Psychosomatics 2015:56:542–546
& 2015 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Original Research Reports Thiothixene in the Management of Delirium: A Case Series Jonathan G. Leung, Pharm.D., Folabo Y. Dare, D.O., Lee M. Flowers, M.D., Lauren L. Murphy, D.O., Eliza M. Sukiennik, M.D., Kemuel L. Philbrick, M.D., Keith G. Rasmussen, M.D.
Background: Pharmacologic strategies are often required to help manage agitated patients with delirium. First-and second-generation antipsychotic medications (such as haloperidol, quetiapine, and olanzapine) are commonly used. Objective: On the psychiatric consultation service in our hospital, thiothixene has been used based on its favorable potency, sedative, and cost profiles. Little has been written about the utility of this drug for management of delirium. Methods: We reviewed our experience with thiothixene in this setting using pharmacy records to identify patients who received at least 1 dose between July 2011 and March 2014. We
scrutinized the relevant medical records (n = 111) and recorded the following data: age, sex, medical diagnoses, signs and symptoms of delirium, dosing of thiothixene, and response to thiothixene in terms of both apparent benefit as well as side effects. Results: Resolution or improvement was documented in 78% of patients and good tolerability in 82% of patients. Conclusions: Although further data from a randomized, controlled trial would be ideal, our experience suggests that thiothixene could be a safe and effective pharmacologic treatment for agitation and psychosis due to delirium. (Psychosomatics 2015; 56:542–546)
INTRODUCTION
administration. Our hospital psychiatric consultation service at the Mayo Clinic has used thiothixene, a midto high-potency first-generation antipsychotic, for management of delirium. Compared with haloperidol, thiothixene has mild sedative effects, which we postulate to be clinically beneficial for reducing agitation and improving sleep.7 As there are limited data available regarding thiothixene use for the management of delirium, we describe our experience using it.
Delirium with agitation is commonly encountered on hospital psychiatry consultation services. Pharmacologic strategies are often required to help manage such patients.1 Although the exact pathophysiology of delirium has yet to be fully elucidated, many hypotheses have been proposed, including deficiency in the cholinergic system as well as hyperactivity in the dopaminergic system.2,3 Dopamine antagonists are recommended in various guidelines.4,5 Although more well-conducted trials have been performed in the past decade, there are still limited data that identify a specific agent as the treatment of choice in the management of delirium.6 Thus, antipsychotic selection is based on clinical factors such as target symptoms, side effect profile, and available routes of
542
www.psychosomaticsjournal.org
Received January 22, 2015; revised February 10, 2015; accepted February 11, 2015. From Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN. Send correspondence and reprint requests to Keith G. Rasmussen, M.D., Department of Psychiatry and Psychology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905; e-mail: [email protected] & 2015 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Psychosomatics 56:5, September/October 2015
Leung et al. We believe that thiothixene is an effective and welltolerated treatment for agitation in patients with delirium. METHOD This project was approved by the Mayo Clinic Institutional Review Board. Pharmacy records were obtained to identify patients who were dispensed at least 1 dose of thiothixene between July 2011 and March 2014. Only those patients given a diagnosis of delirium and for whom thiothixene was specifically administered for delirium were included. The diagnosis of delirium was recorded by either the psychiatric consultant who saw the patient or the primary service team personnel. The medical records were reviewed by personnel familiar with the diagnosis of delirium, and patients who received thiothixene for reasons other than delirium were excluded (e.g., schizophrenia, schizoaffective disorder, bipolar disorder, or dementia with agitation). We scrutinized the relevant medical records to record age, sex, medical diagnoses, and the signs and symptoms of delirium. Dose and duration of thiothixene use, documented response, potential side effects, and data regarding other antipsychotics that were administered while the patient was receiving thiothixene were also collected. Given the nature of this study, descriptive statistics were used to describe outcome variables as means with standard deviations or proportions where appropriate. RESULTS Tables 1–4 provide relevant characteristics of the patients and outcomes. In total, 111 patients were identified as having received thiothixene for the management of delirium during the study period. The mean age (⫾standard deviation [SD]) of these patients was 67.5 ⫾ 13.3 years, and 63% were men. Patients had been admitted to a wide variety of hospital services, but critically ill patients represented a small number (8.1%) of the sample (Table 1). Most patients (93%) had symptoms characteristic of hyperactive or mixed-type delirium, with only 7% of patients specifically noted to have a hypoactive delirium. The average daily dose (⫾SD) of thiothixene was 6.9 ⫾ 4.6 mg. The mean maximum dose (⫾SD) of thiothixene received by any patient was 9.4 ⫾ 6.8 mg. Based on review of medical record notes, 78% Psychosomatics 56:5, September/October 2015
TABLE 1.
