to acute corticosteroid therapy.2 This article reviews case reports and open-label trials of antipsychotics, mood stabilizers, and anticonvulsants to treat corticosteroid-induced mania and psychosis and outlines treatment options.

Symptoms

Corticosteroid-induced psychosis represents a spectrum of psychological changes that can occur at any time during treatment. Mild-to-moderate symptoms include agitation, anxiety, insomnia, irritability, and restlessness, whereas severe symptoms include mania, depression, and psychosis.3 Case reports reveal:

 

  • mania and hypomania in 35% of patients with corticosteroid-induced psychosis
  • acute psychotic disorder in 24% of patients, with hallucinations reported in one-half of these cases
  • depression, which is more common with chronic corticosteroid therapy, in 28% of patients.4

Delirium and cognitive deficits also have been reported, although these symptoms generally subside with corticosteroid reduction or withdrawal.4,5

Psychiatric symptoms often develop after 4 days of corticosteroid therapy, although they can occur late in therapy or after treatment ends.6 Delirium often resolves within a few days, psychosis within 7 days, and mania within 2 to 3 weeks, whereas depression can last for more than 3 weeks.4 A 3-level grading system can gauge severity of corticosteroid-induced psychosis; grade 2 or 3 warrants treatment (Table 1).4

Table 1

Grading scale for corticosteroid-induced psychiatric symptoms

 

GradeSymptoms
Grade 1Mild, nonpathologic, and subclinical euphoria
Grade 2Reversible acute or subacute mania and/or depression
Grade 3Bipolar disorder with relapses possible without steroids
Source: Reference 4

Risk factors

 

Clinical Point

High corticosteroid dose is the primary risk factor for psychosis but does not predict onset, severity, type of reaction, or duration

High corticosteroid dose is the primary risk factor for psychosis. The Boston Collaborative Drug Surveillance Program reported that among individuals taking prednisone, psychiatric disturbances are seen in:

 

  • 1.3% of patients taking <40 mg/d
  • 4.6% of patients taking 40 to 80 mg/d
  • 18.4% of patients taking >80 mg/d.7

However, the corticosteroid dosage does not predict onset, severity, type of reaction, or duration.3,7 Female patients are at higher risk of corticosteroid-induced psychosis, even after one controls for medical conditions diagnosed more often in women, such as SLE and rheumatoid arthritis.3 Previous episodes of corticosteroid-induced psychosis, history of psychiatric illness, and age are not associated with corticosteroid-induced psychosis.3

Treatment

Management includes tapering corticosteroids, with or without adding medications to treat the acute state. Decreasing corticosteroids to the lowest dose possible—<40 mg/d—or gradually discontinuing therapy to prevent triggering adrenal insufficiency may improve psychotic symptoms and avoids the risk of adverse effects from adjunctive medications.

Psychopharmacologic treatment may be necessary, depending on the severity of psychosis or the underlying disease, particularly if corticosteroids cannot be tapered or discontinued. Evidence from open-label trials (Table 2)8-12 and case reports indicates that psychotic symptoms could be prevented and treated with off-label antipsychotics, mood stabilizers, and anticonvulsants.

Consider your patient’s underlying medical condition when selecting psychotropics. For example, try to avoid prescribing:

 

  • antipsychotics to patients with cardiac conduction abnormalities
  • lithium to patients who need diuretic or angiotensin-converting enzyme inhibitor therapy or those with underlying renal insufficiency.

When appropriate, collaborate with the provider who prescribed the corticosteroids because tapering or discontinuation might not be possible.

Table 2

 

 

Corticosteroid-induced psychosis: Adjunctive treatment studies

 

Medication and sourcePatient populationResults
Olanzapine
(Brown et al, 20058)		12 outpatients experiencing manic or mixed symptoms received olanzapine, mean 8.5 mg/dReductions on YMRS, HRSD, and BPRS with no change in extrapyramidal symptom side-effect scales, weight, or glucose measurements
Lithium
(Falk et al, 19799)		27 patients diagnosed with multiple sclerosis or retrobulbar neuritis treated with corticotropin received lithium38% of lithium patients developed psychiatric symptoms compared with 62% of controls
Phenytoin
(Brown et al, 200510)		39 patients received phenytoin, 300 mg/d, or placebo at prednisone therapy initiationPatients receiving phenytoin reported a smaller increase in ACT score compared with controls
Levetiracetam
(Brown et al, 200711)		30 outpatients receiving corticosteroids randomized to levetiracetam, 1500 mg/d, or placeboNo significant change in HRSD, YMRS, or ACT scores
Lamotrigine
(Brown et al, 200312)		5 patients on chronic corticosteroid treatment received open-label lamotrigine, mean dose 340 mg/dNo significant difference in HRSD, YMRS, or the depression subscale of the Internal State Scale
ACT: Internal State Scale Activation subscale; BPRS: Brief Psychiatric Rating Scale; HRSD: Hamilton Rating Scale for Depression; YMRS: Young Mania Rating Scale

Antipsychotics

Open-label trial. Olanzapine reduced psychiatric symptoms in a 5-week, open-label trial of 12 outpatients experiencing manic or mixed symptoms secondary to corticosteroids.8 At baseline, patients had a mean score of 15.25 on the Young Mania Rating Scale (YMRS) on a mean prednisone dose of 14.4 mg/d. After receiving olanzapine, 2.5 mg/d titrated to a maximum 20 mg/d (mean 8.5 mg/d), subjects demonstrated a significant decrease on the YMRS (P=.002), Hamilton Rating Scale for Depression (HRSD) (P=.005), and Brief Psychiatric Rating Scale (BPRS) (P=.006) with no change in extrapyramidal side-effect scales, weight, or glucose measurements.

 

Clinical Point

Benefit with olanzapine was seen at dosages from 2.5 to 15 mg/d and improvement occurred within days to weeks

Case reports. Among antipsychotics, olanzapine has the greatest number of case reports for treating corticosteroid-induced psychosis, mainly for mania.13-15 Benefit with olanzapine was demonstrated at dosages from 2.5 to 15 mg/d and improvement occurred within days to weeks. Several patients remained symptom-free with olanzapine and continued corticosteroid therapy.

Other reports describe benefit with risperidone for a variety of psychiatric symptoms—including hypomania, hallucinations, and delusions—associated with corticosteroid therapy.16-19 Risperidone dosing ranged from 1 to 4 mg/d, and symptoms improved within days to weeks.

One case report describes quetiapine for the treatment of corticosteroid-induced mania.20 The patient’s symptoms improved within 10 hours of initiating quetiapine, 25 mg/d, and YMRS score decreased from 31 before therapy to 5 at discharge. No case reports exist for ziprasidone or aripiprazole.

Mood stabilizers

Cohort study. One study suggests that lithium may be effective for preventing and treating corticosteroid-induced psychosis. A retrospective cohort study examined records of patients diagnosed with multiple sclerosis or retrobulbar neuritis who were treated with corticotropin.9 Corticotropin has been reported to cause psychotic reactions in up to 11% of patients through a mechanism thought to mirror corticosteroid-induced psychosis (Box).21-23 Psychiatric symptoms developed in 38% of patients treated with lithium compared with 62% of controls. No patients pretreated with lithium maintained at 0.8 to 1.2 mEq/L reported mood disturbances or psychotic reactions.

