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Second-generation antipsychotics (SGAs) represent 5% of all U.S. drug expenditures.1 Their use for indications not approved by the FDA (“off-label” use) increased to a total of $6 billion in 2008, $5.4 billion of which was for uses with limited or uncertain evidence.1
Off-label use of antipsychotics usually is based on novel applications of known receptor binding affinities (Table 1).2-5 For example, antipsychotics with strong antihistamine effects may promote sedation and could be used to treat insomnia. Clinicians also might use antipsychotics to treat a specific symptom of an illness when other treatment options are limited6 or when patients do not respond to standard treatments.
Table 1
Possible rationales for antipsychotic use for nonpsychotic conditions
| Condition | Possible rationale |
|---|---|
| Insomnia2 | Effects on H1 α-1 adrenergic and muscarinic cholinergic receptors. 5-HT2 antagonism activity also has been implicated |
| Tics of Tourette’s disorder3 | By blocking dopamine receptors antipsychotics decrease the primarily dopaminergic input from the substantia nigra and ventral tegmentum to the basal ganglia |
| Delirium4 | Patients have reversible impairment of cerebral oxidative metabolism and multiple neurotransmitter abnormalities (dopamine acetylcholine CNS γ-aminobutyric acid and serotonin). Other hypotheses include inflammatory reactions damage to certain structural pathways and disruption of cortisol and β-endorphin circadian rhythms |
| Stuttering5 | Stutterers have a marked increase in dopaminergic afferent activity in the tail of the left caudate nucleus compared with healthy controls |
| H1: histamine | |
To safely use any medication off-label, clinicians should become familiar with literature on the proposed use. Clinicians should consider off-label use only after carefully weighing the potential therapeutic benefits against the risks. Patients should be aware that the prescribed use is not FDA-approved and informed consent should include a discussion of alternative treatments. The high cost of SGAs may be a limiting factor and should be discussed with patients.
This article reviews the evidence for using antipsychotics to treat insomnia, tics, delirium, and stuttering (Table 2). Click here for a review of the evidence supporting antipsychotics for treating migraine and cluster headaches and nausea
Table 2
Antipsychotics for nonpsychotic disorders: Strength of the evidence
| Condition | Strength of evidencea |
|---|---|
| Insomnia | Weak to intermediate: Haloperidol olanzapine quetiapine risperidone ziprasidone |
| Tics of Tourette’s disorder | Strong: Haloperidol pimozide |
| Intermediate: Chlorpromazine fluphenazine penfluridol perphenazine thioridazine trifluoperazine | |
| Weak: Risperidone | |
| Very weak: Aripiprazole olanzapine quetiapine ziprasidone | |
| Not effective: Clozapine | |
| Delirium | Intermediate: Haloperidol |
| Weak: Olanzapine quetiapine risperidone | |
| Very weak: Aripiprazole ziprasidone | |
| Stuttering | Very weak: Chlorpromazine haloperidol olanzapine risperidone |
| aStrong: Multiple well-designed RCTs directly relevant to the recommendation yielding consistent findings Intermediate: Some evidence from RCTs that support the recommendation but the scientific support was not optimal Weak: Consensus recommendation in the absence of relevant RCTs and better evidence than case report or series Very weak: Case reports case series or preliminary studies RCTs: randomized controlled trials INSOMNIA Arvanitis LA, Miller BG. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry. 1997;42(4):233-246. Beasley CM Jr, Tollefson G, Tran P, et al. Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology. 1996;14(2):111-123. Cohrs S, Meier A, Neumann AC, et al. Improved sleep continuity and increased slow wave sleep and REM latency during ziprasidone treatment: a randomized, controlled, crossover trial of 12 healthy male subjects. J Clin Psychiatry. 2005;66(8):989-996. Cohrs S, Rodenbeck A, Guan Z, et al. Sleep-promoting properties of quetiapine in healthy subjects. Psychopharmacology. 2004;174(3):421-429. Juri C, Chaná P, Tapia J, et al. Quetiapine for insomnia in Parkinson’s disease: results from an open-label trial. Clin Neuropharmacol. 2005;28(4):185-187. Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry. 1994;151(6):825-835. Pasquini M, Speca A, Biondi M. Quetiapine for tamoxifen-induced insomnia in women with breast cancer. Psychosomatics. 2009;50(2):159-161. Sharpley AL, Vassallo CM, Cowen PJ. Olanzapine increases slow-wave sleep: evidence for blockade of central 5-HT(2C) receptors in vivo. Biol Psychiatry. 2000;47(5):468-470. Terán A, Majadas S, Galan J. Quetiapine in the treatment of sleep disturbances associated with addictive conditions: a retrospective study. Subst Use Misuse. 2008;43(14):2169-2171. Wiegand MH, Landry F, Brückner T, et al. Quetiapine in primary insomnia: a pilot study. Psychopharmacology (Berl). 2008;196(2):337-338. TICS OF TOURETTE’S DISORDER Abuzzahab FS, Anderson FO. Gilles de la Tourette’s syndrome: international registry. Minn Med. 1973;56(6):492-496. Borison RL, Ang L, Chang S, et al. New pharmacological approaches in the treatment of Tourette’s syndrome. Adv Neurol. 1982;35:377-382. Bubl E, Perlov E, Tebartz Van Elst L. Aripiprazole in patients with Tourette syndrome. World Biol J Psychiatry. 2006;7(2):123-125. Caine ED, Polinsky RJ, Kartzinel R, et al. The trial use of clozapine for abnormal involuntary movement disorders. Am J Psychiatry. 1979;136(3):317-320. Dion Y, Annable L, Sabdor P, et al. Risperidone in the treatment of Tourette’s syndrome: a double-blind, placebo-controlled trial. J Clin Psychopharmacol. 2002;22(1):31-39. McCracken JT, Suddath R, Chang S, et al. Effectiveness and tolerability of open label olanzapine in children and adolescents with Tourette’s syndrome. J Child Adolesc Psychopharmacol. 2008;18(5):501-508. Mikkelsen EJ, Detlor J, Cohen DJ. School avoidance and social phobia triggered by haloperidol in patients with Tourette’s disorder. Am J Psychiatry. 1981;138(12):1572-1576. Murphy TK, Bengston MA, Soto O, et al. Case series on the use of aripiprazole for Tourette syndrome. Int J Neuropsychopharmacol. 2005;8(3):489-490. Párraga HC, Párraga M, Woodward R, et al. Quetiapine treatment of children with Tourette’s syndrome: report of two cases. J Child Adolesc Psychopharmacol. 2001;11(2):187-191. Regeur L, Pakkenberg B, Fog R, et al. Clinical features and long-term treatment with pimozide in 65 patients with Gilles de la Tourette’s syndrome. J Neurol Neurosurg Psychiatry. 1986;49(7):791-795. Sallee FR, Kurlan R, Goetz CG, et al. Ziprasidone treatment of children and adolescents with Tourette’s syndrome: a pilot study. J Am Acad Child Adolesc Psychiatry. 2000;39(3):292-299. Sallee FR, Nesbitt L, Jackson C, et al. Relative efficacy of haloperidol and pimozide in children and adolescents with Tourette’s disorder. Am J Psychiatry. 1997;154(8):1057-1062. Scahill L, Leckman JF, Schultz RT, et al. A placebo-controlled trial of risperidone in Tourette syndrome. Neurology. 2003; 60(7):1130-1135. Shapiro AK, Shapiro E, Eisenkraft GJ. Treatment of Tourette’s disorder with penfluridol. Compr Psychiatry. 1983;24(4): 327-331. Shapiro AK, Shapiro E, Wayne HL. Treatment of Tourette’s syndrome with haloperidol: review of 34 cases. Arch Gen Psychiatry. 1973;28(1):92-96. Shapiro AK, Shapiro E, Young JG, et al. Gilles de la Tourette’s syndrome. 2nd ed. New York, NY: Raven Press; 1998:387-390. Stephens RJ, Bassel C, Sandor P. Olanzapine in the treatment of aggression and tics in children with Tourette’s syndrome-a pilot study. J Child Adolesc Psychopharmacol. 2004;14(2):255-266. DELIRIUM Alao AO, Moskowitz L. Aripiprazole and delirium. Ann Clin Psychiatry. 2006;18(4):267-269. Al-Samarrai S, Dunn J, Newmark T, et al. Quetiapine for treatment-resistant delirium. Psychosomatics. 2003;44(4): 350-351. Bourgeois JA, Hilty DM. Prolonged delirium managed with risperidone. Psychosomatics. 2005;46(1):90-91. Breitbart W, Tremblay A, Gibson C. An open trial of olanzapine for the treatment of delirium in hospitalized cancer patients. Psychosomatics. 2002;43(3):175-182. 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(2):419-427. Hans CS, Kim YK. A double-blind trial of risperidone and haloperidol for the treatment of delirium. Psychosomatics. 2004;45(4):297-301. Horikawa N, Yamazaki T, Miyamoto K, et al. Treatment for delirium with risperidone: results of a prospective open trial with 10 patients. Gen Hosp Psychiatry. 2003;25(4):289-292. Hu H, Deng W, Yang H. A prospective random control study comparison of olanzapine and haloperidol in senile delirium [in Chinese]. Chong’qing Medical Journal. 2004;8:1234-1237. 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(11):1966-1973. Leso L, Schwartz TL. Ziprasidone treatment of delirium. Psychosomatics. 2002;43(1):61-62. Parellada E, Baeza I, de Pablo J, et al. Risperidone in the treatment of patients with delirium. J Clin Psychiatry. 2004;65(3):348-353. 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(11):1316-1321. Sipahimalani A, Masand PS. Olanzapine in the treatment of delirium. Psychosomatics. 1998;39(5):422-430. Sipahimalani A, Masand PS. Use of risperidone in delirium: case reports. Ann Clin Psychiatry. 1997;9(2):105-107. Straker DA, Shapiro PA, Muskin PR. Aripiprazole in the treatment of delirium. Psychosomatics. 2006;47(5):385-391. Young CC, Lujan E. Intravenous ziprasidone for treatment of delirium in the intensive care unit. Anesthesiology. 2004;101(3): 794-795. STUTTERING Burr HG, Mullendore JM. Recent investigations on tranquilizers and stuttering. J Speech Hear Disord. 1960;25;33-37. Lavid N, Franklin DL, Maguire GA. Management of child and adolescent stuttering with olanzapine: three case reports. Ann Clin Psychiatry. 1999;11(4):233-236. Tapia F. Haldol in the treatment of children with tics and stutterers and an incidental finding. Behav Neuropsychiatry. 1969;1(3):28. van Wattum PJ. Stuttering improved with risperidone. J Am Acad Child Adolesc Psychiatry. 2006;45(2):133. | |
Current use of antipsychotics
Antipsychotics are divided into 2 major classes—first-generation antipsychotics (FGAs) and SGAs—and principally are FDA-approved for treating schizophrenia. Some antipsychotics have received FDA approval for maintenance treatment of schizophrenia and bipolar disorder (BD), and others have been approved to treat tic disorders (haloperidol and pimozide).
To varying degrees, all antipsychotics block D2 receptors, which is thought to be necessary for treating psychosis. However, some SGAs have significant affinity at other receptors—such as 5-HT2A and 5-HT1A—that confer additional properties that are not fully understood (Table 3). For example, it is believed that 5-HT2A blockade in the striatum reduces the potential for extrapyramidal symptoms (EPS).
Each antipsychotic blocks a unique set of receptors in the brain, leading to a specific set of intended and potentially untoward effects. For example, olanzapine’s effect on psychosis largely stems from its action at the D2 receptor, whereas its sedative and anticholinergic properties are a result of activity at histamine (H1) receptors and muscarinic receptors, respectively. Clinicians can make rational use of unintended effects by carefully selecting a medication based on receptor binding profile (eg, using an antipsychotic with sedating properties in a patient who has psychosis and insomnia). This approach can limit use of multiple medications and maximize a medication’s known effects while attempting to minimize side effects.
