Evidence-Based Reviews

Antipsychotics for nonpsychotic illness

Current Psychiatry. 2013 February;12(2):22-30

Limited evidence suggests possible efficacy based on known receptor binding affinities

References

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 evidence^a
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.