Case reports. Among mood stabilizers, lithium has the greatest number of case reports on its use for prevention and treatment of corticosteroid-induced psychosis. In these reports, patients pretreated with lithium did not experience a relapse of psychosis related to chronic corticosteroid therapy.24-27 Case reports also describe benefit with valproic acid and carbamazepine.28-30

Anticonvulsants

Trials. In a 1-week trial, 39 patients without previous psychiatric diagnosis or psychotropic use were randomly assigned to phenytoin, 300 mg/d, or placebo as prednisone therapy was initiated.10 Compared with placebo, the phenytoin group reported a smaller increase on the Internal State Scale Activation subscale (ACT), a self-report measure of mania symptom severity. No significant differences were found on the YMRS or HRSD scales. Based on the ACT scale finding, the authors concluded that phenytoin attenuated manic or hypomanic effects of prednisone.

A study of levetiracetam, 1500 mg/d, showed no significant change in HRSD, YMRS, or ACT scores from baseline to end point for either levetiracetam or placebo.11

A 12-week, open-label trial of lamotrigine in 5 patients receiving corticosteroids continuously for 6 months showed no significant difference in mood changes as measured by the HRSD, YMRS, or the depression sub-scale of the Internal State Scale.12

Case reports show that lamotrigine and gabapentin have been used effectively to prevent manic symptoms in patients receiving corticosteroid therapy.31,32

Treatment recommendations

Establishing a treatment algorithm for corticosteroid-induced psychosis is hampered by the lack of prospective placebo-controlled trials. However, most case reports describe benefit from administrating atypical antipsychotics and lithium.

 

 

Box

 

Pathophysiology of corticosteroid-induced psychosis

How corticosteroids cause psychosis is not well understood. One theory suggests that corticosteroids act at steroid-specific receptors and suppress filtering by the hippocampus of irrelevant stimuli.21

Supporting this theory of hippocampal change, a study of 17 patients receiving corticosteroid therapy for >6 months found decreased hippocampal volume compared with a control group.22 Other possible causes include suppressed hypothalamus-pituitary axis and enhanced dopamine neurotransmission.23

Consider adding a low-dose atypical antipsychotic with which case studies report quick symptom resolution and patients tolerating these agents. Monitor carefully for metabolic changes, a risk associated with antipsychotics and corticosteroids. Lithium would be a good second-line therapy because of its demonstrated benefit for both prophylaxis and treatment of psychiatric disturbances.

 

Clinical Point

Consider adding a low-dose atypical antipsychotic to corticosteroid therapy; lithium may be second-line with precautions

Lithium use can be complicated and dangerous in patients who have underlying diseases associated with renal dysfunction, however—such as nephrotic syndromes and SLE—leading some authors to suggest valproic acid or carbamazepine instead.33 In addition, corticosteroid-induced changes in sodium balance could increase the risk of lithium toxicity.34

When patients cannot tolerate atypical antipsychotics or lithium, case reports support the use of valproic acid, carbamazepine, lamotrigine, or gabapentin to treat symptoms of corticosteroid-induced psychosis.

Related resources

 

  • Cerullo MA. Expect psychiatric side effects from corticosteroid use in the elderly. Geriatrics. 2008;63(1):15-18.
  • Sirois F. Steroid psychosis: a review. Gen Hosp Psychiatry. 2003;25:27-33.
  • Patten SB, Neutel CI. Corticosteroid-induced adverse psychiatric effects: incidence, diagnosis, and management. Drug Safety. 2000;22(2):111-122.
  • Warrington TP, Bostwick JM. Psychiatric adverse effects of corticosteroids. Mayo Clin Proc. 2006;81(10):1361-1367.

Drug brand names

 

  • Aripiprazole • Abilify
  • Carbamazepine • Tegretol
  • Corticotropin • Acthar
  • Gabapentin • Neurontin
  • Lamotrigine • Lamictal
  • Levetiracetam • Keppra
  • Lithium • Lithobid, Eskalith, others
  • Methylprednisolone • Medrol
  • Olanzapine • Zyprexa
  • Phenytoin • Dilantin
  • Prednisone • Deltasone
  • Quetiapine • Seroquel
  • Risperidone • Risperdal
  • Valproic acid • Depakene
  • Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

References

 

1. Lewis DA, Smith RE. Steroid-induced psychiatric syndromes: a report of 14 cases and a review of the literature. J Affect Disord. 1983;5:319-332.

2. Bolanos SH, Khan DA, Hanczyc M, et al. Assessment of mood states in patients receiving long-term corticosteroid therapy and in controls with patient-rated and clinician-rated scales. Ann Allergy Asthma Immunol. 2004;92:500-505.

3. Warrington TP, Bostwick JM. Psychiatric adverse effect of corticosteroids. Mayo Clin Proc. 2006;81(10):1361-1367.

4. Sirois F. Steroid psychosis: a review. Gen Hosp Psychiatry. 2003;25:27-33.

5. Newcomer JW, Craft S, Hershey T, et al. Glucocorticoid-induced impairments in declarative memory performance in adult humans. J Neurosci. 1991;14:2047-2053.

6. Hall RC, Popkin MK, Stickney SK, et al. Presentation of the steroid induced psychosis. J Nerv Ment Dis. 1979;167:229-236.

7. The Boston Collaborative Drug Surveillance Program. Acute adverse reactions to prednisone in relation to dosage. Clin Pharmacol Ther. 1972;13:694-698.

8. Brown ES, Chamberlain W, Dhanani N, et al. An open-label trial of olanzapine for corticosteroid-induced mood symptoms. J Affect Disord. 2004;83:277-281.

9. Falk WE, Mahnke MW, Poskanzer DC. Lithium prophylaxis of corticotropin-induced psychosis. JAMA. 1979;241:1011-1012.

10. Brown ES, Stuard G, Liggin JD, et al. Effect of phenytoin on mood and declarative memory during prescription corticosteroid therapy. Bio Psychiatry. 2005;57:543-548.

11. Brown ES, Frol AB, Khan DA, et al. Impact of levetiracetam on mood and cognition during prednisone therapy. Eur Psychiatry. 2007;22:448-452.

12. Brown ES, Frol A, Bobadilla L, et al. Effect of lamotrigine on mood and cognition in patients receiving chronic exogenous corticosteroids. Psychosomatics. 2003;44(3):204-208.

13. Goldman LS, Goveas J. Olanzapine treatment of corticosteroid-induced mood disorders. Psychosomatics. 2002;43(6):495-497.

14. Brown ES, Khan DA, Suppes T. Treatment of corticosteroid-induced mood changes with olanzapine. Am J Psychiatry. 1999;156(6):968.-

15. Budur K, Pozuelo L. Olanzapine for corticosteroid-induced mood disorders. Psychosomatics. 2003;44(4):353.-

16. Herguner S, Bilge I, Yavuz Yilmaz A, et al. Steroid-induced psychosis in an adolescent: treatment and prophylaxis with risperidone. Turk J Pediatr. 2006;48:244-247.