Table 3
Antipsychotics: Receptor pharmacology and common side effects
| Antipsychotic | Pharmacology | Common side effectsa |
|---|---|---|
| Prochlorperazinea,b | D2 receptor antagonist and α-1 adrenergic receptor antagonism | EPS, akathisia, prolactinemia, orthostatic hypotension, altered cardiac conduction, agranulocytosis, sexual dysfunction |
| Chlorpromazinea,b | D2 receptor antagonist. Also binds to H1 and cholinergic M1 | EPS, akathisia, prolactinemia, orthostatic hypotension, urinary retention, non-specific QT changes, agranulocytosis, sexual dysfunction |
| Droperidola,b | D2 receptor antagonist and antagonist at peripheral α-1 activity | EPS, akathisia, prolactinemia, orthostatic hypotension, urinary retention, QT changes (dose dependent) |
| Haloperidola,b | D2 receptor antagonist. Also binds to D1, 5-HT2, H1, and α-2 adrenergic receptors | EPS, akathisia, prolactinemia, QT changes (dose dependent) |
| Aripiprazolea,c,d | D2 and 5-HT1A partial agonism, 5-HT2A antagonism | Akathisia, EPS, sedation, restlessness, insomnia, tremor, anxiety, nausea, vomiting, possible weight gain (20% to 30%) |
| Clozapinea,c,e | 5-HT2, D1, D2, D3, D4, M1, H1, α-1, and α-2 antagonism | Sedation, dizziness, tachycardia, weight gain, nausea, vomiting, constipation |
| Olanzapinea,c | 5-HT2A, 5-HT2C, D1, D2, D3, D4, M1-5, H1, and α1- antagonism | Sedation, EPS, prolactinemia, weight gain, constipation |
| Quetiapinea,c,d | D1, D2, 5-HT2A, 5-HT1A, H1, α-1, and α-2 antagonism | Sedation, orthostatic hypotension, weight gain, triglyceride abnormalities, hypertension (frequently diastolic), constipation |
| Risperidonea,c | 5-HT2, D2, H1, α-1, and α-2 antagonism | Sedation, akathisia, EPS, prolactinemia, weight gain, tremor |
| Ziprasidonea,c | D2, D3, 5-HT2A, 5-HT2C, 5-HT1D, and α-1 antagonism; moderate inhibition of 5-HT and NE reuptake; 5-HT1A agonism | EPS, sedation, headache, dizziness, nausea |
| aSide effects and their prominence usually are based on receptor binding profile. All antipsychotics to varying degrees share the following symptoms: EPS, neuroleptic malignant syndrome, QTc prolongation, anticholinergic side effects (urinary retention, decreased gastrointestinal motility, xerostomia), sedation, orthostatic hypotension, blood dyscrasias, and problems with temperature regulation. The class as a whole also carries a “black-box” warning regarding increased mortality when treating geriatric patients with psychosis related to dementia bNo frequencies were available cOnly side effects with frequency >10% listed d”Black-box” warning for suicidal ideation and behavior in children, adolescents, and young adults (age 18 to 24) with major depressive disorder and other psychiatric disorders e”Black-box” warnings for agranulocytosis, myocarditis, orthostatic hypotension, seizure risk EPS: extrapyramidal symptoms; H1: histamine; M1: muscarinic; NE: norepinephrine | ||
Insomnia
Clinicians use FGAs and SGAs to treat insomnia because of their sedating effects, although evidence supporting this use is questionable. Among the FGAs, chlorpromazine produces moderate to severe sedation, whereas haloperidol is only mildly sedating. Clozapine is believed to be the most sedating SGA, whereas quetiapine and olanzapine produce moderate sedation.7
Most data on antipsychotics’ sedating effects comes from studies completed for schizophrenia or BD. Few studies have evaluated using antipsychotics to treat primary insomnia or other sleep disorders in otherwise healthy patients.2 However, data from phase I studies of antipsychotics has shown that schizophrenia patients tolerate a higher maximum dose compared with healthy volunteers, who often experience more sedation.
An antipsychotic’s potential for sedation is directly related to its affinity at H1 receptors and total drug concentration at the H1 receptor binding site. Because drugs with lower affinity for D2 receptors typically are prescribed at higher doses when treating psychiatric illness, the corresponding concentration at H1 receptors can lead to greater sedation compared with equivalent doses of higher-potency agents.
The same phenomenon is seen with high-potency agents. Haloperidol has a relatively weak binding affinity to the H1 receptor,8 but causes more sedation at higher doses. Haloperidol, 20 mg/d, produces sedation in more patients than a moderate dose of risperidone, 2 to 10 mg/d.8 These observations correlate with “the high milligram-low-potency” spectrum seen with FGAs.7
Among SGAs, a double-blind, placebo-controlled, crossover study of the effects of ziprasidone, 40 mg/d, on sleep in a group of healthy volunteers found a significant increase in total sleep time and sleep efficiency.9 A double-blind trial compared patients taking low, medium, or high daily doses of olanzapine with patients receiving haloperidol or placebo.10 Sedation was reported in 20% of patients taking low doses of olanzapine (5 ± 2.5 mg/d) compared with 29.7% on medium doses (10 ± 2.5 mg/d) and 39.1% on high doses (15 ± 2.5 mg/d).10
A double-blind, placebo-controlled, crossover study demonstrated that olanzapine produced significant increases in sleep continuity, slow wave sleep, and subjective ratings of sleep quality in healthy men.11 Similarly, a study comparing haloperidol, 12 mg/d, and quetiapine, 75 to 750 mg/d, for treating acute schizophrenia found an 8% to 11% incidence of somnolence in the quetiapine group compared with 6% and 8% in the haloperidol and placebo groups, respectively.12 Somnolence was reported as an adverse event in these studies, which were designed to examine the drug’s effect on acute schizophrenia and did not evaluate its effect on sleep.
A double-blind, placebo-controlled, crossover study examining quetiapine’s effects on sleep in 14 healthy patients demonstrated a significant difference in total sleep time, sleep period time, and sleep efficiency.13 Similarly, an open-label pilot study of quetiapine’s effect on primary insomnia showed significant improvement in total sleep time and sleep efficiency.14
Studies examining quetiapine’s effects on insomnia in patients with substance abuse15 and women with localized breast cancer16 showed improved sleep scores on multiple assessment tools, while an open-label study of quetiapine for Parkinson’s disease demonstrated decreased sleep latency.17 Adjunctive quetiapine administered over a 6-week, open-label trial in veterans with posttraumatic stress disorder revealed significant improvement from baseline in sleep quality and duration and diminished dreaming.18
Sedating antipsychotics such as thioridazine and chlorpromazine historically were used off-label for insomnia, but fell out of favor because of their associated cardiac risks. More recently, clinicians have been using SGAs in a similar manner19 even though SGAs are costly and have significant risks such as metabolic problems.
Studies supporting the use of SGAs for the short-term or long-term treatment of insomnia are limited by small sample sizes or open-label designs.20 In 2005 the National Institutes of Health State-of-the-Science Conference Panel did not recommend using SGAs for treating chronic insomnia.21
Tics in Tourette’s disorder
FGAs and SGAs have been used to treat tics associated with Tourette’s disorder (TD).22 Haloperidol is FDA-approved for treating tics in adult and pediatric patients with TD. Many studies have reported the efficacy of haloperidol in this population; however, cognitive blunting, weight gain, lethargy, and akathisia limit its use.23
Pimozide, the most widely used alternative to haloperidol for treating TD, can cause clinically significant QTc prolongation and sudden death. Penfluridol demonstrated significant symptomatic improvement compared with haloperidol in 1 study, but its carcinogenic potential limits its use.24
A double-blind, placebo-controlled study comparing fluphenazine and trifluoperazine with haloperidol for treating TD showed that both are significantly more effective than placebo, but none was more effective than the others.25 Studies show chlorpromazine, perphenazine, and thioridazine are less effective than haloperidol and their use is limited by photosensitivity, dermatitis, EPS, and blood and liver dyscrasias.26
Risperidone is superior to placebo for treating tics associated with TD.27 A placebo-controlled trial of ziprasidone showed the drug has efficacy similar to risperidone in reducing tics in children and adolescents with TD.28 However, ziprasidone is not FDA-approved for this use.
Evidence supporting the use of other SGAs for treating TD is more limited. Several small studies of olanzapine and aripiprazole had limited but favorable results. Quetiapine has not been studied for treating TD, but several case reports have indicated a positive response. In a double-blind, placebo-controlled trial, clozapine showed no therapeutic benefit for TD.29
Delirium
American Psychiatric Association practice guidelines suggest using psychotropic medications to treat neuropsychiatric symptoms of delirium.30 Antipsychotics are considered first-line agents that lower hospital mortality rates, decrease lengths of hospital stays, and improve delirium symptoms, in some cases before the underlying medical etiologies resolve.30,31 Available in liquid, oral, IM, and IV formulations, haloperidol is the mainstay of symptomatic treatment of delirium.31 Although not FDA-approved, it is recommended by the Society of Critical Care Medicine as a safe, cost-effective, and efficacious therapy for the psychiatric symptoms associated with delirium.
The most extensively studied SGA for treating delirium, risperidone often is used as an alternative to haloperidol. Case reports describe its potential efficacy.32 In a head-to-head study, risperidone was as effective as low-dose haloperidol for acute delirium treatment.33
Olanzapine was effective in managing delirium in several case studies.34 Also, in a 7-day, randomized, placebo-controlled study, olanzapine and haloperidol showed significantly greater and relatively equivalent improvement compared with placebo; patients treated with olanzapine experienced more rapid improvement in 1 study.35
Case reports and prospective studies also have described quetiapine as effective for treating delirium.36,37 In a prospective, double-blind, placebo-controlled study, patients taking quetiapine had a faster resolution of delirium with reduced overall duration and less agitation than those taking placebo.37 Mortality, intensive care unit length of stay, and incidence of QTc prolongation did not differ, but patients treated with quetiapine were more likely to have increased somnolence and were more frequently discharged to home or rehabilitation centers. One limitation of the study is that concomitant haloperidol use on an “as needed” basis was permitted.38
Evidence supporting the efficacy of ziprasidone for delirium is limited to case reports.39 In 1 case report, a patient with chronic HIV infection and acute cryptococcal meningitis experienced significant improvement of delirium symptoms but could not continue ziprasidone because of fluctuating QTc intervals.40
In 2 patients with delirium, aripiprazole, 15 and 30 mg/d, improved confusion, disorientation, and agitation within 7 days.41 In another study of delirium, 13 of 14 patients on flexibly dosed aripiprazole (5 to 15 mg/d) showed improvement in Clinical Global Impressions Scale scores, although 3 patients developed prolonged QTc intervals.42
Stuttering or stammering
Stuttering or stammering are age-inappropriate disturbances in normal fluency and time patterning of speech. The evidence for antipsychotics to treat stuttering or stammering speech mainly consists of case reports and does not include disfluency frequency data, which makes it difficult to accept claims of efficacy. Disfluency frequency data describe how often a patient has specific disfluencies (blocks, prolongations, interjection, and repetition of syllables, words, or phrases).
Two FGAs (chlorpromazine and haloperidol) and 2 SGAs (risperidone and olanzapine) have been evaluated for treating stuttering. Children were 2.5 times more likely to demonstrate significant improvement when taking chlorpromazine vs placebo.43 An open-label study of haloperidol lacked disfluency frequency data, therefore casting doubts on haloperidol’s reported efficacy in the study.44
In a case report, a 4-year-old boy with severe behavioral dyscontrol showed complete remission of stammering after 1 day of risperidone, 0.25 mg/d.45 The patient’s symptoms reappeared several days after the drug was stopped. In a case series of 2 patients with developmental stuttering, 1 patient reported significant improvement in fluency with olanzapine, 2.5 mg/d, and the other showed marked improvement in fluency with 5 mg/d.46
Related Resources
- Sipahimalani A, Masand PS. Use of risperidone in delirium: case reports. Ann Clin Psychiatry. 1997;9(2):105-107.
- Shapiro AK, Shapiro E, Wayne HL. Treatment of Tourette’s syndrome with haloperidol: review of 34 cases. Arch Gen Psychiatry. 1973;28(1):92-96.