Demographic Data
Patient characteristic
Result
Age, y ⫾ SD Sex, male (%) Floor type (n, %)
67.5 ⫾ 13.3 63% General—103 (93%) ICU—9 (8.1%) Cardiology—5 (4.5%) Critical care unit—9 (8.1%) General medicine—41 (37%) Hematology/oncology—6 (5.4%) Neurology—6 (5.4%) Respiratory—4 (3.6%) Surgical—31 (27.9%) Transplant—9 (8.1%)
Service type (n, %)
ICU ¼ intensive care unit; SD ¼ standard deviation.
demonstrated improvement of symptoms associated with delirium, most commonly behavioral agitation, while thiothixene was used (Table 2). Only 13% demonstrated no benefit as stated in the medical record. Monotherapy with thiothixene was found in 76.5% of patients. At least 1 dose of another antipsychotic was given during a course of thiothixene therapy in 23.5% of patients (Table 3). The majority of concomitant use involved haloperidol (15 patients), chiefly owing to its ability to be given parenterally. Thiothixene was continued after hospitalization in 48% of the patients who either received specific instructions for a taper or were advised to have a provider assess the need for the agent at follow-up. For those patients in whom thiothixene was not continued on discharge, the average duration of therapy was 5.4 ⫾ 4.4 days. Table 4 lists possible adverse effects of thiothixene, demonstrating that thiothixene appears to have been well tolerated in this medically complicated sample. DISCUSSION There are no Federal Food Drug Administration– approved pharmacologic agents for the management of delirium, but antipsychotics are most commonly used.8 TABLE 2.
Documented Effectiveness of Thiothixene
Documented effect described
Result, n (%)
Resolution/improvement Minimal improvement No benefit Not documented/unknown
87 8 14 2
(78) (7) (13) (2)
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543
Thiothixene in the Management of Delirium
TABLE 3.
Description of Concomitant Antipsychotic Administration During Thiothixene Utilization
Therapy
Result, n (%)
Thiothixene monotherapy Haloperidol Olanzapine Quetiapine 41 Antipsychotic
85 15 2 7 2
(76.5) (13.5) (2) (6) (2)
Among this class of medications, the first-generation antipsychotic, haloperidol, has been the most widely studied and used, as it provides several clinical advantages, including availability in a parenteral formulation and low cost. Haloperidol also lacks potent antagonism of alphaadrenergic or muscarinic receptors, reducing the risk of hypotension or anticholinergic adverse events.9 However, depending on the dosage form, haloperidol is associated with a greater risk of extrapyramidal symptoms and QT interval (QTc) prolongation compared with secondgeneration antipsychotics, though extrapyramidal symptoms and QTc prolongation represent class effects for both first-generation antipsychotic and second-generation antipsychotics.1,10 The second-generation antipsychotics are increasingly being used in clinical practice, with many specific agents having limited data to support their use.10,11 At our institution, quetiapine is the most frequently selected second-generation antipsychotics in the treatment of delirium, likely owing to its sedative effects and perceived benefits on sleep.12 Clinical issues surrounding use of quetiapine include lack of availability in parenteral form, relatively low potency, and alpha-1 antagonism, which may pose greater risks in certain medically ill patients.12 Additionally, quetiapine has a relatively short half-life, and with doses that are typically
TABLE 4.
Adverse Events Associated with Thiothixene
Adverse event type
Result, n (%)
Agitation Akathisia Confusion Dystonia Excessive somnolence Nausea None noted QTc prolongation Respiratory depression Seizure
2 2 1 1 5 1 91 7 1 1
QTc ¼ QT interval.