17. DeSilva CC, Nurse MC, Vokey K. Steroid-induced psychosis treated with risperidone. Can J Psychiatry. 2002;47:388-389.

18. Kato O, Misawa H. Steroid-induced psychosis treated with valproic acid and risperidone in a patient with systemic lupus erythematosus. Prim Care Companion J Clin Psychiatry. 2005;7(6):312.-

19. Kramer TM, Cottingham EM. Risperidone in the treatment of steroid-induced psychosis. J Child Adolec Psychopharmacol. 1999;9:315-316.

20. Siddiqui Z, Ramaswamy S, Petty F. Quetiapine therapy for coricosteroid-induced mania. Can J Psychiatry. 2005;50(1):77-78.

21. Naber D, Sand P, Heigl B. Psychopathological and neuropsychological effects of 8-days’ corticosteroid treatment. A prospective study. Psychoneuroendocrinology. 1996;21(1):25-31.

22. Brown ES, Woolston DJ, Frol A, et al. Hippocampal volume, spectroscopy, cognition, and mood in patients receiving corticosteroid therapy. Biol Psychiatry. 2004;55:538-545.

23. Schatzberg AF, Rothschild AJ, Langlais PJ, et al. A corticosteroid/dopamine hypothesis for psychotic depression and related states. J Psychiat Res. 1985;19(1):57-64.

24. Sabet-Sharghi F, Hutzler JC. Prophylaxis of steroid-induced psychiatric syndromes. Psychosomatics. 1990;31(1):113-114.

25. Siegal FP. Lithium for steroid-induced psychosis. N Engl J Med. 1978;299(3):155-156.

26. Goggans FC, Weisberg LJ, Koran LM. Lithium prophylaxis of prednisone psychosis: a case report. J Clin Psychiatry. 1983;44(3):111-112.

27. Merrill W. Case 35-1998: use of lithium to prevent corticosteroid-induced mania. N Engl J Med. 1999;340(14):1123.-

28. Himelhoch S, Haller E. Extreme mood lability associated with systemic lupus erythematosus and stroke successfully treated with valproic acid. J Clin Psychopharmacol. 1996;16(6):469-470.

29. Kahn D, Stevenson E, Douglas CJ. Effect of sodium valproate in three patients with organic brain syndromes. Am J Psychiatry. 1998;145(8):1010-1011.

30. Abbas A, Styra R. Valproate prophylaxis against steroid induced psychosis. Can J Psychiatry. 1994;39(3):188-189.

31. Preda A, Fazeli A, McKay BG, et al. Lamotrigine as prophylaxis against steroid-induced mania. J Clin Psychiatry. 1999;60(10):708-709.

32. Ginsberg DL, Sussman N. Gabapentin as prophylaxis against corticosteroid-induced mania. Can J Psychiatry. 2001;44:455-456.

33. Wada K, Yamada N, Yamauchi Y, et al. Carbamazepine treatment of corticosteroid-induced mood disorder. J Affect Disord. 2001;65:315-317.

34. Saklad S. Management of corticosteroid-induced psychosis with lithium. Clin Pharm. 1987;6(3):186.-

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Andrew J. Muzyk, PharmD
Clinical pharmacist, Duke University School of Medicine, Durham, NC
Shannon Holt, PharmD
Clinical pharmacist, Duke University School of Medicine, Durham, NC
Jane P. Gagliardi, MD
Assistant professor of psychiatry and behavioral sciences, Assistant professor of medicine, Duke University School of Medicine, Durham, NC

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Current Psychiatry
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corticosteroids;psychosisAndrew Muzyk;Shannon Holt;Jane Gagliardi
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Andrew J. Muzyk, PharmD
Clinical pharmacist, Duke University School of Medicine, Durham, NC
Shannon Holt, PharmD
Clinical pharmacist, Duke University School of Medicine, Durham, NC
Jane P. Gagliardi, MD
Assistant professor of psychiatry and behavioral sciences, Assistant professor of medicine, Duke University School of Medicine, Durham, NC

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Andrew J. Muzyk, PharmD
Clinical pharmacist, Duke University School of Medicine, Durham, NC
Shannon Holt, PharmD
Clinical pharmacist, Duke University School of Medicine, Durham, NC
Jane P. Gagliardi, MD
Assistant professor of psychiatry and behavioral sciences, Assistant professor of medicine, Duke University School of Medicine, Durham, NC

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Mrs. E, age 31, develops rapid, pressured speech and insomnia for 4 consecutive nights, but reports a normal energy level after receiving high-dose methylprednisolone for an acute flare of systemic lupus erythematosus (SLE).

Her medical history indicates an overlap syndrome between SLE and systemic sclerosis for the last 5 years, migraine headaches, and 4 spontaneous miscarriages, but she has no psychiatric history. Her family history is negative for psychiatric illness and positive for diabetes mellitus, hypertension, and coronary artery disease.

Mrs. E lives with her husband and 10-year-old son. She admits to multiple stressors, including her health problems and financial dificulties, which recently led to the family’s decision to move to her mother-in-law’s house. Mrs. E denies using illicit drugs, cigarettes, or alcohol.

Mrs. E is admitted to the hospital, and her corticosteroid dosage is reduced with a switch to prednisone, 60 mg/d. She is started on risperidone, 1 mg at bedtime, which is titrated without adverse effect. Her psychotic symptoms improve over 4 days, and she is discharged on prednisone, 60 mg/d, and risperidone, 0.5 mg in the morning and 2 mg at night.

After completing her corticosteroid course, Mrs. E experiences complete resolution of psychiatric symptoms and is tapered off risperidone after 6 months.

Corticosteroid use can cause a variety of psychiatric syndromes, including mania, psychosis, depression, and delirium. A meta-analysis reports severe psychotic reactions in 5.7% of patients taking corticosteroids and mild-to-moderate reactions in 28% of patients.1 Hypomania, mania, and psychosis are the most common psychiatric reactions to acute corticosteroid therapy.2 This article reviews case reports and open-label trials of antipsychotics, mood stabilizers, and anticonvulsants to treat corticosteroid-induced mania and psychosis and outlines treatment options.