- Sipahimalani A, Masand PS. Olanzapine in the treatment of delirium. Psychosomatics. 1998;39(5):422-430.
Drug Brand Names
- Aripiprazole • Abilify
- Chlorpromazine • Thorazine
- Clozapine • Clozaril
- Fluphenazine • Permitil, Prolixin
- Haloperidol • Haldol
- Olanzapine • Zyprexa
- Perphenazine • Trilafon
- Pimozide • Orap
- Prochlorperazine • Compazine
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Thioridazine • Mellaril
- Trifluoperazine • Stelazine
- Ziprasidone • Geodon
Disclosure
Dr. Macaluso has received grant or research support from EnVivo Pharmaceuticals, Janssen, L.P., and Pfizer, Inc.
Dr. Tripathi reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
1. Alexander GC, Gallagher SA, Mascola A, et al. Increasing off-label use of antipsychotic medications in the United States, 1995-2008. Pharmacoepidemiol Drug Saf. 2011;20(2):177-184.
2. DeMartinis N, Winokur A. Effects of psychiatric medications on sleep and sleep disorders. CNS Neurol Disord Drug Targets. 2007;6(1):17-29.
3. Leckman JF, Bloch MH, Smith ME, et al. Neurobiological substrates of Tourette’s disorder. J Child Adolesc Psychopharmacol. 2010;20(4):237-247.
4. Maldonado JR. Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment. Crit Care Clin. 2008;24(4):789-856.
5. Wu JC, Maguire G, Riley G, et al. Increased dopamine activity associated with stuttering. Neuroreport. 1997;8(3):767-770.
6. Devulapalli K, Nasrallah HA. An analysis of the high psychotropic off-label use in psychiatric disorders: the majority of psychiatric diagnoses have no approved drug. Asian J Psychiatr. 2009;2(1):29-36.
7. Miller DD. Atypical antipsychotics: sleep sedation, and efficacy. Prim Care Companion J Clin Psychiatry. 2004;6(suppl 2):3-7.
8. Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry. 1994;151(6):825-835.
9. Cohrs S, Meier A, Neumann AC, et al. Improved sleep continuity and increased slow wave sleep and REM latency during ziprasidone treatment: a randomized, controlled, crossover trial of 12 healthy male subjects. J Clin Psychiatry. 2005;66(8):989-996.
10. Beasley CM Jr, Tollefson G, Tran P, et al. Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology. 1996;14(2):111-123.
11. Sharpley AL, Vassallo CM, Cowen PJ. Olanzapine increases slow-wave sleep: evidence for blockade of central 5-HT(2C) receptors in vivo. Biol Psychiatry. 2000;47(5):468-470.
12. Arvanitis LA, Miller BG. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry. 1997;42(4):233-246.
13. Cohrs S, Rodenbeck A, Guan Z, et al. Sleep-promoting properties of quetiapine in healthy subjects. Psychopharmacology. 2004;174(3):421-429.
14. Wiegand MH, Landry F, Brückner T, et al. Quetiapine in primary insomnia: a pilot study. Psychopharmacology (Berl). 2008;196(2):337-338.
15. Terán A, Majadas S, Galan J. Quetiapine in the treatment of sleep disturbances associated with addictive conditions: a retrospective study. Subst Use Misuse. 2008;43(14):2169-2171.
16. Pasquini M, Speca A, Biondi M. Quetiapine for tamoxifen-induced insomnia in women with breast cancer. Psychosomatics. 2009;50(2):159-161.
17. Juri C, Chaná P, Tapia J, et al. Quetiapine for insomnia in Parkinson’s disease: results from an open-label trial. Clin Neuropharmacol. 2005;28(4):185-187.
18. Robert S, Hamner MB, Kose S, et al. Quetiapine improves sleep disturbances in combat veterans with PTSD: sleep data from a prospective, open-label study. J Clin Psychopharmacol. 2005;25(4):387-388.
19. Wilson S, Nutt D. Management of insomnia: treatments and mechanisms. Br J Psychiatry. 2007;191:195-197.
20. Morin CM, Benca R. Chronic insomnia. Lancet. 2012;379(9821):1129-1141.
21. National Institutes of Health. National Institutes of Health State of the Science Conference statement on manifestations and management of chronic insomnia in adults June 13-15, 2005. Sleep. 2005;28(9):1049-1057.
22. Párraga HC, Harris KM, Párraga KL, et al. An overview of the treatment of Tourette’s disorder and tics. J Child Adolesc Psychopharmacol. 2010;20(4):249-262.
23. Mikkelsen EJ, Detlor J, Cohen DJ. School avoidance and social phobia triggered by haloperidol in patients with Tourette’s disorder. Am J Psychiatry. 1981;138(12):1572-1576.
24. Shapiro AK, Shapiro E, Eisenkraft GJ. Treatment of Tourette’s disorder with penfluridol. Compr Psychiatry. 1983;24(4):327-331.
25. Borison RL, Ang L, Chang S, et al. New pharmacological approaches in the treatment of Tourette’s syndrome. Adv Neurol. 1982;35:377-382.
26. Shapiro AK, Shapiro E, Young JG, et al. Gilles de la Tourette’s syndrome. 2nd ed. New York, NY: Raven Press; 1998:387–390.
27. Dion Y, Annable L, Sabdor P, et al. Risperidone in the treatment of Tourette’s syndrome: a double-blind, placebo-controlled trial. J Clin Psychopharmacol. 2002;22(1):31-39.
28. Sallee FR, Kurlan R, Goetz CG, et al. Ziprasidone treatment of children and adolescents with Tourette’s syndrome: a pilot study. J Am Acad Child Adolesc Psychiatry. 2000;39(3):292-299.
29. Caine ED, Polinsky RJ, Kartzinel R, et al. The trial use of clozapine for abnormal involuntary movement disorders. Am J Psychiatry. 1979;136(3):317-320.
30. American Psychiatric Association. Practice guideline for the treatment of patients with delirium. Am J Psychiatry. 1999;156(suppl 5):1-20.
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(11):1966-1973.
32. Parellada E, Baeza I, de Pablo J, et al. Risperidone in the treatment of patients with delirium. J Clin Psychiatry. 2004;65(3):348-353.
33. Hans CS, Kim YK. A double-blind trial of risperidone and haloperidol for the treatment of delirium. Psychosomatics. 2004;45(4):297-301.
34. Breitbart W, Tremblay A, Gibson C. An open trial of olanzapine for the treatment of delirium in hospitalized cancer patients. Psychosomatics. 2002;43(3):175-182.
35. Hu H, Deng W, Yang H. A prospective random control study comparison of olanzapine and haloperidol in senile delirium [in Chinese]. Chong’qing Medical Journal. 2004;8:1234-1237.
36. Al-Samarrai S, Dunn J, Newmark T, et al. Quetiapine for treatment-resistant delirium. Psychosomatics. 2003;44(4):350-351.
37. 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(11):1316-1321.
38. 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(2):419-427.
39. Young CC, Lujan E. Intravenous ziprasidone for treatment of delirium in the intensive care unit. Anesthesiology. 2004;101(3):794-795.
40. Leso L, Schwartz TL. Ziprasidone treatment of delirium. Psychosomatics. 2002;43(1):61-62.
41. Alao AO, Moskowitz L. Aripiprazole and delirium. Ann Clin Psychiatry. 2006;18(4):267-269.
42. Straker DA, Shapiro PA, Muskin PR. Aripiprazole in the treatment of delirium. Psychosomatics. 2006;47(5):385-391.
43. Burr HG, Mullendore JM. Recent investigations on tranquilizers and stuttering. J Speech Hear Disord. 1960;25:33-37.
44. Tapia F. Haldol in the treatment of children with tics and stutterers and an incidental finding. Behav Neuropsychiatry. 1969;1(3):28.-
45. van Wattum PJ. Stuttering improved with risperidone. J Am Acad Child Adolesc Psychiatry. 2006;45(2):133.-
46. Lavid N, Franklin DL, Maguire GA. Management of child and adolescent stuttering with olanzapine: three case reports. Ann Clin Psychiatry. 1999;11(4):233-236.
Second-generation antipsychotics (SGAs) represent 5% of all U.S. drug expenditures.1 Their use for indications not approved by the FDA (“off-label” use) increased to a total of $6 billion in 2008, $5.4 billion of which was for uses with limited or uncertain evidence.1
Off-label use of antipsychotics usually is based on novel applications of known receptor binding affinities (Table 1).2-5 For example, antipsychotics with strong antihistamine effects may promote sedation and could be used to treat insomnia. Clinicians also might use antipsychotics to treat a specific symptom of an illness when other treatment options are limited6 or when patients do not respond to standard treatments.
Table 1
Possible rationales for antipsychotic use for nonpsychotic conditions
| Condition | Possible rationale |
|---|---|
| Insomnia2 | Effects on H1 α-1 adrenergic and muscarinic cholinergic receptors. 5-HT2 antagonism activity also has been implicated |
| Tics of Tourette’s disorder3 | By blocking dopamine receptors antipsychotics decrease the primarily dopaminergic input from the substantia nigra and ventral tegmentum to the basal ganglia |
| Delirium4 | Patients have reversible impairment of cerebral oxidative metabolism and multiple neurotransmitter abnormalities (dopamine acetylcholine CNS γ-aminobutyric acid and serotonin). Other hypotheses include inflammatory reactions damage to certain structural pathways and disruption of cortisol and β-endorphin circadian rhythms |
| Stuttering5 | Stutterers have a marked increase in dopaminergic afferent activity in the tail of the left caudate nucleus compared with healthy controls |
| H1: histamine | |
To safely use any medication off-label, clinicians should become familiar with literature on the proposed use. Clinicians should consider off-label use only after carefully weighing the potential therapeutic benefits against the risks. Patients should be aware that the prescribed use is not FDA-approved and informed consent should include a discussion of alternative treatments. The high cost of SGAs may be a limiting factor and should be discussed with patients.