544
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(1.8) (1.8) (0.9) (0.9) (4.5) (0.9) (81.9) (6.4) (0.9) (0.9)
used in delirium, serum levels of the drug are undetectable after 8-12 hours.13 Thiothixene has a 34-hour half-life.14 Thiothixene is a high potency antagonist at D2, but like quetiapine, also causes antagonism at H1 receptors to a greater extent than haloperidol.15 The moderate potency of thiothixene enables a robust initial intervention with diminished need for successive upward titrations in dose in pursuit of an adequate response. The sedative contribution of thiothixene addresses the frequent comorbidity of sleep-wake cycle disruption in patients with delirium. In some patient populations, the mild antiemetic effect is an added bonus, owing to its modest expense. Thiothixene has been the subject of limited investigation in the treatment of delirium; however, many of the studies are decades old and are limited in their sample sizes and diagnostic heterogeneity.3 A doubleblind placebo controlled study of thiothixene dosed at 2-5 mg 3 times daily in 42 geriatric patients with chronic organic brain syndrome by Rada and Kellner in 1976 showed no difference between placebo and thiothixene.16 A single-blind study of haloperidol compared with thiothixene (n ¼ 14) by Peterson and Bongar showed that both medications were effective for the management of delirium.17 There was a trend towards lower Brief Psychiatric Rating Scale scores in those patients treated with thiothixene.18 A randomized trial evaluating the use of thiothixene for agitated patients with dementia suggested a good risk-to-benefit ratio for this agent.19 Another prospective study compared the effects of haloperidol (n ¼ 15) and thiothixene (n ¼ 15) in a double-blind fashion for the management of acute agitation in patients with a psychotic disorder. Both medications were administered parenterally, as parenteral thiothixene was available at the time of the study. Stotsky reported no difference in outcome between the 2 groups as all achieved reduction in agitation. The only noted side effect in the thiothixene group was drowsiness (n ¼ 2).20 Parenteral thiothixene is no longer available, which may limit its utility in severely agitated patients. Historically, in patients with schizophrenia, thiothixene has been described as a “dual-action” antipsychotic, producing activating effects (i.e., excitement and insomnia) at lower doses with dissipation of this effect at higher doses.7 However, like Rada and Kellner we did not observe this phenomenon in patients with delirium: 59% of patients were specifically described as having improved sleep and 4.5% experienced excessive somnolence.16 Yet, this may be Psychosomatics 56:5, September/October 2015
Leung et al. a relevant consideration when initiating thiothixene, as akathisia or increased agitation was described in 2% of our patients. Another adverse event that has not been systematically evaluated in large, prospective studies is the effect of thiothixene on the corrected QTc. Thiothixene has not been reported to increase the QTc significantly, but this is an acknowledged risk among all antipsychotics. A small double-blind study evaluated electrocardiographic changes with thioridazine, thiothixene, and controls (i.e., those receiving no medications). None of the 13 patients administered thiothixene titrated to 40 mg over a 2-week period demonstrated changes in the QTc.21 We did not observe any occurrence of torsades de pointes in our sample, but 7 patients were observed to have prolongation of the QTc during thiothixene therapy. In these 7 patients, the mean (⫾SD) baseline QTc before thiothixene therapy was 463 ⫾ 40.4 ms, whereas the mean (⫾SD) maximum recorded QTc during thiothixene use was 525 ⫾ 25.3 ms. We cannot say with certainty that this was a direct effect of thiothixene, as all patients had at least one other risk factor such as cardiac disease, electrolyte abnormalities, or treatment with concurrent medications known to prolong QTc. Of note, routine monitoring of electrocardiogram was not performed on the entire sample of 111 patients, so we cannot make definitive conclusions about the propensity of thiothixene to affect the QTc interval. Finally, 1 patient experienced a seizure after 2 doses of thiothixene. Although the etiology of this seizure appeared to be multifactorial, given that all antipsychotics may lower the seizure threshold,
thiothixene was discontinued in that patient. There are several limitations in our methodology that should be addressed. All assessments were nonblind, and there was no control group. Additionally, all data abstracted from medical records were collected nonsystematically as part of routine care, so that some aspects of therapeutic and side effect outcomes may not have been detected. Also, there was no standardized, systematic method for diagnosing delirium. Finally, use of concomitant medications with thiothixene may have confounded the results. Nonetheless, our sample size is relatively large, with the data suggesting that thiothixene could potentially be a welltolerated and effective treatment for agitation and psychosis due to delirium.