Symptoms

Corticosteroid-induced psychosis represents a spectrum of psychological changes that can occur at any time during treatment. Mild-to-moderate symptoms include agitation, anxiety, insomnia, irritability, and restlessness, whereas severe symptoms include mania, depression, and psychosis.3 Case reports reveal:

 

  • mania and hypomania in 35% of patients with corticosteroid-induced psychosis
  • acute psychotic disorder in 24% of patients, with hallucinations reported in one-half of these cases
  • depression, which is more common with chronic corticosteroid therapy, in 28% of patients.4

Delirium and cognitive deficits also have been reported, although these symptoms generally subside with corticosteroid reduction or withdrawal.4,5

Psychiatric symptoms often develop after 4 days of corticosteroid therapy, although they can occur late in therapy or after treatment ends.6 Delirium often resolves within a few days, psychosis within 7 days, and mania within 2 to 3 weeks, whereas depression can last for more than 3 weeks.4 A 3-level grading system can gauge severity of corticosteroid-induced psychosis; grade 2 or 3 warrants treatment (Table 1).4

Table 1

Grading scale for corticosteroid-induced psychiatric symptoms

 

GradeSymptoms
Grade 1Mild, nonpathologic, and subclinical euphoria
Grade 2Reversible acute or subacute mania and/or depression
Grade 3Bipolar disorder with relapses possible without steroids
Source: Reference 4

Risk factors

 

Clinical Point

High corticosteroid dose is the primary risk factor for psychosis but does not predict onset, severity, type of reaction, or duration

High corticosteroid dose is the primary risk factor for psychosis. The Boston Collaborative Drug Surveillance Program reported that among individuals taking prednisone, psychiatric disturbances are seen in:

 

  • 1.3% of patients taking <40 mg/d
  • 4.6% of patients taking 40 to 80 mg/d
  • 18.4% of patients taking >80 mg/d.7

However, the corticosteroid dosage does not predict onset, severity, type of reaction, or duration.3,7 Female patients are at higher risk of corticosteroid-induced psychosis, even after one controls for medical conditions diagnosed more often in women, such as SLE and rheumatoid arthritis.3 Previous episodes of corticosteroid-induced psychosis, history of psychiatric illness, and age are not associated with corticosteroid-induced psychosis.3

Treatment

Management includes tapering corticosteroids, with or without adding medications to treat the acute state. Decreasing corticosteroids to the lowest dose possible—<40 mg/d—or gradually discontinuing therapy to prevent triggering adrenal insufficiency may improve psychotic symptoms and avoids the risk of adverse effects from adjunctive medications.

Psychopharmacologic treatment may be necessary, depending on the severity of psychosis or the underlying disease, particularly if corticosteroids cannot be tapered or discontinued. Evidence from open-label trials (Table 2)8-12 and case reports indicates that psychotic symptoms could be prevented and treated with off-label antipsychotics, mood stabilizers, and anticonvulsants.

Consider your patient’s underlying medical condition when selecting psychotropics. For example, try to avoid prescribing:

 

  • antipsychotics to patients with cardiac conduction abnormalities
  • lithium to patients who need diuretic or angiotensin-converting enzyme inhibitor therapy or those with underlying renal insufficiency.

When appropriate, collaborate with the provider who prescribed the corticosteroids because tapering or discontinuation might not be possible.

Table 2

 

 

Corticosteroid-induced psychosis: Adjunctive treatment studies

 

Medication and sourcePatient populationResults
Olanzapine
(Brown et al, 20058)		12 outpatients experiencing manic or mixed symptoms received olanzapine, mean 8.5 mg/dReductions on YMRS, HRSD, and BPRS with no change in extrapyramidal symptom side-effect scales, weight, or glucose measurements
Lithium
(Falk et al, 19799)		27 patients diagnosed with multiple sclerosis or retrobulbar neuritis treated with corticotropin received lithium38% of lithium patients developed psychiatric symptoms compared with 62% of controls
Phenytoin
(Brown et al, 200510)		39 patients received phenytoin, 300 mg/d, or placebo at prednisone therapy initiationPatients receiving phenytoin reported a smaller increase in ACT score compared with controls
Levetiracetam
(Brown et al, 200711)		30 outpatients receiving corticosteroids randomized to levetiracetam, 1500 mg/d, or placeboNo significant change in HRSD, YMRS, or ACT scores
Lamotrigine
(Brown et al, 200312)		5 patients on chronic corticosteroid treatment received open-label lamotrigine, mean dose 340 mg/dNo significant difference in HRSD, YMRS, or the depression subscale of the Internal State Scale
ACT: Internal State Scale Activation subscale; BPRS: Brief Psychiatric Rating Scale; HRSD: Hamilton Rating Scale for Depression; YMRS: Young Mania Rating Scale

Antipsychotics

Open-label trial. Olanzapine reduced psychiatric symptoms in a 5-week, open-label trial of 12 outpatients experiencing manic or mixed symptoms secondary to corticosteroids.8 At baseline, patients had a mean score of 15.25 on the Young Mania Rating Scale (YMRS) on a mean prednisone dose of 14.4 mg/d. After receiving olanzapine, 2.5 mg/d titrated to a maximum 20 mg/d (mean 8.5 mg/d), subjects demonstrated a significant decrease on the YMRS (P=.002), Hamilton Rating Scale for Depression (HRSD) (P=.005), and Brief Psychiatric Rating Scale (BPRS) (P=.006) with no change in extrapyramidal side-effect scales, weight, or glucose measurements.

 

Clinical Point

Benefit with olanzapine was seen at dosages from 2.5 to 15 mg/d and improvement occurred within days to weeks

Case reports. Among antipsychotics, olanzapine has the greatest number of case reports for treating corticosteroid-induced psychosis, mainly for mania.13-15 Benefit with olanzapine was demonstrated at dosages from 2.5 to 15 mg/d and improvement occurred within days to weeks. Several patients remained symptom-free with olanzapine and continued corticosteroid therapy.

Other reports describe benefit with risperidone for a variety of psychiatric symptoms—including hypomania, hallucinations, and delusions—associated with corticosteroid therapy.16-19 Risperidone dosing ranged from 1 to 4 mg/d, and symptoms improved within days to weeks.

One case report describes quetiapine for the treatment of corticosteroid-induced mania.20 The patient’s symptoms improved within 10 hours of initiating quetiapine, 25 mg/d, and YMRS score decreased from 31 before therapy to 5 at discharge. No case reports exist for ziprasidone or aripiprazole.

Mood stabilizers

Cohort study. One study suggests that lithium may be effective for preventing and treating corticosteroid-induced psychosis. A retrospective cohort study examined records of patients diagnosed with multiple sclerosis or retrobulbar neuritis who were treated with corticotropin.9 Corticotropin has been reported to cause psychotic reactions in up to 11% of patients through a mechanism thought to mirror corticosteroid-induced psychosis (Box).21-23 Psychiatric symptoms developed in 38% of patients treated with lithium compared with 62% of controls. No patients pretreated with lithium maintained at 0.8 to 1.2 mEq/L reported mood disturbances or psychotic reactions.

Case reports. Among mood stabilizers, lithium has the greatest number of case reports on its use for prevention and treatment of corticosteroid-induced psychosis. In these reports, patients pretreated with lithium did not experience a relapse of psychosis related to chronic corticosteroid therapy.24-27 Case reports also describe benefit with valproic acid and carbamazepine.28-30

Anticonvulsants

Trials. In a 1-week trial, 39 patients without previous psychiatric diagnosis or psychotropic use were randomly assigned to phenytoin, 300 mg/d, or placebo as prednisone therapy was initiated.10 Compared with placebo, the phenytoin group reported a smaller increase on the Internal State Scale Activation subscale (ACT), a self-report measure of mania symptom severity. No significant differences were found on the YMRS or HRSD scales. Based on the ACT scale finding, the authors concluded that phenytoin attenuated manic or hypomanic effects of prednisone.