This article reviews the evidence for using antipsychotics to treat insomnia, tics, delirium, and stuttering (Table 2). Click here for a review of the evidence supporting antipsychotics for treating migraine and cluster headaches and nausea
Table 2
Antipsychotics for nonpsychotic disorders: Strength of the evidence
| Condition | Strength of evidencea |
|---|---|
| Insomnia | Weak to intermediate: Haloperidol olanzapine quetiapine risperidone ziprasidone |
| Tics of Tourette’s disorder | Strong: Haloperidol pimozide |
| Intermediate: Chlorpromazine fluphenazine penfluridol perphenazine thioridazine trifluoperazine | |
| Weak: Risperidone | |
| Very weak: Aripiprazole olanzapine quetiapine ziprasidone | |
| Not effective: Clozapine | |
| Delirium | Intermediate: Haloperidol |
| Weak: Olanzapine quetiapine risperidone | |
| Very weak: Aripiprazole ziprasidone | |
| Stuttering | Very weak: Chlorpromazine haloperidol olanzapine risperidone |
| aStrong: Multiple well-designed RCTs directly relevant to the recommendation yielding consistent findings Intermediate: Some evidence from RCTs that support the recommendation but the scientific support was not optimal Weak: Consensus recommendation in the absence of relevant RCTs and better evidence than case report or series Very weak: Case reports case series or preliminary studies RCTs: randomized controlled trials INSOMNIA Arvanitis LA, Miller BG. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry. 1997;42(4):233-246. Beasley CM Jr, Tollefson G, Tran P, et al. Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology. 1996;14(2):111-123. Cohrs S, Meier A, Neumann AC, et al. Improved sleep continuity and increased slow wave sleep and REM latency during ziprasidone treatment: a randomized, controlled, crossover trial of 12 healthy male subjects. J Clin Psychiatry. 2005;66(8):989-996. Cohrs S, Rodenbeck A, Guan Z, et al. Sleep-promoting properties of quetiapine in healthy subjects. Psychopharmacology. 2004;174(3):421-429. Juri C, Chaná P, Tapia J, et al. Quetiapine for insomnia in Parkinson’s disease: results from an open-label trial. Clin Neuropharmacol. 2005;28(4):185-187. Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry. 1994;151(6):825-835. Pasquini M, Speca A, Biondi M. Quetiapine for tamoxifen-induced insomnia in women with breast cancer. Psychosomatics. 2009;50(2):159-161. Sharpley AL, Vassallo CM, Cowen PJ. Olanzapine increases slow-wave sleep: evidence for blockade of central 5-HT(2C) receptors in vivo. Biol Psychiatry. 2000;47(5):468-470. Terán A, Majadas S, Galan J. Quetiapine in the treatment of sleep disturbances associated with addictive conditions: a retrospective study. Subst Use Misuse. 2008;43(14):2169-2171. Wiegand MH, Landry F, Brückner T, et al. Quetiapine in primary insomnia: a pilot study. Psychopharmacology (Berl). 2008;196(2):337-338. TICS OF TOURETTE’S DISORDER Abuzzahab FS, Anderson FO. Gilles de la Tourette’s syndrome: international registry. Minn Med. 1973;56(6):492-496. Borison RL, Ang L, Chang S, et al. New pharmacological approaches in the treatment of Tourette’s syndrome. Adv Neurol. 1982;35:377-382. Bubl E, Perlov E, Tebartz Van Elst L. Aripiprazole in patients with Tourette syndrome. World Biol J Psychiatry. 2006;7(2):123-125. Caine ED, Polinsky RJ, Kartzinel R, et al. The trial use of clozapine for abnormal involuntary movement disorders. Am J Psychiatry. 1979;136(3):317-320. Dion Y, Annable L, Sabdor P, et al. Risperidone in the treatment of Tourette’s syndrome: a double-blind, placebo-controlled trial. J Clin Psychopharmacol. 2002;22(1):31-39. McCracken JT, Suddath R, Chang S, et al. Effectiveness and tolerability of open label olanzapine in children and adolescents with Tourette’s syndrome. J Child Adolesc Psychopharmacol. 2008;18(5):501-508. Mikkelsen EJ, Detlor J, Cohen DJ. School avoidance and social phobia triggered by haloperidol in patients with Tourette’s disorder. Am J Psychiatry. 1981;138(12):1572-1576. Murphy TK, Bengston MA, Soto O, et al. Case series on the use of aripiprazole for Tourette syndrome. Int J Neuropsychopharmacol. 2005;8(3):489-490. Párraga HC, Párraga M, Woodward R, et al. Quetiapine treatment of children with Tourette’s syndrome: report of two cases. J Child Adolesc Psychopharmacol. 2001;11(2):187-191. Regeur L, Pakkenberg B, Fog R, et al. Clinical features and long-term treatment with pimozide in 65 patients with Gilles de la Tourette’s syndrome. J Neurol Neurosurg Psychiatry. 1986;49(7):791-795. Sallee FR, Kurlan R, Goetz CG, et al. Ziprasidone treatment of children and adolescents with Tourette’s syndrome: a pilot study. J Am Acad Child Adolesc Psychiatry. 2000;39(3):292-299. Sallee FR, Nesbitt L, Jackson C, et al. Relative efficacy of haloperidol and pimozide in children and adolescents with Tourette’s disorder. Am J Psychiatry. 1997;154(8):1057-1062. Scahill L, Leckman JF, Schultz RT, et al. A placebo-controlled trial of risperidone in Tourette syndrome. Neurology. 2003; 60(7):1130-1135. Shapiro AK, Shapiro E, Eisenkraft GJ. Treatment of Tourette’s disorder with penfluridol. Compr Psychiatry. 1983;24(4): 327-331. Shapiro AK, Shapiro E, Wayne HL. Treatment of Tourette’s syndrome with haloperidol: review of 34 cases. Arch Gen Psychiatry. 1973;28(1):92-96. Shapiro AK, Shapiro E, Young JG, et al. Gilles de la Tourette’s syndrome. 2nd ed. New York, NY: Raven Press; 1998:387-390. Stephens RJ, Bassel C, Sandor P. Olanzapine in the treatment of aggression and tics in children with Tourette’s syndrome-a pilot study. J Child Adolesc Psychopharmacol. 2004;14(2):255-266. DELIRIUM Alao AO, Moskowitz L. Aripiprazole and delirium. Ann Clin Psychiatry. 2006;18(4):267-269. Al-Samarrai S, Dunn J, Newmark T, et al. Quetiapine for treatment-resistant delirium. Psychosomatics. 2003;44(4): 350-351. Bourgeois JA, Hilty DM. Prolonged delirium managed with risperidone. Psychosomatics. 2005;46(1):90-91. Breitbart W, Tremblay A, Gibson C. An open trial of olanzapine for the treatment of delirium in hospitalized cancer patients. Psychosomatics. 2002;43(3):175-182. 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(2):419-427. Hans CS, Kim YK. A double-blind trial of risperidone and haloperidol for the treatment of delirium. Psychosomatics. 2004;45(4):297-301. Horikawa N, Yamazaki T, Miyamoto K, et al. Treatment for delirium with risperidone: results of a prospective open trial with 10 patients. Gen Hosp Psychiatry. 2003;25(4):289-292. Hu H, Deng W, Yang H. A prospective random control study comparison of olanzapine and haloperidol in senile delirium [in Chinese]. Chong’qing Medical Journal. 2004;8:1234-1237. 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(11):1966-1973. Leso L, Schwartz TL. Ziprasidone treatment of delirium. Psychosomatics. 2002;43(1):61-62. Parellada E, Baeza I, de Pablo J, et al. Risperidone in the treatment of patients with delirium. J Clin Psychiatry. 2004;65(3):348-353. 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(11):1316-1321. Sipahimalani A, Masand PS. Olanzapine in the treatment of delirium. Psychosomatics. 1998;39(5):422-430. Sipahimalani A, Masand PS. Use of risperidone in delirium: case reports. Ann Clin Psychiatry. 1997;9(2):105-107. Straker DA, Shapiro PA, Muskin PR. Aripiprazole in the treatment of delirium. Psychosomatics. 2006;47(5):385-391. Young CC, Lujan E. Intravenous ziprasidone for treatment of delirium in the intensive care unit. Anesthesiology. 2004;101(3): 794-795. STUTTERING Burr HG, Mullendore JM. Recent investigations on tranquilizers and stuttering. J Speech Hear Disord. 1960;25;33-37. Lavid N, Franklin DL, Maguire GA. Management of child and adolescent stuttering with olanzapine: three case reports. Ann Clin Psychiatry. 1999;11(4):233-236. Tapia F. Haldol in the treatment of children with tics and stutterers and an incidental finding. Behav Neuropsychiatry. 1969;1(3):28. van Wattum PJ. Stuttering improved with risperidone. J Am Acad Child Adolesc Psychiatry. 2006;45(2):133. | |
Current use of antipsychotics
Antipsychotics are divided into 2 major classes—first-generation antipsychotics (FGAs) and SGAs—and principally are FDA-approved for treating schizophrenia. Some antipsychotics have received FDA approval for maintenance treatment of schizophrenia and bipolar disorder (BD), and others have been approved to treat tic disorders (haloperidol and pimozide).
To varying degrees, all antipsychotics block D2 receptors, which is thought to be necessary for treating psychosis. However, some SGAs have significant affinity at other receptors—such as 5-HT2A and 5-HT1A—that confer additional properties that are not fully understood (Table 3). For example, it is believed that 5-HT2A blockade in the striatum reduces the potential for extrapyramidal symptoms (EPS).
Each antipsychotic blocks a unique set of receptors in the brain, leading to a specific set of intended and potentially untoward effects. For example, olanzapine’s effect on psychosis largely stems from its action at the D2 receptor, whereas its sedative and anticholinergic properties are a result of activity at histamine (H1) receptors and muscarinic receptors, respectively. Clinicians can make rational use of unintended effects by carefully selecting a medication based on receptor binding profile (eg, using an antipsychotic with sedating properties in a patient who has psychosis and insomnia). This approach can limit use of multiple medications and maximize a medication’s known effects while attempting to minimize side effects.
Table 3
Antipsychotics: Receptor pharmacology and common side effects
| Antipsychotic | Pharmacology | Common side effectsa |
|---|---|---|
| Prochlorperazinea,b | D2 receptor antagonist and α-1 adrenergic receptor antagonism | EPS, akathisia, prolactinemia, orthostatic hypotension, altered cardiac conduction, agranulocytosis, sexual dysfunction |
| Chlorpromazinea,b | D2 receptor antagonist. Also binds to H1 and cholinergic M1 | EPS, akathisia, prolactinemia, orthostatic hypotension, urinary retention, non-specific QT changes, agranulocytosis, sexual dysfunction |
| Droperidola,b | D2 receptor antagonist and antagonist at peripheral α-1 activity | EPS, akathisia, prolactinemia, orthostatic hypotension, urinary retention, QT changes (dose dependent) |
| Haloperidola,b | D2 receptor antagonist. Also binds to D1, 5-HT2, H1, and α-2 adrenergic receptors | EPS, akathisia, prolactinemia, QT changes (dose dependent) |
| Aripiprazolea,c,d | D2 and 5-HT1A partial agonism, 5-HT2A antagonism | Akathisia, EPS, sedation, restlessness, insomnia, tremor, anxiety, nausea, vomiting, possible weight gain (20% to 30%) |
| Clozapinea,c,e | 5-HT2, D1, D2, D3, D4, M1, H1, α-1, and α-2 antagonism | Sedation, dizziness, tachycardia, weight gain, nausea, vomiting, constipation |
| Olanzapinea,c | 5-HT2A, 5-HT2C, D1, D2, D3, D4, M1-5, H1, and α1- antagonism | Sedation, EPS, prolactinemia, weight gain, constipation |
| Quetiapinea,c,d | D1, D2, 5-HT2A, 5-HT1A, H1, α-1, and α-2 antagonism | Sedation, orthostatic hypotension, weight gain, triglyceride abnormalities, hypertension (frequently diastolic), constipation |
| Risperidonea,c | 5-HT2, D2, H1, α-1, and α-2 antagonism | Sedation, akathisia, EPS, prolactinemia, weight gain, tremor |
| Ziprasidonea,c | D2, D3, 5-HT2A, 5-HT2C, 5-HT1D, and α-1 antagonism; moderate inhibition of 5-HT and NE reuptake; 5-HT1A agonism | EPS, sedation, headache, dizziness, nausea |
| aSide effects and their prominence usually are based on receptor binding profile. All antipsychotics to varying degrees share the following symptoms: EPS, neuroleptic malignant syndrome, QTc prolongation, anticholinergic side effects (urinary retention, decreased gastrointestinal motility, xerostomia), sedation, orthostatic hypotension, blood dyscrasias, and problems with temperature regulation. The class as a whole also carries a “black-box” warning regarding increased mortality when treating geriatric patients with psychosis related to dementia bNo frequencies were available cOnly side effects with frequency >10% listed d”Black-box” warning for suicidal ideation and behavior in children, adolescents, and young adults (age 18 to 24) with major depressive disorder and other psychiatric disorders e”Black-box” warnings for agranulocytosis, myocarditis, orthostatic hypotension, seizure risk EPS: extrapyramidal symptoms; H1: histamine; M1: muscarinic; NE: norepinephrine | ||
Insomnia
Clinicians use FGAs and SGAs to treat insomnia because of their sedating effects, although evidence supporting this use is questionable. Among the FGAs, chlorpromazine produces moderate to severe sedation, whereas haloperidol is only mildly sedating. Clozapine is believed to be the most sedating SGA, whereas quetiapine and olanzapine produce moderate sedation.7
Most data on antipsychotics’ sedating effects comes from studies completed for schizophrenia or BD. Few studies have evaluated using antipsychotics to treat primary insomnia or other sleep disorders in otherwise healthy patients.2 However, data from phase I studies of antipsychotics has shown that schizophrenia patients tolerate a higher maximum dose compared with healthy volunteers, who often experience more sedation.
An antipsychotic’s potential for sedation is directly related to its affinity at H1 receptors and total drug concentration at the H1 receptor binding site. Because drugs with lower affinity for D2 receptors typically are prescribed at higher doses when treating psychiatric illness, the corresponding concentration at H1 receptors can lead to greater sedation compared with equivalent doses of higher-potency agents.