CONCLUSION Thiothixene is a potent first-generation antipsychotic that possess mild sedative effects but is not associated with significant hypotension or anticholinergic side effects. This is the first retrospective review that suggests thiothixene may provide a benefit in patients with delirium. However, confirmation is needed from randomized, double-blind trials. Additionally, the field of pharmacologic interventions for delirium would benefit from a large, randomized, doubleblind trial comparing several of these agents. Disclosure: The authors disclosed no proprietary or commercial interest in any product mentioned or concept discussed in this article.
References 1. Maldonado JR: Delirium in the acute care setting: characteristics, diagnosis and treatment. Crit Care Clin 2008; 24 (4):657–722 [vii] 2. Fong TG, Tulebaev SR, Inouye SK: Delirium in elderly adults: diagnosis, prevention and treatment. Nat Rev Neurol 2009; 5(4):210–220 3. Markowitz JD, Narasimhan M: Delirium and antipsychotics: a systematic review of epidemiology and somatic treatment options. Psychiatry (Edgmont) 2008; 5(10):29–36 4. American Psychiatric Association: Practice guideline for the treatment of patients with delirium. Am J Psychiatry 1999; 156(5 Suppl):1–20 5. Barr J, Fraser GL, Puntillo K, et al: Clinical practice guidelines for the management of pain, agitation, and
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delirium in adult patients in the intensive care unit. Crit Care Med 2013; 41(1):263–306 6. Page VJ, Ely EW, Gates S, et al: Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, doubleblind, placebo-controlled trial. Lancet Respir Med 2013; 1(7):515–523, http://dx.doi.org/10.1016/S2213-2600(13) 70166-8 [Epub 2014/01/28] 7. Gardos G, Cole JO: The dual action of thiothixene. Arch Gen Psychiatry 1973; 29(2):222–225 8. 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(7): 848–853
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Thiothixene in the Management of Delirium 9. Wilson MP, Pepper D, Currier GW, et al: The psychopharmacology of agitation: consensus statement of the American Association for Emergency Psychiatry Project Beta psychopharmacology workgroup. West J Emerg Med 2012; 13(1):26–34 10. Wang HR, Woo YS, Bahk WM: Atypical antipsychotics in the treatment of delirium. Psychiatry Clin Neurosci 2013; 67 (5):323–331 11. Boettger S, Breitbart W: Atypical antipsychotics in management of delirium: a review of the empirical literature. Palliat Support Care 2005; 3:227–238 12. Farah A: Atypicality of atypical antipsychotics. Prim Care Companion J Clin Psychiatry 2005; 7(6):268–274 13. DeVane CL, Nemeroff CB: Clinical pharmacokinetics of quetiapine: an atypical antipsychotic. Clin Pharmacokinet 2001; 40(7):509–522 14. Hobbs DC, Welch WM, Short MJ, et al: Pharmacokinetics of thiothixene in man. Clin Pharmacol Ther 1974; 16(3): 473–478 15. Kroeze WK, Hufeisen SJ, Popadak BA, et al: H1-histamine receptor affinity predicts short-term weight gain for typical
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16.
17.
18. 19.
20.
21.
and atypical antipsychotic drugs. Neuropsychopharmacology 2003; 28(3):519–526 Rada RT, Kellner R: Thiothixene in the treatment of geriatric patients with chronic organic brain syndrome. J Am Geriatr Soc 1976; 24(3):105–107 Peterson LG, Bongar B: Navane versus haldol. Treatment of acute organic mental syndromes in the general hospital. Gen Hosp Psychiatry 1989; 11(6):412–417 Overall JE, Gorham DR: The brief psychiatric rating scale. Psychol Rep 1962; 10:799–812 Finkel SI, Lyons JS, Anderson RL, et al: A randomized, placebo-controlled trial of thiothixene in agitated, demented nursing home patients. Int J Geriat Psychiatry 1995; 10:129–136 Stotsky BA: Relative efficacy of parenteral haloperidol and thiothixene for the emergency treatment of acutely excited and agitated patients. Dis Nerv Syst 1977; 38(12):967–973 Dillenkoffer RL, George RB, Bishop MP, et al: Electrocardiographic evaluation of thiothixene: a double-blind comparison with thioridazine. Adv Biochem Psychopharmacol 1974; 9(0):487–495
Psychosomatics 56:5, September/October 2015
& 2015 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Original Research Reports Thiothixene in the Management of Delirium: A Case Series Jonathan G. Leung, Pharm.D., Folabo Y. Dare, D.O., Lee M. Flowers, M.D., Lauren L. Murphy, D.O., Eliza M. Sukiennik, M.D., Kemuel L. Philbrick, M.D., Keith G. Rasmussen, M.D.