A study of levetiracetam, 1500 mg/d, showed no significant change in HRSD, YMRS, or ACT scores from baseline to end point for either levetiracetam or placebo.11

A 12-week, open-label trial of lamotrigine in 5 patients receiving corticosteroids continuously for 6 months showed no significant difference in mood changes as measured by the HRSD, YMRS, or the depression sub-scale of the Internal State Scale.12

Case reports show that lamotrigine and gabapentin have been used effectively to prevent manic symptoms in patients receiving corticosteroid therapy.31,32

Treatment recommendations

Establishing a treatment algorithm for corticosteroid-induced psychosis is hampered by the lack of prospective placebo-controlled trials. However, most case reports describe benefit from administrating atypical antipsychotics and lithium.

 

 

Box

 

Pathophysiology of corticosteroid-induced psychosis

How corticosteroids cause psychosis is not well understood. One theory suggests that corticosteroids act at steroid-specific receptors and suppress filtering by the hippocampus of irrelevant stimuli.21

Supporting this theory of hippocampal change, a study of 17 patients receiving corticosteroid therapy for >6 months found decreased hippocampal volume compared with a control group.22 Other possible causes include suppressed hypothalamus-pituitary axis and enhanced dopamine neurotransmission.23

Consider adding a low-dose atypical antipsychotic with which case studies report quick symptom resolution and patients tolerating these agents. Monitor carefully for metabolic changes, a risk associated with antipsychotics and corticosteroids. Lithium would be a good second-line therapy because of its demonstrated benefit for both prophylaxis and treatment of psychiatric disturbances.

 

Clinical Point

Consider adding a low-dose atypical antipsychotic to corticosteroid therapy; lithium may be second-line with precautions

Lithium use can be complicated and dangerous in patients who have underlying diseases associated with renal dysfunction, however—such as nephrotic syndromes and SLE—leading some authors to suggest valproic acid or carbamazepine instead.33 In addition, corticosteroid-induced changes in sodium balance could increase the risk of lithium toxicity.34

When patients cannot tolerate atypical antipsychotics or lithium, case reports support the use of valproic acid, carbamazepine, lamotrigine, or gabapentin to treat symptoms of corticosteroid-induced psychosis.

Related resources

 

  • Cerullo MA. Expect psychiatric side effects from corticosteroid use in the elderly. Geriatrics. 2008;63(1):15-18.
  • Sirois F. Steroid psychosis: a review. Gen Hosp Psychiatry. 2003;25:27-33.
  • Patten SB, Neutel CI. Corticosteroid-induced adverse psychiatric effects: incidence, diagnosis, and management. Drug Safety. 2000;22(2):111-122.
  • Warrington TP, Bostwick JM. Psychiatric adverse effects of corticosteroids. Mayo Clin Proc. 2006;81(10):1361-1367.

Drug brand names

 

  • Aripiprazole • Abilify
  • Carbamazepine • Tegretol
  • Corticotropin • Acthar
  • Gabapentin • Neurontin
  • Lamotrigine • Lamictal
  • Levetiracetam • Keppra
  • Lithium • Lithobid, Eskalith, others
  • Methylprednisolone • Medrol
  • Olanzapine • Zyprexa
  • Phenytoin • Dilantin
  • Prednisone • Deltasone
  • Quetiapine • Seroquel
  • Risperidone • Risperdal
  • Valproic acid • Depakene
  • Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Mrs. E, age 31, develops rapid, pressured speech and insomnia for 4 consecutive nights, but reports a normal energy level after receiving high-dose methylprednisolone for an acute flare of systemic lupus erythematosus (SLE).

Her medical history indicates an overlap syndrome between SLE and systemic sclerosis for the last 5 years, migraine headaches, and 4 spontaneous miscarriages, but she has no psychiatric history. Her family history is negative for psychiatric illness and positive for diabetes mellitus, hypertension, and coronary artery disease.

Mrs. E lives with her husband and 10-year-old son. She admits to multiple stressors, including her health problems and financial dificulties, which recently led to the family’s decision to move to her mother-in-law’s house. Mrs. E denies using illicit drugs, cigarettes, or alcohol.

Mrs. E is admitted to the hospital, and her corticosteroid dosage is reduced with a switch to prednisone, 60 mg/d. She is started on risperidone, 1 mg at bedtime, which is titrated without adverse effect. Her psychotic symptoms improve over 4 days, and she is discharged on prednisone, 60 mg/d, and risperidone, 0.5 mg in the morning and 2 mg at night.

After completing her corticosteroid course, Mrs. E experiences complete resolution of psychiatric symptoms and is tapered off risperidone after 6 months.

Corticosteroid use can cause a variety of psychiatric syndromes, including mania, psychosis, depression, and delirium. A meta-analysis reports severe psychotic reactions in 5.7% of patients taking corticosteroids and mild-to-moderate reactions in 28% of patients.1 Hypomania, mania, and psychosis are the most common psychiatric reactions to acute corticosteroid therapy.2 This article reviews case reports and open-label trials of antipsychotics, mood stabilizers, and anticonvulsants to treat corticosteroid-induced mania and psychosis and outlines treatment options.

Symptoms

Corticosteroid-induced psychosis represents a spectrum of psychological changes that can occur at any time during treatment. Mild-to-moderate symptoms include agitation, anxiety, insomnia, irritability, and restlessness, whereas severe symptoms include mania, depression, and psychosis.3 Case reports reveal:

 

  • mania and hypomania in 35% of patients with corticosteroid-induced psychosis
  • acute psychotic disorder in 24% of patients, with hallucinations reported in one-half of these cases
  • depression, which is more common with chronic corticosteroid therapy, in 28% of patients.4

Delirium and cognitive deficits also have been reported, although these symptoms generally subside with corticosteroid reduction or withdrawal.4,5

Psychiatric symptoms often develop after 4 days of corticosteroid therapy, although they can occur late in therapy or after treatment ends.6 Delirium often resolves within a few days, psychosis within 7 days, and mania within 2 to 3 weeks, whereas depression can last for more than 3 weeks.4 A 3-level grading system can gauge severity of corticosteroid-induced psychosis; grade 2 or 3 warrants treatment (Table 1).4

Table 1

Grading scale for corticosteroid-induced psychiatric symptoms

 

GradeSymptoms
Grade 1Mild, nonpathologic, and subclinical euphoria
Grade 2Reversible acute or subacute mania and/or depression
Grade 3Bipolar disorder with relapses possible without steroids
Source: Reference 4

Risk factors

 

Clinical Point

High corticosteroid dose is the primary risk factor for psychosis but does not predict onset, severity, type of reaction, or duration

High corticosteroid dose is the primary risk factor for psychosis. The Boston Collaborative Drug Surveillance Program reported that among individuals taking prednisone, psychiatric disturbances are seen in:

 

  • 1.3% of patients taking <40 mg/d
  • 4.6% of patients taking 40 to 80 mg/d
  • 18.4% of patients taking >80 mg/d.7

However, the corticosteroid dosage does not predict onset, severity, type of reaction, or duration.3,7 Female patients are at higher risk of corticosteroid-induced psychosis, even after one controls for medical conditions diagnosed more often in women, such as SLE and rheumatoid arthritis.3 Previous episodes of corticosteroid-induced psychosis, history of psychiatric illness, and age are not associated with corticosteroid-induced psychosis.3

Treatment

Management includes tapering corticosteroids, with or without adding medications to treat the acute state. Decreasing corticosteroids to the lowest dose possible—<40 mg/d—or gradually discontinuing therapy to prevent triggering adrenal insufficiency may improve psychotic symptoms and avoids the risk of adverse effects from adjunctive medications.