The same phenomenon is seen with high-potency agents. Haloperidol has a relatively weak binding affinity to the H1 receptor,8 but causes more sedation at higher doses. Haloperidol, 20 mg/d, produces sedation in more patients than a moderate dose of risperidone, 2 to 10 mg/d.8 These observations correlate with “the high milligram-low-potency” spectrum seen with FGAs.7
Among SGAs, a double-blind, placebo-controlled, crossover study of the effects of ziprasidone, 40 mg/d, on sleep in a group of healthy volunteers found a significant increase in total sleep time and sleep efficiency.9 A double-blind trial compared patients taking low, medium, or high daily doses of olanzapine with patients receiving haloperidol or placebo.10 Sedation was reported in 20% of patients taking low doses of olanzapine (5 ± 2.5 mg/d) compared with 29.7% on medium doses (10 ± 2.5 mg/d) and 39.1% on high doses (15 ± 2.5 mg/d).10
A double-blind, placebo-controlled, crossover study demonstrated that olanzapine produced significant increases in sleep continuity, slow wave sleep, and subjective ratings of sleep quality in healthy men.11 Similarly, a study comparing haloperidol, 12 mg/d, and quetiapine, 75 to 750 mg/d, for treating acute schizophrenia found an 8% to 11% incidence of somnolence in the quetiapine group compared with 6% and 8% in the haloperidol and placebo groups, respectively.12 Somnolence was reported as an adverse event in these studies, which were designed to examine the drug’s effect on acute schizophrenia and did not evaluate its effect on sleep.
A double-blind, placebo-controlled, crossover study examining quetiapine’s effects on sleep in 14 healthy patients demonstrated a significant difference in total sleep time, sleep period time, and sleep efficiency.13 Similarly, an open-label pilot study of quetiapine’s effect on primary insomnia showed significant improvement in total sleep time and sleep efficiency.14
Studies examining quetiapine’s effects on insomnia in patients with substance abuse15 and women with localized breast cancer16 showed improved sleep scores on multiple assessment tools, while an open-label study of quetiapine for Parkinson’s disease demonstrated decreased sleep latency.17 Adjunctive quetiapine administered over a 6-week, open-label trial in veterans with posttraumatic stress disorder revealed significant improvement from baseline in sleep quality and duration and diminished dreaming.18
Sedating antipsychotics such as thioridazine and chlorpromazine historically were used off-label for insomnia, but fell out of favor because of their associated cardiac risks. More recently, clinicians have been using SGAs in a similar manner19 even though SGAs are costly and have significant risks such as metabolic problems.
Studies supporting the use of SGAs for the short-term or long-term treatment of insomnia are limited by small sample sizes or open-label designs.20 In 2005 the National Institutes of Health State-of-the-Science Conference Panel did not recommend using SGAs for treating chronic insomnia.21
Tics in Tourette’s disorder
FGAs and SGAs have been used to treat tics associated with Tourette’s disorder (TD).22 Haloperidol is FDA-approved for treating tics in adult and pediatric patients with TD. Many studies have reported the efficacy of haloperidol in this population; however, cognitive blunting, weight gain, lethargy, and akathisia limit its use.23
Pimozide, the most widely used alternative to haloperidol for treating TD, can cause clinically significant QTc prolongation and sudden death. Penfluridol demonstrated significant symptomatic improvement compared with haloperidol in 1 study, but its carcinogenic potential limits its use.24
A double-blind, placebo-controlled study comparing fluphenazine and trifluoperazine with haloperidol for treating TD showed that both are significantly more effective than placebo, but none was more effective than the others.25 Studies show chlorpromazine, perphenazine, and thioridazine are less effective than haloperidol and their use is limited by photosensitivity, dermatitis, EPS, and blood and liver dyscrasias.26
Risperidone is superior to placebo for treating tics associated with TD.27 A placebo-controlled trial of ziprasidone showed the drug has efficacy similar to risperidone in reducing tics in children and adolescents with TD.28 However, ziprasidone is not FDA-approved for this use.
Evidence supporting the use of other SGAs for treating TD is more limited. Several small studies of olanzapine and aripiprazole had limited but favorable results. Quetiapine has not been studied for treating TD, but several case reports have indicated a positive response. In a double-blind, placebo-controlled trial, clozapine showed no therapeutic benefit for TD.29
Delirium
American Psychiatric Association practice guidelines suggest using psychotropic medications to treat neuropsychiatric symptoms of delirium.30 Antipsychotics are considered first-line agents that lower hospital mortality rates, decrease lengths of hospital stays, and improve delirium symptoms, in some cases before the underlying medical etiologies resolve.30,31 Available in liquid, oral, IM, and IV formulations, haloperidol is the mainstay of symptomatic treatment of delirium.31 Although not FDA-approved, it is recommended by the Society of Critical Care Medicine as a safe, cost-effective, and efficacious therapy for the psychiatric symptoms associated with delirium.
The most extensively studied SGA for treating delirium, risperidone often is used as an alternative to haloperidol. Case reports describe its potential efficacy.32 In a head-to-head study, risperidone was as effective as low-dose haloperidol for acute delirium treatment.33
Olanzapine was effective in managing delirium in several case studies.34 Also, in a 7-day, randomized, placebo-controlled study, olanzapine and haloperidol showed significantly greater and relatively equivalent improvement compared with placebo; patients treated with olanzapine experienced more rapid improvement in 1 study.35
Case reports and prospective studies also have described quetiapine as effective for treating delirium.36,37 In a prospective, double-blind, placebo-controlled study, patients taking quetiapine had a faster resolution of delirium with reduced overall duration and less agitation than those taking placebo.37 Mortality, intensive care unit length of stay, and incidence of QTc prolongation did not differ, but patients treated with quetiapine were more likely to have increased somnolence and were more frequently discharged to home or rehabilitation centers. One limitation of the study is that concomitant haloperidol use on an “as needed” basis was permitted.38
Evidence supporting the efficacy of ziprasidone for delirium is limited to case reports.39 In 1 case report, a patient with chronic HIV infection and acute cryptococcal meningitis experienced significant improvement of delirium symptoms but could not continue ziprasidone because of fluctuating QTc intervals.40
In 2 patients with delirium, aripiprazole, 15 and 30 mg/d, improved confusion, disorientation, and agitation within 7 days.41 In another study of delirium, 13 of 14 patients on flexibly dosed aripiprazole (5 to 15 mg/d) showed improvement in Clinical Global Impressions Scale scores, although 3 patients developed prolonged QTc intervals.42
Stuttering or stammering
Stuttering or stammering are age-inappropriate disturbances in normal fluency and time patterning of speech. The evidence for antipsychotics to treat stuttering or stammering speech mainly consists of case reports and does not include disfluency frequency data, which makes it difficult to accept claims of efficacy. Disfluency frequency data describe how often a patient has specific disfluencies (blocks, prolongations, interjection, and repetition of syllables, words, or phrases).
Two FGAs (chlorpromazine and haloperidol) and 2 SGAs (risperidone and olanzapine) have been evaluated for treating stuttering. Children were 2.5 times more likely to demonstrate significant improvement when taking chlorpromazine vs placebo.43 An open-label study of haloperidol lacked disfluency frequency data, therefore casting doubts on haloperidol’s reported efficacy in the study.44
In a case report, a 4-year-old boy with severe behavioral dyscontrol showed complete remission of stammering after 1 day of risperidone, 0.25 mg/d.45 The patient’s symptoms reappeared several days after the drug was stopped. In a case series of 2 patients with developmental stuttering, 1 patient reported significant improvement in fluency with olanzapine, 2.5 mg/d, and the other showed marked improvement in fluency with 5 mg/d.46
Related Resources
- Sipahimalani A, Masand PS. Use of risperidone in delirium: case reports. Ann Clin Psychiatry. 1997;9(2):105-107.
- Shapiro AK, Shapiro E, Wayne HL. Treatment of Tourette’s syndrome with haloperidol: review of 34 cases. Arch Gen Psychiatry. 1973;28(1):92-96.
- Sipahimalani A, Masand PS. Olanzapine in the treatment of delirium. Psychosomatics. 1998;39(5):422-430.
Drug Brand Names
- Aripiprazole • Abilify
- Chlorpromazine • Thorazine
- Clozapine • Clozaril
- Fluphenazine • Permitil, Prolixin
- Haloperidol • Haldol
- Olanzapine • Zyprexa
- Perphenazine • Trilafon
- Pimozide • Orap
- Prochlorperazine • Compazine
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Thioridazine • Mellaril
- Trifluoperazine • Stelazine
- Ziprasidone • Geodon
Disclosure
Dr. Macaluso has received grant or research support from EnVivo Pharmaceuticals, Janssen, L.P., and Pfizer, Inc.
Dr. Tripathi reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Second-generation antipsychotics (SGAs) represent 5% of all U.S. drug expenditures.1 Their use for indications not approved by the FDA (“off-label” use) increased to a total of $6 billion in 2008, $5.4 billion of which was for uses with limited or uncertain evidence.1
Off-label use of antipsychotics usually is based on novel applications of known receptor binding affinities (Table 1).2-5 For example, antipsychotics with strong antihistamine effects may promote sedation and could be used to treat insomnia. Clinicians also might use antipsychotics to treat a specific symptom of an illness when other treatment options are limited6 or when patients do not respond to standard treatments.
Table 1
Possible rationales for antipsychotic use for nonpsychotic conditions
| Condition | Possible rationale |
|---|---|
| Insomnia2 | Effects on H1 α-1 adrenergic and muscarinic cholinergic receptors. 5-HT2 antagonism activity also has been implicated |
| Tics of Tourette’s disorder3 | By blocking dopamine receptors antipsychotics decrease the primarily dopaminergic input from the substantia nigra and ventral tegmentum to the basal ganglia |
| Delirium4 | Patients have reversible impairment of cerebral oxidative metabolism and multiple neurotransmitter abnormalities (dopamine acetylcholine CNS γ-aminobutyric acid and serotonin). Other hypotheses include inflammatory reactions damage to certain structural pathways and disruption of cortisol and β-endorphin circadian rhythms |
| Stuttering5 | Stutterers have a marked increase in dopaminergic afferent activity in the tail of the left caudate nucleus compared with healthy controls |
| H1: histamine | |
To safely use any medication off-label, clinicians should become familiar with literature on the proposed use. Clinicians should consider off-label use only after carefully weighing the potential therapeutic benefits against the risks. Patients should be aware that the prescribed use is not FDA-approved and informed consent should include a discussion of alternative treatments. The high cost of SGAs may be a limiting factor and should be discussed with patients.