Background: Pharmacologic strategies are often required to help manage agitated patients with delirium. First-and second-generation antipsychotic medications (such as haloperidol, quetiapine, and olanzapine) are commonly used. Objective: On the psychiatric consultation service in our hospital, thiothixene has been used based on its favorable potency, sedative, and cost profiles. Little has been written about the utility of this drug for management of delirium. Methods: We reviewed our experience with thiothixene in this setting using pharmacy records to identify patients who received at least 1 dose between July 2011 and March 2014. We
scrutinized the relevant medical records (n = 111) and recorded the following data: age, sex, medical diagnoses, signs and symptoms of delirium, dosing of thiothixene, and response to thiothixene in terms of both apparent benefit as well as side effects. Results: Resolution or improvement was documented in 78% of patients and good tolerability in 82% of patients. Conclusions: Although further data from a randomized, controlled trial would be ideal, our experience suggests that thiothixene could be a safe and effective pharmacologic treatment for agitation and psychosis due to delirium. (Psychosomatics 2015; 56:542–546)
INTRODUCTION
administration. Our hospital psychiatric consultation service at the Mayo Clinic has used thiothixene, a midto high-potency first-generation antipsychotic, for management of delirium. Compared with haloperidol, thiothixene has mild sedative effects, which we postulate to be clinically beneficial for reducing agitation and improving sleep.7 As there are limited data available regarding thiothixene use for the management of delirium, we describe our experience using it.
Delirium with agitation is commonly encountered on hospital psychiatry consultation services. Pharmacologic strategies are often required to help manage such patients.1 Although the exact pathophysiology of delirium has yet to be fully elucidated, many hypotheses have been proposed, including deficiency in the cholinergic system as well as hyperactivity in the dopaminergic system.2,3 Dopamine antagonists are recommended in various guidelines.4,5 Although more well-conducted trials have been performed in the past decade, there are still limited data that identify a specific agent as the treatment of choice in the management of delirium.6 Thus, antipsychotic selection is based on clinical factors such as target symptoms, side effect profile, and available routes of
542
www.psychosomaticsjournal.org
Received January 22, 2015; revised February 10, 2015; accepted February 11, 2015. From Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN. Send correspondence and reprint requests to Keith G. Rasmussen, M.D., Department of Psychiatry and Psychology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905; e-mail: [email protected] & 2015 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Psychosomatics 56:5, September/October 2015
Leung et al. We believe that thiothixene is an effective and welltolerated treatment for agitation in patients with delirium. METHOD This project was approved by the Mayo Clinic Institutional Review Board. Pharmacy records were obtained to identify patients who were dispensed at least 1 dose of thiothixene between July 2011 and March 2014. Only those patients given a diagnosis of delirium and for whom thiothixene was specifically administered for delirium were included. The diagnosis of delirium was recorded by either the psychiatric consultant who saw the patient or the primary service team personnel. The medical records were reviewed by personnel familiar with the diagnosis of delirium, and patients who received thiothixene for reasons other than delirium were excluded (e.g., schizophrenia, schizoaffective disorder, bipolar disorder, or dementia with agitation). We scrutinized the relevant medical records to record age, sex, medical diagnoses, and the signs and symptoms of delirium. Dose and duration of thiothixene use, documented response, potential side effects, and data regarding other antipsychotics that were administered while the patient was receiving thiothixene were also collected. Given the nature of this study, descriptive statistics were used to describe outcome variables as means with standard deviations or proportions where appropriate. RESULTS Tables 1–4 provide relevant characteristics of the patients and outcomes. In total, 111 patients were identified as having received thiothixene for the management of delirium during the study period. The mean age (⫾standard deviation [SD]) of these patients was 67.5 ⫾ 13.3 years, and 63% were men. Patients had been admitted to a wide variety of hospital services, but critically ill patients represented a small number (8.1%) of the sample (Table 1). Most patients (93%) had symptoms characteristic of hyperactive or mixed-type delirium, with only 7% of patients specifically noted to have a hypoactive delirium. The average daily dose (⫾SD) of thiothixene was 6.9 ⫾ 4.6 mg. The mean maximum dose (⫾SD) of thiothixene received by any patient was 9.4 ⫾ 6.8 mg. Based on review of medical record notes, 78% Psychosomatics 56:5, September/October 2015
TABLE 1.