Psychopharmacologic treatment may be necessary, depending on the severity of psychosis or the underlying disease, particularly if corticosteroids cannot be tapered or discontinued. Evidence from open-label trials (Table 2)8-12 and case reports indicates that psychotic symptoms could be prevented and treated with off-label antipsychotics, mood stabilizers, and anticonvulsants.

Consider your patient’s underlying medical condition when selecting psychotropics. For example, try to avoid prescribing:

 

  • antipsychotics to patients with cardiac conduction abnormalities
  • lithium to patients who need diuretic or angiotensin-converting enzyme inhibitor therapy or those with underlying renal insufficiency.

When appropriate, collaborate with the provider who prescribed the corticosteroids because tapering or discontinuation might not be possible.

Table 2

 

 

Corticosteroid-induced psychosis: Adjunctive treatment studies

 

Medication and sourcePatient populationResults
Olanzapine
(Brown et al, 20058)		12 outpatients experiencing manic or mixed symptoms received olanzapine, mean 8.5 mg/dReductions on YMRS, HRSD, and BPRS with no change in extrapyramidal symptom side-effect scales, weight, or glucose measurements
Lithium
(Falk et al, 19799)		27 patients diagnosed with multiple sclerosis or retrobulbar neuritis treated with corticotropin received lithium38% of lithium patients developed psychiatric symptoms compared with 62% of controls
Phenytoin
(Brown et al, 200510)		39 patients received phenytoin, 300 mg/d, or placebo at prednisone therapy initiationPatients receiving phenytoin reported a smaller increase in ACT score compared with controls
Levetiracetam
(Brown et al, 200711)		30 outpatients receiving corticosteroids randomized to levetiracetam, 1500 mg/d, or placeboNo significant change in HRSD, YMRS, or ACT scores
Lamotrigine
(Brown et al, 200312)		5 patients on chronic corticosteroid treatment received open-label lamotrigine, mean dose 340 mg/dNo significant difference in HRSD, YMRS, or the depression subscale of the Internal State Scale
ACT: Internal State Scale Activation subscale; BPRS: Brief Psychiatric Rating Scale; HRSD: Hamilton Rating Scale for Depression; YMRS: Young Mania Rating Scale

Antipsychotics

Open-label trial. Olanzapine reduced psychiatric symptoms in a 5-week, open-label trial of 12 outpatients experiencing manic or mixed symptoms secondary to corticosteroids.8 At baseline, patients had a mean score of 15.25 on the Young Mania Rating Scale (YMRS) on a mean prednisone dose of 14.4 mg/d. After receiving olanzapine, 2.5 mg/d titrated to a maximum 20 mg/d (mean 8.5 mg/d), subjects demonstrated a significant decrease on the YMRS (P=.002), Hamilton Rating Scale for Depression (HRSD) (P=.005), and Brief Psychiatric Rating Scale (BPRS) (P=.006) with no change in extrapyramidal side-effect scales, weight, or glucose measurements.

 

Clinical Point

Benefit with olanzapine was seen at dosages from 2.5 to 15 mg/d and improvement occurred within days to weeks

Case reports. Among antipsychotics, olanzapine has the greatest number of case reports for treating corticosteroid-induced psychosis, mainly for mania.13-15 Benefit with olanzapine was demonstrated at dosages from 2.5 to 15 mg/d and improvement occurred within days to weeks. Several patients remained symptom-free with olanzapine and continued corticosteroid therapy.

Other reports describe benefit with risperidone for a variety of psychiatric symptoms—including hypomania, hallucinations, and delusions—associated with corticosteroid therapy.16-19 Risperidone dosing ranged from 1 to 4 mg/d, and symptoms improved within days to weeks.

One case report describes quetiapine for the treatment of corticosteroid-induced mania.20 The patient’s symptoms improved within 10 hours of initiating quetiapine, 25 mg/d, and YMRS score decreased from 31 before therapy to 5 at discharge. No case reports exist for ziprasidone or aripiprazole.

Mood stabilizers

Cohort study. One study suggests that lithium may be effective for preventing and treating corticosteroid-induced psychosis. A retrospective cohort study examined records of patients diagnosed with multiple sclerosis or retrobulbar neuritis who were treated with corticotropin.9 Corticotropin has been reported to cause psychotic reactions in up to 11% of patients through a mechanism thought to mirror corticosteroid-induced psychosis (Box).21-23 Psychiatric symptoms developed in 38% of patients treated with lithium compared with 62% of controls. No patients pretreated with lithium maintained at 0.8 to 1.2 mEq/L reported mood disturbances or psychotic reactions.

Case reports. Among mood stabilizers, lithium has the greatest number of case reports on its use for prevention and treatment of corticosteroid-induced psychosis. In these reports, patients pretreated with lithium did not experience a relapse of psychosis related to chronic corticosteroid therapy.24-27 Case reports also describe benefit with valproic acid and carbamazepine.28-30

Anticonvulsants

Trials. In a 1-week trial, 39 patients without previous psychiatric diagnosis or psychotropic use were randomly assigned to phenytoin, 300 mg/d, or placebo as prednisone therapy was initiated.10 Compared with placebo, the phenytoin group reported a smaller increase on the Internal State Scale Activation subscale (ACT), a self-report measure of mania symptom severity. No significant differences were found on the YMRS or HRSD scales. Based on the ACT scale finding, the authors concluded that phenytoin attenuated manic or hypomanic effects of prednisone.

A study of levetiracetam, 1500 mg/d, showed no significant change in HRSD, YMRS, or ACT scores from baseline to end point for either levetiracetam or placebo.11

A 12-week, open-label trial of lamotrigine in 5 patients receiving corticosteroids continuously for 6 months showed no significant difference in mood changes as measured by the HRSD, YMRS, or the depression sub-scale of the Internal State Scale.12

Case reports show that lamotrigine and gabapentin have been used effectively to prevent manic symptoms in patients receiving corticosteroid therapy.31,32

Treatment recommendations

Establishing a treatment algorithm for corticosteroid-induced psychosis is hampered by the lack of prospective placebo-controlled trials. However, most case reports describe benefit from administrating atypical antipsychotics and lithium.