This article reviews the evidence for using antipsychotics to treat insomnia, tics, delirium, and stuttering (Table 2). Click here for a review of the evidence supporting antipsychotics for treating migraine and cluster headaches and nausea
Table 2
Antipsychotics for nonpsychotic disorders: Strength of the evidence
| Condition | Strength of evidencea |
|---|---|
| Insomnia | Weak to intermediate: Haloperidol olanzapine quetiapine risperidone ziprasidone |
| Tics of Tourette’s disorder | Strong: Haloperidol pimozide |
| Intermediate: Chlorpromazine fluphenazine penfluridol perphenazine thioridazine trifluoperazine | |
| Weak: Risperidone | |
| Very weak: Aripiprazole olanzapine quetiapine ziprasidone | |
| Not effective: Clozapine | |
| Delirium | Intermediate: Haloperidol |
| Weak: Olanzapine quetiapine risperidone | |
| Very weak: Aripiprazole ziprasidone | |
| Stuttering | Very weak: Chlorpromazine haloperidol olanzapine risperidone |
| aStrong: Multiple well-designed RCTs directly relevant to the recommendation yielding consistent findings Intermediate: Some evidence from RCTs that support the recommendation but the scientific support was not optimal Weak: Consensus recommendation in the absence of relevant RCTs and better evidence than case report or series Very weak: Case reports case series or preliminary studies RCTs: randomized controlled trials INSOMNIA Arvanitis LA, Miller BG. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry. 1997;42(4):233-246. Beasley CM Jr, Tollefson G, Tran P, et al. Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology. 1996;14(2):111-123. Cohrs S, Meier A, Neumann AC, et al. Improved sleep continuity and increased slow wave sleep and REM latency during ziprasidone treatment: a randomized, controlled, crossover trial of 12 healthy male subjects. J Clin Psychiatry. 2005;66(8):989-996. Cohrs S, Rodenbeck A, Guan Z, et al. Sleep-promoting properties of quetiapine in healthy subjects. Psychopharmacology. 2004;174(3):421-429. Juri C, Chaná P, Tapia J, et al. Quetiapine for insomnia in Parkinson’s disease: results from an open-label trial. Clin Neuropharmacol. 2005;28(4):185-187. Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry. 1994;151(6):825-835. Pasquini M, Speca A, Biondi M. Quetiapine for tamoxifen-induced insomnia in women with breast cancer. Psychosomatics. 2009;50(2):159-161. Sharpley AL, Vassallo CM, Cowen PJ. Olanzapine increases slow-wave sleep: evidence for blockade of central 5-HT(2C) receptors in vivo. Biol Psychiatry. 2000;47(5):468-470. Terán A, Majadas S, Galan J. Quetiapine in the treatment of sleep disturbances associated with addictive conditions: a retrospective study. Subst Use Misuse. 2008;43(14):2169-2171. Wiegand MH, Landry F, Brückner T, et al. Quetiapine in primary insomnia: a pilot study. Psychopharmacology (Berl). 2008;196(2):337-338. TICS OF TOURETTE’S DISORDER Abuzzahab FS, Anderson FO. Gilles de la Tourette’s syndrome: international registry. Minn Med. 1973;56(6):492-496. Borison RL, Ang L, Chang S, et al. New pharmacological approaches in the treatment of Tourette’s syndrome. Adv Neurol. 1982;35:377-382. Bubl E, Perlov E, Tebartz Van Elst L. Aripiprazole in patients with Tourette syndrome. World Biol J Psychiatry. 2006;7(2):123-125. Caine ED, Polinsky RJ, Kartzinel R, et al. The trial use of clozapine for abnormal involuntary movement disorders. Am J Psychiatry. 1979;136(3):317-320. Dion Y, Annable L, Sabdor P, et al. Risperidone in the treatment of Tourette’s syndrome: a double-blind, placebo-controlled trial. J Clin Psychopharmacol. 2002;22(1):31-39. McCracken JT, Suddath R, Chang S, et al. Effectiveness and tolerability of open label olanzapine in children and adolescents with Tourette’s syndrome. J Child Adolesc Psychopharmacol. 2008;18(5):501-508. Mikkelsen EJ, Detlor J, Cohen DJ. School avoidance and social phobia triggered by haloperidol in patients with Tourette’s disorder. Am J Psychiatry. 1981;138(12):1572-1576. Murphy TK, Bengston MA, Soto O, et al. Case series on the use of aripiprazole for Tourette syndrome. Int J Neuropsychopharmacol. 2005;8(3):489-490. Párraga HC, Párraga M, Woodward R, et al. Quetiapine treatment of children with Tourette’s syndrome: report of two cases. J Child Adolesc Psychopharmacol. 2001;11(2):187-191. Regeur L, Pakkenberg B, Fog R, et al. Clinical features and long-term treatment with pimozide in 65 patients with Gilles de la Tourette’s syndrome. J Neurol Neurosurg Psychiatry. 1986;49(7):791-795. Sallee FR, Kurlan R, Goetz CG, et al. Ziprasidone treatment of children and adolescents with Tourette’s syndrome: a pilot study. J Am Acad Child Adolesc Psychiatry. 2000;39(3):292-299. Sallee FR, Nesbitt L, Jackson C, et al. Relative efficacy of haloperidol and pimozide in children and adolescents with Tourette’s disorder. Am J Psychiatry. 1997;154(8):1057-1062. Scahill L, Leckman JF, Schultz RT, et al. A placebo-controlled trial of risperidone in Tourette syndrome. Neurology. 2003; 60(7):1130-1135. Shapiro AK, Shapiro E, Eisenkraft GJ. Treatment of Tourette’s disorder with penfluridol. Compr Psychiatry. 1983;24(4): 327-331. Shapiro AK, Shapiro E, Wayne HL. Treatment of Tourette’s syndrome with haloperidol: review of 34 cases. Arch Gen Psychiatry. 1973;28(1):92-96. Shapiro AK, Shapiro E, Young JG, et al. Gilles de la Tourette’s syndrome. 2nd ed. New York, NY: Raven Press; 1998:387-390. Stephens RJ, Bassel C, Sandor P. Olanzapine in the treatment of aggression and tics in children with Tourette’s syndrome-a pilot study. J Child Adolesc Psychopharmacol. 2004;14(2):255-266. DELIRIUM Alao AO, Moskowitz L. Aripiprazole and delirium. Ann Clin Psychiatry. 2006;18(4):267-269. Al-Samarrai S, Dunn J, Newmark T, et al. Quetiapine for treatment-resistant delirium. Psychosomatics. 2003;44(4): 350-351. Bourgeois JA, Hilty DM. Prolonged delirium managed with risperidone. Psychosomatics. 2005;46(1):90-91. Breitbart W, Tremblay A, Gibson C. An open trial of olanzapine for the treatment of delirium in hospitalized cancer patients. Psychosomatics. 2002;43(3):175-182. 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(2):419-427. Hans CS, Kim YK. A double-blind trial of risperidone and haloperidol for the treatment of delirium. Psychosomatics. 2004;45(4):297-301. Horikawa N, Yamazaki T, Miyamoto K, et al. Treatment for delirium with risperidone: results of a prospective open trial with 10 patients. Gen Hosp Psychiatry. 2003;25(4):289-292. Hu H, Deng W, Yang H. A prospective random control study comparison of olanzapine and haloperidol in senile delirium [in Chinese]. Chong’qing Medical Journal. 2004;8:1234-1237. 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(11):1966-1973. Leso L, Schwartz TL. Ziprasidone treatment of delirium. Psychosomatics. 2002;43(1):61-62. Parellada E, Baeza I, de Pablo J, et al. Risperidone in the treatment of patients with delirium. J Clin Psychiatry. 2004;65(3):348-353. 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(11):1316-1321. Sipahimalani A, Masand PS. Olanzapine in the treatment of delirium. Psychosomatics. 1998;39(5):422-430. Sipahimalani A, Masand PS. Use of risperidone in delirium: case reports. Ann Clin Psychiatry. 1997;9(2):105-107. Straker DA, Shapiro PA, Muskin PR. Aripiprazole in the treatment of delirium. Psychosomatics. 2006;47(5):385-391. Young CC, Lujan E. Intravenous ziprasidone for treatment of delirium in the intensive care unit. Anesthesiology. 2004;101(3): 794-795. STUTTERING Burr HG, Mullendore JM. Recent investigations on tranquilizers and stuttering. J Speech Hear Disord. 1960;25;33-37. Lavid N, Franklin DL, Maguire GA. Management of child and adolescent stuttering with olanzapine: three case reports. Ann Clin Psychiatry. 1999;11(4):233-236. Tapia F. Haldol in the treatment of children with tics and stutterers and an incidental finding. Behav Neuropsychiatry. 1969;1(3):28. van Wattum PJ. Stuttering improved with risperidone. J Am Acad Child Adolesc Psychiatry. 2006;45(2):133. | |
Current use of antipsychotics
Antipsychotics are divided into 2 major classes—first-generation antipsychotics (FGAs) and SGAs—and principally are FDA-approved for treating schizophrenia. Some antipsychotics have received FDA approval for maintenance treatment of schizophrenia and bipolar disorder (BD), and others have been approved to treat tic disorders (haloperidol and pimozide).
To varying degrees, all antipsychotics block D2 receptors, which is thought to be necessary for treating psychosis. However, some SGAs have significant affinity at other receptors—such as 5-HT2A and 5-HT1A—that confer additional properties that are not fully understood (Table 3). For example, it is believed that 5-HT2A blockade in the striatum reduces the potential for extrapyramidal symptoms (EPS).
Each antipsychotic blocks a unique set of receptors in the brain, leading to a specific set of intended and potentially untoward effects. For example, olanzapine’s effect on psychosis largely stems from its action at the D2 receptor, whereas its sedative and anticholinergic properties are a result of activity at histamine (H1) receptors and muscarinic receptors, respectively. Clinicians can make rational use of unintended effects by carefully selecting a medication based on receptor binding profile (eg, using an antipsychotic with sedating properties in a patient who has psychosis and insomnia). This approach can limit use of multiple medications and maximize a medication’s known effects while attempting to minimize side effects.
Table 3
Antipsychotics: Receptor pharmacology and common side effects
| Antipsychotic | Pharmacology | Common side effectsa |
|---|---|---|
| Prochlorperazinea,b | D2 receptor antagonist and α-1 adrenergic receptor antagonism | EPS, akathisia, prolactinemia, orthostatic hypotension, altered cardiac conduction, agranulocytosis, sexual dysfunction |
| Chlorpromazinea,b | D2 receptor antagonist. Also binds to H1 and cholinergic M1 | EPS, akathisia, prolactinemia, orthostatic hypotension, urinary retention, non-specific QT changes, agranulocytosis, sexual dysfunction |
| Droperidola,b | D2 receptor antagonist and antagonist at peripheral α-1 activity | EPS, akathisia, prolactinemia, orthostatic hypotension, urinary retention, QT changes (dose dependent) |
| Haloperidola,b | D2 receptor antagonist. Also binds to D1, 5-HT2, H1, and α-2 adrenergic receptors | EPS, akathisia, prolactinemia, QT changes (dose dependent) |
| Aripiprazolea,c,d | D2 and 5-HT1A partial agonism, 5-HT2A antagonism | Akathisia, EPS, sedation, restlessness, insomnia, tremor, anxiety, nausea, vomiting, possible weight gain (20% to 30%) |
| Clozapinea,c,e | 5-HT2, D1, D2, D3, D4, M1, H1, α-1, and α-2 antagonism | Sedation, dizziness, tachycardia, weight gain, nausea, vomiting, constipation |
| Olanzapinea,c | 5-HT2A, 5-HT2C, D1, D2, D3, D4, M1-5, H1, and α1- antagonism | Sedation, EPS, prolactinemia, weight gain, constipation |
| Quetiapinea,c,d | D1, D2, 5-HT2A, 5-HT1A, H1, α-1, and α-2 antagonism | Sedation, orthostatic hypotension, weight gain, triglyceride abnormalities, hypertension (frequently diastolic), constipation |
| Risperidonea,c | 5-HT2, D2, H1, α-1, and α-2 antagonism | Sedation, akathisia, EPS, prolactinemia, weight gain, tremor |
| Ziprasidonea,c | D2, D3, 5-HT2A, 5-HT2C, 5-HT1D, and α-1 antagonism; moderate inhibition of 5-HT and NE reuptake; 5-HT1A agonism | EPS, sedation, headache, dizziness, nausea |
| aSide effects and their prominence usually are based on receptor binding profile. All antipsychotics to varying degrees share the following symptoms: EPS, neuroleptic malignant syndrome, QTc prolongation, anticholinergic side effects (urinary retention, decreased gastrointestinal motility, xerostomia), sedation, orthostatic hypotension, blood dyscrasias, and problems with temperature regulation. The class as a whole also carries a “black-box” warning regarding increased mortality when treating geriatric patients with psychosis related to dementia bNo frequencies were available cOnly side effects with frequency >10% listed d”Black-box” warning for suicidal ideation and behavior in children, adolescents, and young adults (age 18 to 24) with major depressive disorder and other psychiatric disorders e”Black-box” warnings for agranulocytosis, myocarditis, orthostatic hypotension, seizure risk EPS: extrapyramidal symptoms; H1: histamine; M1: muscarinic; NE: norepinephrine | ||
Insomnia
Clinicians use FGAs and SGAs to treat insomnia because of their sedating effects, although evidence supporting this use is questionable. Among the FGAs, chlorpromazine produces moderate to severe sedation, whereas haloperidol is only mildly sedating. Clozapine is believed to be the most sedating SGA, whereas quetiapine and olanzapine produce moderate sedation.7
Most data on antipsychotics’ sedating effects comes from studies completed for schizophrenia or BD. Few studies have evaluated using antipsychotics to treat primary insomnia or other sleep disorders in otherwise healthy patients.2 However, data from phase I studies of antipsychotics has shown that schizophrenia patients tolerate a higher maximum dose compared with healthy volunteers, who often experience more sedation.