Demographic Data
Patient characteristic
Result
Age, y ⫾ SD Sex, male (%) Floor type (n, %)
67.5 ⫾ 13.3 63% General—103 (93%) ICU—9 (8.1%) Cardiology—5 (4.5%) Critical care unit—9 (8.1%) General medicine—41 (37%) Hematology/oncology—6 (5.4%) Neurology—6 (5.4%) Respiratory—4 (3.6%) Surgical—31 (27.9%) Transplant—9 (8.1%)
Service type (n, %)
ICU ¼ intensive care unit; SD ¼ standard deviation.
demonstrated improvement of symptoms associated with delirium, most commonly behavioral agitation, while thiothixene was used (Table 2). Only 13% demonstrated no benefit as stated in the medical record. Monotherapy with thiothixene was found in 76.5% of patients. At least 1 dose of another antipsychotic was given during a course of thiothixene therapy in 23.5% of patients (Table 3). The majority of concomitant use involved haloperidol (15 patients), chiefly owing to its ability to be given parenterally. Thiothixene was continued after hospitalization in 48% of the patients who either received specific instructions for a taper or were advised to have a provider assess the need for the agent at follow-up. For those patients in whom thiothixene was not continued on discharge, the average duration of therapy was 5.4 ⫾ 4.4 days. Table 4 lists possible adverse effects of thiothixene, demonstrating that thiothixene appears to have been well tolerated in this medically complicated sample. DISCUSSION There are no Federal Food Drug Administration– approved pharmacologic agents for the management of delirium, but antipsychotics are most commonly used.8 TABLE 2.
Documented Effectiveness of Thiothixene
Documented effect described
Result, n (%)
Resolution/improvement Minimal improvement No benefit Not documented/unknown
87 8 14 2
(78) (7) (13) (2)
www.psychosomaticsjournal.org
543
Thiothixene in the Management of Delirium
TABLE 3.
Description of Concomitant Antipsychotic Administration During Thiothixene Utilization
Therapy
Result, n (%)
Thiothixene monotherapy Haloperidol Olanzapine Quetiapine 41 Antipsychotic
85 15 2 7 2
(76.5) (13.5) (2) (6) (2)
Among this class of medications, the first-generation antipsychotic, haloperidol, has been the most widely studied and used, as it provides several clinical advantages, including availability in a parenteral formulation and low cost. Haloperidol also lacks potent antagonism of alphaadrenergic or muscarinic receptors, reducing the risk of hypotension or anticholinergic adverse events.9 However, depending on the dosage form, haloperidol is associated with a greater risk of extrapyramidal symptoms and QT interval (QTc) prolongation compared with secondgeneration antipsychotics, though extrapyramidal symptoms and QTc prolongation represent class effects for both first-generation antipsychotic and second-generation antipsychotics.1,10 The second-generation antipsychotics are increasingly being used in clinical practice, with many specific agents having limited data to support their use.10,11 At our institution, quetiapine is the most frequently selected second-generation antipsychotics in the treatment of delirium, likely owing to its sedative effects and perceived benefits on sleep.12 Clinical issues surrounding use of quetiapine include lack of availability in parenteral form, relatively low potency, and alpha-1 antagonism, which may pose greater risks in certain medically ill patients.12 Additionally, quetiapine has a relatively short half-life, and with doses that are typically
TABLE 4.
Adverse Events Associated with Thiothixene
Adverse event type
Result, n (%)
Agitation Akathisia Confusion Dystonia Excessive somnolence Nausea None noted QTc prolongation Respiratory depression Seizure
2 2 1 1 5 1 91 7 1 1
QTc ¼ QT interval.