 

 

Box

 

Pathophysiology of corticosteroid-induced psychosis

How corticosteroids cause psychosis is not well understood. One theory suggests that corticosteroids act at steroid-specific receptors and suppress filtering by the hippocampus of irrelevant stimuli.21

Supporting this theory of hippocampal change, a study of 17 patients receiving corticosteroid therapy for >6 months found decreased hippocampal volume compared with a control group.22 Other possible causes include suppressed hypothalamus-pituitary axis and enhanced dopamine neurotransmission.23

Consider adding a low-dose atypical antipsychotic with which case studies report quick symptom resolution and patients tolerating these agents. Monitor carefully for metabolic changes, a risk associated with antipsychotics and corticosteroids. Lithium would be a good second-line therapy because of its demonstrated benefit for both prophylaxis and treatment of psychiatric disturbances.

 

Clinical Point

Consider adding a low-dose atypical antipsychotic to corticosteroid therapy; lithium may be second-line with precautions

Lithium use can be complicated and dangerous in patients who have underlying diseases associated with renal dysfunction, however—such as nephrotic syndromes and SLE—leading some authors to suggest valproic acid or carbamazepine instead.33 In addition, corticosteroid-induced changes in sodium balance could increase the risk of lithium toxicity.34

When patients cannot tolerate atypical antipsychotics or lithium, case reports support the use of valproic acid, carbamazepine, lamotrigine, or gabapentin to treat symptoms of corticosteroid-induced psychosis.

Related resources

 

  • Cerullo MA. Expect psychiatric side effects from corticosteroid use in the elderly. Geriatrics. 2008;63(1):15-18.
  • Sirois F. Steroid psychosis: a review. Gen Hosp Psychiatry. 2003;25:27-33.
  • Patten SB, Neutel CI. Corticosteroid-induced adverse psychiatric effects: incidence, diagnosis, and management. Drug Safety. 2000;22(2):111-122.
  • Warrington TP, Bostwick JM. Psychiatric adverse effects of corticosteroids. Mayo Clin Proc. 2006;81(10):1361-1367.

Drug brand names

 

  • Aripiprazole • Abilify
  • Carbamazepine • Tegretol
  • Corticotropin • Acthar
  • Gabapentin • Neurontin
  • Lamotrigine • Lamictal
  • Levetiracetam • Keppra
  • Lithium • Lithobid, Eskalith, others
  • Methylprednisolone • Medrol
  • Olanzapine • Zyprexa
  • Phenytoin • Dilantin
  • Prednisone • Deltasone
  • Quetiapine • Seroquel
  • Risperidone • Risperdal
  • Valproic acid • Depakene
  • Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

References

 

1. Lewis DA, Smith RE. Steroid-induced psychiatric syndromes: a report of 14 cases and a review of the literature. J Affect Disord. 1983;5:319-332.

2. Bolanos SH, Khan DA, Hanczyc M, et al. Assessment of mood states in patients receiving long-term corticosteroid therapy and in controls with patient-rated and clinician-rated scales. Ann Allergy Asthma Immunol. 2004;92:500-505.

3. Warrington TP, Bostwick JM. Psychiatric adverse effect of corticosteroids. Mayo Clin Proc. 2006;81(10):1361-1367.

4. Sirois F. Steroid psychosis: a review. Gen Hosp Psychiatry. 2003;25:27-33.

5. Newcomer JW, Craft S, Hershey T, et al. Glucocorticoid-induced impairments in declarative memory performance in adult humans. J Neurosci. 1991;14:2047-2053.

6. Hall RC, Popkin MK, Stickney SK, et al. Presentation of the steroid induced psychosis. J Nerv Ment Dis. 1979;167:229-236.

7. The Boston Collaborative Drug Surveillance Program. Acute adverse reactions to prednisone in relation to dosage. Clin Pharmacol Ther. 1972;13:694-698.

8. Brown ES, Chamberlain W, Dhanani N, et al. An open-label trial of olanzapine for corticosteroid-induced mood symptoms. J Affect Disord. 2004;83:277-281.

9. Falk WE, Mahnke MW, Poskanzer DC. Lithium prophylaxis of corticotropin-induced psychosis. JAMA. 1979;241:1011-1012.

10. Brown ES, Stuard G, Liggin JD, et al. Effect of phenytoin on mood and declarative memory during prescription corticosteroid therapy. Bio Psychiatry. 2005;57:543-548.

11. Brown ES, Frol AB, Khan DA, et al. Impact of levetiracetam on mood and cognition during prednisone therapy. Eur Psychiatry. 2007;22:448-452.

12. Brown ES, Frol A, Bobadilla L, et al. Effect of lamotrigine on mood and cognition in patients receiving chronic exogenous corticosteroids. Psychosomatics. 2003;44(3):204-208.

13. Goldman LS, Goveas J. Olanzapine treatment of corticosteroid-induced mood disorders. Psychosomatics. 2002;43(6):495-497.

14. Brown ES, Khan DA, Suppes T. Treatment of corticosteroid-induced mood changes with olanzapine. Am J Psychiatry. 1999;156(6):968.-

15. Budur K, Pozuelo L. Olanzapine for corticosteroid-induced mood disorders. Psychosomatics. 2003;44(4):353.-

16. Herguner S, Bilge I, Yavuz Yilmaz A, et al. Steroid-induced psychosis in an adolescent: treatment and prophylaxis with risperidone. Turk J Pediatr. 2006;48:244-247.

17. DeSilva CC, Nurse MC, Vokey K. Steroid-induced psychosis treated with risperidone. Can J Psychiatry. 2002;47:388-389.

18. Kato O, Misawa H. Steroid-induced psychosis treated with valproic acid and risperidone in a patient with systemic lupus erythematosus. Prim Care Companion J Clin Psychiatry. 2005;7(6):312.-

19. Kramer TM, Cottingham EM. Risperidone in the treatment of steroid-induced psychosis. J Child Adolec Psychopharmacol. 1999;9:315-316.

20. Siddiqui Z, Ramaswamy S, Petty F. Quetiapine therapy for coricosteroid-induced mania. Can J Psychiatry. 2005;50(1):77-78.

21. Naber D, Sand P, Heigl B. Psychopathological and neuropsychological effects of 8-days’ corticosteroid treatment. A prospective study. Psychoneuroendocrinology. 1996;21(1):25-31.

22. Brown ES, Woolston DJ, Frol A, et al. Hippocampal volume, spectroscopy, cognition, and mood in patients receiving corticosteroid therapy. Biol Psychiatry. 2004;55:538-545.

23. Schatzberg AF, Rothschild AJ, Langlais PJ, et al. A corticosteroid/dopamine hypothesis for psychotic depression and related states. J Psychiat Res. 1985;19(1):57-64.

24. Sabet-Sharghi F, Hutzler JC. Prophylaxis of steroid-induced psychiatric syndromes. Psychosomatics. 1990;31(1):113-114.

25. Siegal FP. Lithium for steroid-induced psychosis. N Engl J Med. 1978;299(3):155-156.

26. Goggans FC, Weisberg LJ, Koran LM. Lithium prophylaxis of prednisone psychosis: a case report. J Clin Psychiatry. 1983;44(3):111-112.