An antipsychotic’s potential for sedation is directly related to its affinity at H1 receptors and total drug concentration at the H1 receptor binding site. Because drugs with lower affinity for D2 receptors typically are prescribed at higher doses when treating psychiatric illness, the corresponding concentration at H1 receptors can lead to greater sedation compared with equivalent doses of higher-potency agents.
The same phenomenon is seen with high-potency agents. Haloperidol has a relatively weak binding affinity to the H1 receptor,8 but causes more sedation at higher doses. Haloperidol, 20 mg/d, produces sedation in more patients than a moderate dose of risperidone, 2 to 10 mg/d.8 These observations correlate with “the high milligram-low-potency” spectrum seen with FGAs.7
Among SGAs, a double-blind, placebo-controlled, crossover study of the effects of ziprasidone, 40 mg/d, on sleep in a group of healthy volunteers found a significant increase in total sleep time and sleep efficiency.9 A double-blind trial compared patients taking low, medium, or high daily doses of olanzapine with patients receiving haloperidol or placebo.10 Sedation was reported in 20% of patients taking low doses of olanzapine (5 ± 2.5 mg/d) compared with 29.7% on medium doses (10 ± 2.5 mg/d) and 39.1% on high doses (15 ± 2.5 mg/d).10
A double-blind, placebo-controlled, crossover study demonstrated that olanzapine produced significant increases in sleep continuity, slow wave sleep, and subjective ratings of sleep quality in healthy men.11 Similarly, a study comparing haloperidol, 12 mg/d, and quetiapine, 75 to 750 mg/d, for treating acute schizophrenia found an 8% to 11% incidence of somnolence in the quetiapine group compared with 6% and 8% in the haloperidol and placebo groups, respectively.12 Somnolence was reported as an adverse event in these studies, which were designed to examine the drug’s effect on acute schizophrenia and did not evaluate its effect on sleep.
A double-blind, placebo-controlled, crossover study examining quetiapine’s effects on sleep in 14 healthy patients demonstrated a significant difference in total sleep time, sleep period time, and sleep efficiency.13 Similarly, an open-label pilot study of quetiapine’s effect on primary insomnia showed significant improvement in total sleep time and sleep efficiency.14
Studies examining quetiapine’s effects on insomnia in patients with substance abuse15 and women with localized breast cancer16 showed improved sleep scores on multiple assessment tools, while an open-label study of quetiapine for Parkinson’s disease demonstrated decreased sleep latency.17 Adjunctive quetiapine administered over a 6-week, open-label trial in veterans with posttraumatic stress disorder revealed significant improvement from baseline in sleep quality and duration and diminished dreaming.18
Sedating antipsychotics such as thioridazine and chlorpromazine historically were used off-label for insomnia, but fell out of favor because of their associated cardiac risks. More recently, clinicians have been using SGAs in a similar manner19 even though SGAs are costly and have significant risks such as metabolic problems.
Studies supporting the use of SGAs for the short-term or long-term treatment of insomnia are limited by small sample sizes or open-label designs.20 In 2005 the National Institutes of Health State-of-the-Science Conference Panel did not recommend using SGAs for treating chronic insomnia.21
Tics in Tourette’s disorder
FGAs and SGAs have been used to treat tics associated with Tourette’s disorder (TD).22 Haloperidol is FDA-approved for treating tics in adult and pediatric patients with TD. Many studies have reported the efficacy of haloperidol in this population; however, cognitive blunting, weight gain, lethargy, and akathisia limit its use.23
Pimozide, the most widely used alternative to haloperidol for treating TD, can cause clinically significant QTc prolongation and sudden death. Penfluridol demonstrated significant symptomatic improvement compared with haloperidol in 1 study, but its carcinogenic potential limits its use.24
A double-blind, placebo-controlled study comparing fluphenazine and trifluoperazine with haloperidol for treating TD showed that both are significantly more effective than placebo, but none was more effective than the others.25 Studies show chlorpromazine, perphenazine, and thioridazine are less effective than haloperidol and their use is limited by photosensitivity, dermatitis, EPS, and blood and liver dyscrasias.26
Risperidone is superior to placebo for treating tics associated with TD.27 A placebo-controlled trial of ziprasidone showed the drug has efficacy similar to risperidone in reducing tics in children and adolescents with TD.28 However, ziprasidone is not FDA-approved for this use.
Evidence supporting the use of other SGAs for treating TD is more limited. Several small studies of olanzapine and aripiprazole had limited but favorable results. Quetiapine has not been studied for treating TD, but several case reports have indicated a positive response. In a double-blind, placebo-controlled trial, clozapine showed no therapeutic benefit for TD.29
Delirium
American Psychiatric Association practice guidelines suggest using psychotropic medications to treat neuropsychiatric symptoms of delirium.30 Antipsychotics are considered first-line agents that lower hospital mortality rates, decrease lengths of hospital stays, and improve delirium symptoms, in some cases before the underlying medical etiologies resolve.30,31 Available in liquid, oral, IM, and IV formulations, haloperidol is the mainstay of symptomatic treatment of delirium.31 Although not FDA-approved, it is recommended by the Society of Critical Care Medicine as a safe, cost-effective, and efficacious therapy for the psychiatric symptoms associated with delirium.
The most extensively studied SGA for treating delirium, risperidone often is used as an alternative to haloperidol. Case reports describe its potential efficacy.32 In a head-to-head study, risperidone was as effective as low-dose haloperidol for acute delirium treatment.33
Olanzapine was effective in managing delirium in several case studies.34 Also, in a 7-day, randomized, placebo-controlled study, olanzapine and haloperidol showed significantly greater and relatively equivalent improvement compared with placebo; patients treated with olanzapine experienced more rapid improvement in 1 study.35
Case reports and prospective studies also have described quetiapine as effective for treating delirium.36,37 In a prospective, double-blind, placebo-controlled study, patients taking quetiapine had a faster resolution of delirium with reduced overall duration and less agitation than those taking placebo.37 Mortality, intensive care unit length of stay, and incidence of QTc prolongation did not differ, but patients treated with quetiapine were more likely to have increased somnolence and were more frequently discharged to home or rehabilitation centers. One limitation of the study is that concomitant haloperidol use on an “as needed” basis was permitted.38
Evidence supporting the efficacy of ziprasidone for delirium is limited to case reports.39 In 1 case report, a patient with chronic HIV infection and acute cryptococcal meningitis experienced significant improvement of delirium symptoms but could not continue ziprasidone because of fluctuating QTc intervals.40
In 2 patients with delirium, aripiprazole, 15 and 30 mg/d, improved confusion, disorientation, and agitation within 7 days.41 In another study of delirium, 13 of 14 patients on flexibly dosed aripiprazole (5 to 15 mg/d) showed improvement in Clinical Global Impressions Scale scores, although 3 patients developed prolonged QTc intervals.42
Stuttering or stammering
Stuttering or stammering are age-inappropriate disturbances in normal fluency and time patterning of speech. The evidence for antipsychotics to treat stuttering or stammering speech mainly consists of case reports and does not include disfluency frequency data, which makes it difficult to accept claims of efficacy. Disfluency frequency data describe how often a patient has specific disfluencies (blocks, prolongations, interjection, and repetition of syllables, words, or phrases).
Two FGAs (chlorpromazine and haloperidol) and 2 SGAs (risperidone and olanzapine) have been evaluated for treating stuttering. Children were 2.5 times more likely to demonstrate significant improvement when taking chlorpromazine vs placebo.43 An open-label study of haloperidol lacked disfluency frequency data, therefore casting doubts on haloperidol’s reported efficacy in the study.44
In a case report, a 4-year-old boy with severe behavioral dyscontrol showed complete remission of stammering after 1 day of risperidone, 0.25 mg/d.45 The patient’s symptoms reappeared several days after the drug was stopped. In a case series of 2 patients with developmental stuttering, 1 patient reported significant improvement in fluency with olanzapine, 2.5 mg/d, and the other showed marked improvement in fluency with 5 mg/d.46
Related Resources
- Sipahimalani A, Masand PS. Use of risperidone in delirium: case reports. Ann Clin Psychiatry. 1997;9(2):105-107.
- Shapiro AK, Shapiro E, Wayne HL. Treatment of Tourette’s syndrome with haloperidol: review of 34 cases. Arch Gen Psychiatry. 1973;28(1):92-96.
- Sipahimalani A, Masand PS. Olanzapine in the treatment of delirium. Psychosomatics. 1998;39(5):422-430.
Drug Brand Names
- Aripiprazole • Abilify
- Chlorpromazine • Thorazine
- Clozapine • Clozaril
- Fluphenazine • Permitil, Prolixin
- Haloperidol • Haldol
- Olanzapine • Zyprexa
- Perphenazine • Trilafon
- Pimozide • Orap
- Prochlorperazine • Compazine
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Thioridazine • Mellaril
- Trifluoperazine • Stelazine
- Ziprasidone • Geodon
Disclosure
Dr. Macaluso has received grant or research support from EnVivo Pharmaceuticals, Janssen, L.P., and Pfizer, Inc.
Dr. Tripathi reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
1. Alexander GC, Gallagher SA, Mascola A, et al. Increasing off-label use of antipsychotic medications in the United States, 1995-2008. Pharmacoepidemiol Drug Saf. 2011;20(2):177-184.
2. DeMartinis N, Winokur A. Effects of psychiatric medications on sleep and sleep disorders. CNS Neurol Disord Drug Targets. 2007;6(1):17-29.
3. Leckman JF, Bloch MH, Smith ME, et al. Neurobiological substrates of Tourette’s disorder. J Child Adolesc Psychopharmacol. 2010;20(4):237-247.
4. Maldonado JR. Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment. Crit Care Clin. 2008;24(4):789-856.
5. Wu JC, Maguire G, Riley G, et al. Increased dopamine activity associated with stuttering. Neuroreport. 1997;8(3):767-770.
6. Devulapalli K, Nasrallah HA. An analysis of the high psychotropic off-label use in psychiatric disorders: the majority of psychiatric diagnoses have no approved drug. Asian J Psychiatr. 2009;2(1):29-36.
7. Miller DD. Atypical antipsychotics: sleep sedation, and efficacy. Prim Care Companion J Clin Psychiatry. 2004;6(suppl 2):3-7.
8. Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry. 1994;151(6):825-835.
9. Cohrs S, Meier A, Neumann AC, et al. Improved sleep continuity and increased slow wave sleep and REM latency during ziprasidone treatment: a randomized, controlled, crossover trial of 12 healthy male subjects. J Clin Psychiatry. 2005;66(8):989-996.
10. Beasley CM Jr, Tollefson G, Tran P, et al. Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology. 1996;14(2):111-123.
11. Sharpley AL, Vassallo CM, Cowen PJ. Olanzapine increases slow-wave sleep: evidence for blockade of central 5-HT(2C) receptors in vivo. Biol Psychiatry. 2000;47(5):468-470.
12. Arvanitis LA, Miller BG. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry. 1997;42(4):233-246.
13. Cohrs S, Rodenbeck A, Guan Z, et al. Sleep-promoting properties of quetiapine in healthy subjects. Psychopharmacology. 2004;174(3):421-429.
14. Wiegand MH, Landry F, Brückner T, et al. Quetiapine in primary insomnia: a pilot study. Psychopharmacology (Berl). 2008;196(2):337-338.
15. Terán A, Majadas S, Galan J. Quetiapine in the treatment of sleep disturbances associated with addictive conditions: a retrospective study. Subst Use Misuse. 2008;43(14):2169-2171.
