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Initiate the at a reasonable, not overly high dose, then use a nonantipsychotic to help control , , and agitation

For mass reproduction, content licensing and permissions contact Dowden Health Media. pSYCHIATRY i PSYCHOTICSon edation is a frequent side effect of antipsychot- ics, especially at relatively high doses. Antipsy- S chotics’ effects can reduce agitation in acute and promote in insomnia, but Manage, don’t long-term may: • interfere with patients’ efforts to go accept adverse to work or school or engage in normal socialization • prevent improvement from psychosocial training, psychiatric rehabilitation, and other treatments. ‘calming’ eff ect This article discusses how to manage acute psycho- sis without oversedation and ways to address persistent sedation and chronic insomnia with less-sedating anti- Del D. Miller, PharmD, MD Professor of psychiatry psychotics or adjunctive medications. University of Iowa Carver College of Iowa City Neurobiology or psychopharmacology? Many patients experience only mild, transient som- nolence at the beginning of antipsychotic treatment, and most develop some tolerance to the sedating ef- fects with continued administration. Others may have persistent daytime sedation that interferes with nor- mal functioning. Sedation is especially common in elderly patients re- ceiving . Compared with younger patients, older patients receiving the same doses of the same med- ications become more heavily sedated for longer periods of time. The resulting sedation can impair arousal levels during the day and increase the risk of falls. continued MANLEY MATT Current Psychiatry

2007 Vol. 6, No. 8

© 39 Table 1 Antipsychotics’ potency, dosages, and sedative properties Relative Common dosage Medication potency (mg)* (mg/d) Sedation First-generation antipsychotics

Chlorpromazine 100.0 300 to 600 Moderate Sedation 1.0 to 2.0 4 to 20 Mild 2.0 5 to 20 Mild

Second-generation antipsychotics

Aripiprazole 7.5 15 to 30 Mild 50.0 250 to 500 Marked 4.0 15 to 30 Moderate 80.0 300 to 800 Moderate 1.0 2 to 6 Mild 20.0 80 to 160 Mild Clinical Point * Approximate dose equivalent to 100 mg of Source: Data from reference 9. Choose the initial antipsychotic for Sedation can occur with fi rst-generation Effi cacy and sedation its eff ectiveness, antipsychotics (FGAs) and second-genera- Antipsychotics are thought to exert their rather than relying tion antipsychotics (SGAs), but it is seen effect by antagonism of postsynaptic do- on its side eff ects more commonly and tends to be more pamine D2 and 5HT2A receptors to control disease severe with low-potency FGAs than with and possibly other receptors in the brain. SGAs. Clinical challenges come with: Four SGAs—risperidone, olanzapine, que- manifestations • distinguishing between sedation and tiapine, and ziprasidone—act as negative symptoms of schizophrenia such D2 and 5HT2A antagonists. as avolition, amotivation, withdrawal, and is a dopamine D2 partial , sero- anhedonia tonin 5HT1A partial agonist, and serotonin • determining whether an individual’s 5HT2A antagonist.1 Effi cacy data compar- cognitive impairment is related to the anti- ing SGAs with each other and with FGAs psychotic’s sedative properties. vary, but all 5 of these SGAs have been Because the treatments are different, it shown to be effective antipsychotics.2-4 is important to try to distinguish negative They also generally cause less sedation symptoms and/or cognitive impairment than FGAs. related to schizophrenia’s neurobiology Patients with acute exacerbation of psy- from sedation related to the antipsychotic. chosis often have insomnia and frequently Ask patients if they nap during the day report paranoia that “something” will or just lie around, and if they want to do happen to them while they sleep. When things but can’t: treating agitated patients, many clinicians • If they want to do things but feel too consider calming effects and true antipsy- tired, this likely is sedation caused by the chotic effects to be one in the same, which antipsychotic. Treatment might be a dose is not correct. All available antipsychotics reduction. are, on average, equally effective in treat- • If they are not interested in doing ing acute psychotic symptoms but vary things, the likely cause is negative symp- considerably in the amount of sedation toms. Treatment might be a medication such they produce. Studies of short-acting in- as a selective serotonin inhibitor. jectable SGAs, such as ziprasidone and ar- • If they want to do things but can- ipiprazole, have shown that agitation and not organize themselves to be able to do acute symptoms can be controlled without them, this likely is cognitive impairment. signifi cant sedation.5,6 Treatment might be cognitive training or Antipsychotic effects are not immedi- Current Psychiatry 40 August 2007 remediation. ate and historically were thought to occur continued on page 43 continued from page 40 Table 2 Antipsychotics’ sedative eff ects by the numbers: pSYCHIATRY

Equilibrium dissociation constants at brain receptors* CurrentPsychiatry.com Receptors