27. Merrill W. Case 35-1998: use of lithium to prevent corticosteroid-induced mania. N Engl J Med. 1999;340(14):1123.-

28. Himelhoch S, Haller E. Extreme mood lability associated with systemic lupus erythematosus and stroke successfully treated with valproic acid. J Clin Psychopharmacol. 1996;16(6):469-470.

29. Kahn D, Stevenson E, Douglas CJ. Effect of sodium valproate in three patients with organic brain syndromes. Am J Psychiatry. 1998;145(8):1010-1011.

30. Abbas A, Styra R. Valproate prophylaxis against steroid induced psychosis. Can J Psychiatry. 1994;39(3):188-189.

31. Preda A, Fazeli A, McKay BG, et al. Lamotrigine as prophylaxis against steroid-induced mania. J Clin Psychiatry. 1999;60(10):708-709.

32. Ginsberg DL, Sussman N. Gabapentin as prophylaxis against corticosteroid-induced mania. Can J Psychiatry. 2001;44:455-456.

33. Wada K, Yamada N, Yamauchi Y, et al. Carbamazepine treatment of corticosteroid-induced mood disorder. J Affect Disord. 2001;65:315-317.

34. Saklad S. Management of corticosteroid-induced psychosis with lithium. Clin Pharm. 1987;6(3):186.-

References

 

1. Lewis DA, Smith RE. Steroid-induced psychiatric syndromes: a report of 14 cases and a review of the literature. J Affect Disord. 1983;5:319-332.

2. Bolanos SH, Khan DA, Hanczyc M, et al. Assessment of mood states in patients receiving long-term corticosteroid therapy and in controls with patient-rated and clinician-rated scales. Ann Allergy Asthma Immunol. 2004;92:500-505.

3. Warrington TP, Bostwick JM. Psychiatric adverse effect of corticosteroids. Mayo Clin Proc. 2006;81(10):1361-1367.

4. Sirois F. Steroid psychosis: a review. Gen Hosp Psychiatry. 2003;25:27-33.

5. Newcomer JW, Craft S, Hershey T, et al. Glucocorticoid-induced impairments in declarative memory performance in adult humans. J Neurosci. 1991;14:2047-2053.

6. Hall RC, Popkin MK, Stickney SK, et al. Presentation of the steroid induced psychosis. J Nerv Ment Dis. 1979;167:229-236.

7. The Boston Collaborative Drug Surveillance Program. Acute adverse reactions to prednisone in relation to dosage. Clin Pharmacol Ther. 1972;13:694-698.

8. Brown ES, Chamberlain W, Dhanani N, et al. An open-label trial of olanzapine for corticosteroid-induced mood symptoms. J Affect Disord. 2004;83:277-281.

9. Falk WE, Mahnke MW, Poskanzer DC. Lithium prophylaxis of corticotropin-induced psychosis. JAMA. 1979;241:1011-1012.

10. Brown ES, Stuard G, Liggin JD, et al. Effect of phenytoin on mood and declarative memory during prescription corticosteroid therapy. Bio Psychiatry. 2005;57:543-548.

11. Brown ES, Frol AB, Khan DA, et al. Impact of levetiracetam on mood and cognition during prednisone therapy. Eur Psychiatry. 2007;22:448-452.

12. Brown ES, Frol A, Bobadilla L, et al. Effect of lamotrigine on mood and cognition in patients receiving chronic exogenous corticosteroids. Psychosomatics. 2003;44(3):204-208.

13. Goldman LS, Goveas J. Olanzapine treatment of corticosteroid-induced mood disorders. Psychosomatics. 2002;43(6):495-497.

14. Brown ES, Khan DA, Suppes T. Treatment of corticosteroid-induced mood changes with olanzapine. Am J Psychiatry. 1999;156(6):968.-

15. Budur K, Pozuelo L. Olanzapine for corticosteroid-induced mood disorders. Psychosomatics. 2003;44(4):353.-

16. Herguner S, Bilge I, Yavuz Yilmaz A, et al. Steroid-induced psychosis in an adolescent: treatment and prophylaxis with risperidone. Turk J Pediatr. 2006;48:244-247.

17. DeSilva CC, Nurse MC, Vokey K. Steroid-induced psychosis treated with risperidone. Can J Psychiatry. 2002;47:388-389.

18. Kato O, Misawa H. Steroid-induced psychosis treated with valproic acid and risperidone in a patient with systemic lupus erythematosus. Prim Care Companion J Clin Psychiatry. 2005;7(6):312.-

19. Kramer TM, Cottingham EM. Risperidone in the treatment of steroid-induced psychosis. J Child Adolec Psychopharmacol. 1999;9:315-316.

20. Siddiqui Z, Ramaswamy S, Petty F. Quetiapine therapy for coricosteroid-induced mania. Can J Psychiatry. 2005;50(1):77-78.

21. Naber D, Sand P, Heigl B. Psychopathological and neuropsychological effects of 8-days’ corticosteroid treatment. A prospective study. Psychoneuroendocrinology. 1996;21(1):25-31.

22. Brown ES, Woolston DJ, Frol A, et al. Hippocampal volume, spectroscopy, cognition, and mood in patients receiving corticosteroid therapy. Biol Psychiatry. 2004;55:538-545.

23. Schatzberg AF, Rothschild AJ, Langlais PJ, et al. A corticosteroid/dopamine hypothesis for psychotic depression and related states. J Psychiat Res. 1985;19(1):57-64.

24. Sabet-Sharghi F, Hutzler JC. Prophylaxis of steroid-induced psychiatric syndromes. Psychosomatics. 1990;31(1):113-114.

25. Siegal FP. Lithium for steroid-induced psychosis. N Engl J Med. 1978;299(3):155-156.

26. Goggans FC, Weisberg LJ, Koran LM. Lithium prophylaxis of prednisone psychosis: a case report. J Clin Psychiatry. 1983;44(3):111-112.

27. Merrill W. Case 35-1998: use of lithium to prevent corticosteroid-induced mania. N Engl J Med. 1999;340(14):1123.-

28. Himelhoch S, Haller E. Extreme mood lability associated with systemic lupus erythematosus and stroke successfully treated with valproic acid. J Clin Psychopharmacol. 1996;16(6):469-470.

29. Kahn D, Stevenson E, Douglas CJ. Effect of sodium valproate in three patients with organic brain syndromes. Am J Psychiatry. 1998;145(8):1010-1011.

30. Abbas A, Styra R. Valproate prophylaxis against steroid induced psychosis. Can J Psychiatry. 1994;39(3):188-189.

31. Preda A, Fazeli A, McKay BG, et al. Lamotrigine as prophylaxis against steroid-induced mania. J Clin Psychiatry. 1999;60(10):708-709.

32. Ginsberg DL, Sussman N. Gabapentin as prophylaxis against corticosteroid-induced mania. Can J Psychiatry. 2001;44:455-456.

33. Wada K, Yamada N, Yamauchi Y, et al. Carbamazepine treatment of corticosteroid-induced mood disorder. J Affect Disord. 2001;65:315-317.

34. Saklad S. Management of corticosteroid-induced psychosis with lithium. Clin Pharm. 1987;6(3):186.-

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