16. Pasquini M, Speca A, Biondi M. Quetiapine for tamoxifen-induced insomnia in women with breast cancer. Psychosomatics. 2009;50(2):159-161.
17. Juri C, Chaná P, Tapia J, et al. Quetiapine for insomnia in Parkinson’s disease: results from an open-label trial. Clin Neuropharmacol. 2005;28(4):185-187.
18. Robert S, Hamner MB, Kose S, et al. Quetiapine improves sleep disturbances in combat veterans with PTSD: sleep data from a prospective, open-label study. J Clin Psychopharmacol. 2005;25(4):387-388.
19. Wilson S, Nutt D. Management of insomnia: treatments and mechanisms. Br J Psychiatry. 2007;191:195-197.
20. Morin CM, Benca R. Chronic insomnia. Lancet. 2012;379(9821):1129-1141.
21. National Institutes of Health. National Institutes of Health State of the Science Conference statement on manifestations and management of chronic insomnia in adults June 13-15, 2005. Sleep. 2005;28(9):1049-1057.
22. Párraga HC, Harris KM, Párraga KL, et al. An overview of the treatment of Tourette’s disorder and tics. J Child Adolesc Psychopharmacol. 2010;20(4):249-262.
23. Mikkelsen EJ, Detlor J, Cohen DJ. School avoidance and social phobia triggered by haloperidol in patients with Tourette’s disorder. Am J Psychiatry. 1981;138(12):1572-1576.
24. Shapiro AK, Shapiro E, Eisenkraft GJ. Treatment of Tourette’s disorder with penfluridol. Compr Psychiatry. 1983;24(4):327-331.
25. Borison RL, Ang L, Chang S, et al. New pharmacological approaches in the treatment of Tourette’s syndrome. Adv Neurol. 1982;35:377-382.
26. Shapiro AK, Shapiro E, Young JG, et al. Gilles de la Tourette’s syndrome. 2nd ed. New York, NY: Raven Press; 1998:387–390.
27. Dion Y, Annable L, Sabdor P, et al. Risperidone in the treatment of Tourette’s syndrome: a double-blind, placebo-controlled trial. J Clin Psychopharmacol. 2002;22(1):31-39.
28. Sallee FR, Kurlan R, Goetz CG, et al. Ziprasidone treatment of children and adolescents with Tourette’s syndrome: a pilot study. J Am Acad Child Adolesc Psychiatry. 2000;39(3):292-299.
29. Caine ED, Polinsky RJ, Kartzinel R, et al. The trial use of clozapine for abnormal involuntary movement disorders. Am J Psychiatry. 1979;136(3):317-320.
30. American Psychiatric Association. Practice guideline for the treatment of patients with delirium. Am J Psychiatry. 1999;156(suppl 5):1-20.
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(11):1966-1973.
32. Parellada E, Baeza I, de Pablo J, et al. Risperidone in the treatment of patients with delirium. J Clin Psychiatry. 2004;65(3):348-353.
33. Hans CS, Kim YK. A double-blind trial of risperidone and haloperidol for the treatment of delirium. Psychosomatics. 2004;45(4):297-301.
34. Breitbart W, Tremblay A, Gibson C. An open trial of olanzapine for the treatment of delirium in hospitalized cancer patients. Psychosomatics. 2002;43(3):175-182.
35. Hu H, Deng W, Yang H. A prospective random control study comparison of olanzapine and haloperidol in senile delirium [in Chinese]. Chong’qing Medical Journal. 2004;8:1234-1237.
36. Al-Samarrai S, Dunn J, Newmark T, et al. Quetiapine for treatment-resistant delirium. Psychosomatics. 2003;44(4):350-351.
37. 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(11):1316-1321.
38. 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(2):419-427.
39. Young CC, Lujan E. Intravenous ziprasidone for treatment of delirium in the intensive care unit. Anesthesiology. 2004;101(3):794-795.
40. Leso L, Schwartz TL. Ziprasidone treatment of delirium. Psychosomatics. 2002;43(1):61-62.
41. Alao AO, Moskowitz L. Aripiprazole and delirium. Ann Clin Psychiatry. 2006;18(4):267-269.
42. Straker DA, Shapiro PA, Muskin PR. Aripiprazole in the treatment of delirium. Psychosomatics. 2006;47(5):385-391.
43. Burr HG, Mullendore JM. Recent investigations on tranquilizers and stuttering. J Speech Hear Disord. 1960;25:33-37.
44. Tapia F. Haldol in the treatment of children with tics and stutterers and an incidental finding. Behav Neuropsychiatry. 1969;1(3):28.-
45. van Wattum PJ. Stuttering improved with risperidone. J Am Acad Child Adolesc Psychiatry. 2006;45(2):133.-
46. Lavid N, Franklin DL, Maguire GA. Management of child and adolescent stuttering with olanzapine: three case reports. Ann Clin Psychiatry. 1999;11(4):233-236.
1. Alexander GC, Gallagher SA, Mascola A, et al. Increasing off-label use of antipsychotic medications in the United States, 1995-2008. Pharmacoepidemiol Drug Saf. 2011;20(2):177-184.
2. DeMartinis N, Winokur A. Effects of psychiatric medications on sleep and sleep disorders. CNS Neurol Disord Drug Targets. 2007;6(1):17-29.
3. Leckman JF, Bloch MH, Smith ME, et al. Neurobiological substrates of Tourette’s disorder. J Child Adolesc Psychopharmacol. 2010;20(4):237-247.
4. Maldonado JR. Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment. Crit Care Clin. 2008;24(4):789-856.
5. Wu JC, Maguire G, Riley G, et al. Increased dopamine activity associated with stuttering. Neuroreport. 1997;8(3):767-770.
6. Devulapalli K, Nasrallah HA. An analysis of the high psychotropic off-label use in psychiatric disorders: the majority of psychiatric diagnoses have no approved drug. Asian J Psychiatr. 2009;2(1):29-36.
7. Miller DD. Atypical antipsychotics: sleep sedation, and efficacy. Prim Care Companion J Clin Psychiatry. 2004;6(suppl 2):3-7.
8. Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry. 1994;151(6):825-835.
9. Cohrs S, Meier A, Neumann AC, et al. Improved sleep continuity and increased slow wave sleep and REM latency during ziprasidone treatment: a randomized, controlled, crossover trial of 12 healthy male subjects. J Clin Psychiatry. 2005;66(8):989-996.
10. Beasley CM Jr, Tollefson G, Tran P, et al. Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology. 1996;14(2):111-123.
11. Sharpley AL, Vassallo CM, Cowen PJ. Olanzapine increases slow-wave sleep: evidence for blockade of central 5-HT(2C) receptors in vivo. Biol Psychiatry. 2000;47(5):468-470.
12. Arvanitis LA, Miller BG. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry. 1997;42(4):233-246.
13. Cohrs S, Rodenbeck A, Guan Z, et al. Sleep-promoting properties of quetiapine in healthy subjects. Psychopharmacology. 2004;174(3):421-429.
14. Wiegand MH, Landry F, Brückner T, et al. Quetiapine in primary insomnia: a pilot study. Psychopharmacology (Berl). 2008;196(2):337-338.
15. Terán A, Majadas S, Galan J. Quetiapine in the treatment of sleep disturbances associated with addictive conditions: a retrospective study. Subst Use Misuse. 2008;43(14):2169-2171.
16. Pasquini M, Speca A, Biondi M. Quetiapine for tamoxifen-induced insomnia in women with breast cancer. Psychosomatics. 2009;50(2):159-161.
17. Juri C, Chaná P, Tapia J, et al. Quetiapine for insomnia in Parkinson’s disease: results from an open-label trial. Clin Neuropharmacol. 2005;28(4):185-187.
18. Robert S, Hamner MB, Kose S, et al. Quetiapine improves sleep disturbances in combat veterans with PTSD: sleep data from a prospective, open-label study. J Clin Psychopharmacol. 2005;25(4):387-388.
19. Wilson S, Nutt D. Management of insomnia: treatments and mechanisms. Br J Psychiatry. 2007;191:195-197.
20. Morin CM, Benca R. Chronic insomnia. Lancet. 2012;379(9821):1129-1141.
21. National Institutes of Health. National Institutes of Health State of the Science Conference statement on manifestations and management of chronic insomnia in adults June 13-15, 2005. Sleep. 2005;28(9):1049-1057.
22. Párraga HC, Harris KM, Párraga KL, et al. An overview of the treatment of Tourette’s disorder and tics. J Child Adolesc Psychopharmacol. 2010;20(4):249-262.
23. Mikkelsen EJ, Detlor J, Cohen DJ. School avoidance and social phobia triggered by haloperidol in patients with Tourette’s disorder. Am J Psychiatry. 1981;138(12):1572-1576.
24. Shapiro AK, Shapiro E, Eisenkraft GJ. Treatment of Tourette’s disorder with penfluridol. Compr Psychiatry. 1983;24(4):327-331.
25. Borison RL, Ang L, Chang S, et al. New pharmacological approaches in the treatment of Tourette’s syndrome. Adv Neurol. 1982;35:377-382.
26. Shapiro AK, Shapiro E, Young JG, et al. Gilles de la Tourette’s syndrome. 2nd ed. New York, NY: Raven Press; 1998:387–390.
27. Dion Y, Annable L, Sabdor P, et al. Risperidone in the treatment of Tourette’s syndrome: a double-blind, placebo-controlled trial. J Clin Psychopharmacol. 2002;22(1):31-39.
28. Sallee FR, Kurlan R, Goetz CG, et al. Ziprasidone treatment of children and adolescents with Tourette’s syndrome: a pilot study. J Am Acad Child Adolesc Psychiatry. 2000;39(3):292-299.
29. Caine ED, Polinsky RJ, Kartzinel R, et al. The trial use of clozapine for abnormal involuntary movement disorders. Am J Psychiatry. 1979;136(3):317-320.
30. American Psychiatric Association. Practice guideline for the treatment of patients with delirium. Am J Psychiatry. 1999;156(suppl 5):1-20.
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(11):1966-1973.
32. Parellada E, Baeza I, de Pablo J, et al. Risperidone in the treatment of patients with delirium. J Clin Psychiatry. 2004;65(3):348-353.
33. Hans CS, Kim YK. A double-blind trial of risperidone and haloperidol for the treatment of delirium. Psychosomatics. 2004;45(4):297-301.
34. Breitbart W, Tremblay A, Gibson C. An open trial of olanzapine for the treatment of delirium in hospitalized cancer patients. Psychosomatics. 2002;43(3):175-182.
35. Hu H, Deng W, Yang H. A prospective random control study comparison of olanzapine and haloperidol in senile delirium [in Chinese]. Chong’qing Medical Journal. 2004;8:1234-1237.
36. Al-Samarrai S, Dunn J, Newmark T, et al. Quetiapine for treatment-resistant delirium. Psychosomatics. 2003;44(4):350-351.
37. 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(11):1316-1321.
38. 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(2):419-427.
39. Young CC, Lujan E. Intravenous ziprasidone for treatment of delirium in the intensive care unit. Anesthesiology. 2004;101(3):794-795.
40. Leso L, Schwartz TL. Ziprasidone treatment of delirium. Psychosomatics. 2002;43(1):61-62.
41. Alao AO, Moskowitz L. Aripiprazole and delirium. Ann Clin Psychiatry. 2006;18(4):267-269.
42. Straker DA, Shapiro PA, Muskin PR. Aripiprazole in the treatment of delirium. Psychosomatics. 2006;47(5):385-391.
43. Burr HG, Mullendore JM. Recent investigations on tranquilizers and stuttering. J Speech Hear Disord. 1960;25:33-37.
44. Tapia F. Haldol in the treatment of children with tics and stutterers and an incidental finding. Behav Neuropsychiatry. 1969;1(3):28.-
45. van Wattum PJ. Stuttering improved with risperidone. J Am Acad Child Adolesc Psychiatry. 2006;45(2):133.-
46. Lavid N, Franklin DL, Maguire GA. Management of child and adolescent stuttering with olanzapine: three case reports. Ann Clin Psychiatry. 1999;11(4):233-236.