544
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(1.8) (1.8) (0.9) (0.9) (4.5) (0.9) (81.9) (6.4) (0.9) (0.9)
used in delirium, serum levels of the drug are undetectable after 8-12 hours.13 Thiothixene has a 34-hour half-life.14 Thiothixene is a high potency antagonist at D2, but like quetiapine, also causes antagonism at H1 receptors to a greater extent than haloperidol.15 The moderate potency of thiothixene enables a robust initial intervention with diminished need for successive upward titrations in dose in pursuit of an adequate response. The sedative contribution of thiothixene addresses the frequent comorbidity of sleep-wake cycle disruption in patients with delirium. In some patient populations, the mild antiemetic effect is an added bonus, owing to its modest expense. Thiothixene has been the subject of limited investigation in the treatment of delirium; however, many of the studies are decades old and are limited in their sample sizes and diagnostic heterogeneity.3 A doubleblind placebo controlled study of thiothixene dosed at 2-5 mg 3 times daily in 42 geriatric patients with chronic organic brain syndrome by Rada and Kellner in 1976 showed no difference between placebo and thiothixene.16 A single-blind study of haloperidol compared with thiothixene (n ¼ 14) by Peterson and Bongar showed that both medications were effective for the management of delirium.17 There was a trend towards lower Brief Psychiatric Rating Scale scores in those patients treated with thiothixene.18 A randomized trial evaluating the use of thiothixene for agitated patients with dementia suggested a good risk-to-benefit ratio for this agent.19 Another prospective study compared the effects of haloperidol (n ¼ 15) and thiothixene (n ¼ 15) in a double-blind fashion for the management of acute agitation in patients with a psychotic disorder. Both medications were administered parenterally, as parenteral thiothixene was available at the time of the study. Stotsky reported no difference in outcome between the 2 groups as all achieved reduction in agitation. The only noted side effect in the thiothixene group was drowsiness (n ¼ 2).20 Parenteral thiothixene is no longer available, which may limit its utility in severely agitated patients. Historically, in patients with schizophrenia, thiothixene has been described as a “dual-action” antipsychotic, producing activating effects (i.e., excitement and insomnia) at lower doses with dissipation of this effect at higher doses.7 However, like Rada and Kellner we did not observe this phenomenon in patients with delirium: 59% of patients were specifically described as having improved sleep and 4.5% experienced excessive somnolence.16 Yet, this may be Psychosomatics 56:5, September/October 2015
Leung et al. a relevant consideration when initiating thiothixene, as akathisia or increased agitation was described in 2% of our patients. Another adverse event that has not been systematically evaluated in large, prospective studies is the effect of thiothixene on the corrected QTc. Thiothixene has not been reported to increase the QTc significantly, but this is an acknowledged risk among all antipsychotics. A small double-blind study evaluated electrocardiographic changes with thioridazine, thiothixene, and controls (i.e., those receiving no medications). None of the 13 patients administered thiothixene titrated to 40 mg over a 2-week period demonstrated changes in the QTc.21 We did not observe any occurrence of torsades de pointes in our sample, but 7 patients were observed to have prolongation of the QTc during thiothixene therapy. In these 7 patients, the mean (⫾SD) baseline QTc before thiothixene therapy was 463 ⫾ 40.4 ms, whereas the mean (⫾SD) maximum recorded QTc during thiothixene use was 525 ⫾ 25.3 ms. We cannot say with certainty that this was a direct effect of thiothixene, as all patients had at least one other risk factor such as cardiac disease, electrolyte abnormalities, or treatment with concurrent medications known to prolong QTc. Of note, routine monitoring of electrocardiogram was not performed on the entire sample of 111 patients, so we cannot make definitive conclusions about the propensity of thiothixene to affect the QTc interval. Finally, 1 patient experienced a seizure after 2 doses of thiothixene. Although the etiology of this seizure appeared to be multifactorial, given that all antipsychotics may lower the seizure threshold,
thiothixene was discontinued in that patient. There are several limitations in our methodology that should be addressed. All assessments were nonblind, and there was no control group. Additionally, all data abstracted from medical records were collected nonsystematically as part of routine care, so that some aspects of therapeutic and side effect outcomes may not have been detected. Also, there was no standardized, systematic method for diagnosing delirium. Finally, use of concomitant medications with thiothixene may have confounded the results. Nonetheless, our sample size is relatively large, with the data suggesting that thiothixene could potentially be a welltolerated and effective treatment for agitation and psychosis due to delirium.
CONCLUSION Thiothixene is a potent first-generation antipsychotic that possess mild sedative effects but is not associated with significant hypotension or anticholinergic side effects. This is the first retrospective review that suggests thiothixene may provide a benefit in patients with delirium. However, confirmation is needed from randomized, double-blind trials. Additionally, the field of pharmacologic interventions for delirium would benefit from a large, randomized, doubleblind trial comparing several of these agents. Disclosure: The authors disclosed no proprietary or commercial interest in any product mentioned or concept discussed in this article.
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