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Evidence-Based Reviews

Antipsychotics for nonpsychotic illness

Limited evidence suggests possible efficacy based on known receptor binding affinities

Vol. 12, No. 02 / February 2013

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


Possible rationale


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


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


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


Strength of evidencea


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


Intermediate: Haloperidol

Weak: Olanzapine quetiapine risperidone

Very weak: Aripiprazole ziprasidone


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



Common side effectsa


D2 receptor antagonist and α-1 adrenergic receptor antagonism

EPS, akathisia, prolactinemia, orthostatic hypotension, altered cardiac conduction, agranulocytosis, sexual dysfunction


D2 receptor antagonist. Also binds to H1 and cholinergic M1

EPS, akathisia, prolactinemia, orthostatic hypotension, urinary retention, non-specific QT changes, agranulocytosis, sexual dysfunction


D2 receptor antagonist and antagonist at peripheral α-1 activity

EPS, akathisia, prolactinemia, orthostatic hypotension, urinary retention, QT changes (dose dependent)


D2 receptor antagonist. Also binds to D1, 5-HT2, H1, and α-2 adrenergic receptors

EPS, akathisia, prolactinemia, QT changes (dose dependent)


D2 and 5-HT1A partial agonism, 5-HT2A antagonism

Akathisia, EPS, sedation, restlessness, insomnia, tremor, anxiety, nausea, vomiting, possible weight gain (20% to 30%)


5-HT2, D1, D2, D3, D4, M1, H1, α-1, and α-2 antagonism

Sedation, dizziness, tachycardia, weight gain, nausea, vomiting, constipation


5-HT2A, 5-HT2C, D1, D2, D3, D4, M1-5, H1, and α1- antagonism

Sedation, EPS, prolactinemia, weight gain, constipation


D1, D2, 5-HT2A, 5-HT1A, H1, α-1, and α-2 antagonism

Sedation, orthostatic hypotension, weight gain, triglyceride abnormalities, hypertension (frequently diastolic), constipation


5-HT2, D2, H1, α-1, and α-2 antagonism

Sedation, akathisia, EPS, prolactinemia, weight gain, tremor


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


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

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