Dopamine D2 Serotonin 5-HT2A H1 FGA

Haloperidol 2.60 61.00 260.0

SGAs

Aripiprazole 0.34 3.40 61.00 Clozapine 210.00 2.60 3.10 Olanzapine 20.00 1.50 0.10 Risperidone 3.80 0.15 5.20 Quetiapine 770.00 31.00 19.00 Ziprasidone 2.60 0.12 4.60

* Lower numbers are equivalent to higher receptor binding affi nity. Each antipsychotic’s sedative effect is determined by histamine H1 affi nity and the amount of that reaches H1 receptors in the CNS—which in turn is affected by the agent’s dosage and dopamine Clinical Point D2 receptor affi nity. FGA: fi rst-generation antipsychotic; SGAs: second-generation antipsychotics The combination Source: References 1,14,15 of H1 affi nity and over several weeks. Recent meta-analyses is in remission may support adherence the amount of suggest, however, that some antipsychot- and improve outcomes. drug reaching ic effects are evident within the fi rst week the histamine H1 7,8 of treatment. To avoid overmedication, Dosages and sedation. Not all FGAs have receptors determines therefore, it’s important to separate calm- the same sedative effect, nor do all SGAs ing effects from antipsychotic effects. (Table 1, page 40).9 In general, the high-mil- the sedative eff ect ligram, low-potency FGAs—such as chlor- Recommendations. Choose the initial —produce more sedation than antipsychotic based on its effective- the low-milligram, high-potency FGAs— ness in treating the underlying disease, such as haloperidol and fl uphenazine.9 rather than relying on side effects—such This principle tends to hold true for the as sedation—to control disease manifes- SGAs as well. For example, the high-po- tations. Without sedation, patients are tency, low-dose SGA risperidone is less se- better able to engage in therapy; partici- dating than the lower-potency, high-dose pate in family, social, school, and work SGAs quetiapine and clozapine. activities; and increase their chances of Dose does not always determine seda- recovery. tion, however. Olanzapine, which is com- Initiate the antipsychotic at or titrate to a monly dosed at 15 to 30 mg/d, is more reasonable, not overly high dose—such as: sedating than ziprasidone, for which the • olanzapine, 10 to 20 mg/d usual range is 80 to 160 mg/d.3,10-12 • risperidone, 3 to 6 mg/d • ziprasidone, 100 to 140 mg/d • quetiapine, 400 to 600 mg/d Mechanism and sedation • aripiprazole, 15 mg/d. The mechanisms of antipsychotics’ thera- Continue the patient on that dose, and peutic and sedative properties appear to be use a nonantipsychotic such as a benzodi- different.13 The degree of sedation shows azepine to help control insomnia, anxiety, little relationship with the various anti- and agitation. Two to 4 weeks is generally psychotics’ potency at the dopamine D2 adequate, but some patients may need the receptor, which suggests that dopamine adjunctive therapy for several months. If D2 receptor antagonism is not involved in you initiate a more sedating antipsychotic causing sedation. acutely, switching to a less sedating agent Instead, the degree of sedation may be Current Psychiatry when the patient is stable and the illness associated with each antipsychotic’s affi nity Vol. 6, No. 8 43 Table 3 Normal sleep architecture, Sleep patterns in mental illness which can be disordered Sleep disturbances—including changes in in schizophrenia sleep patterns, insomnia, and excessive sleeping—occur frequently in patients Nonrapid eye movement (NREM) sleep with psychiatric disorders. The sleep pro- Stage 1 Drowsiness; represents transition cess itself (Table 3) is disrupted in patients Sedation between waking and sleeping with schizophrenia. Stage 2 Sleep deepens A study that examined sleep patterns in 40 patients with schizophrenia found lon- Stages 3 Deepest levels of NREM sleep; and 4 subjects are most diffi cult to ger sleep latency, more frequent arousals, arouse (slow-wave or delta sleep) and increased periods of wakefulness after sleep onset compared with controls with- Rapid eye movement (REM) sleep out a psychiatric disorder. Ratings of sleep Vivid dreams; pulse and respiration rates are higher and more variable than during effi ciency—ratio of sleep time to time in NREM sleep bed—were: Clinical Point During the second half of the night, slow-wave sleep • 95% in the control group decreases compared with the fi rst half of the night, but REM • 78% in antipsychotic-naïve patients Patients with sleep periods become more frequent and prolonged. disturbances may with schizophrenia • 72% in patients with chronic schizo- feel more rested for the , which is high- phrenia.15 after awakening ly variable (Table 2, page 43).1,14,15 In general: A study of sleep in 19 patients with schizo- because SGAs have • agents that are more potent histamine phrenia and 13 nonpsychiatric controls16 potential to improve H1 antagonists—such as olanzapine and found individuals with schizophrenia clozapine14—produce more sedation had: sleep quality • agents that are weaker H1 antago- • increased duration of stage 1 sleep nists—such as risperidone, ziprasi- • decreased duration of stages 3 and 4 done, and aripiprazole—produce less (slow-wave) sleep sedation. • 83% total sleep effi ciency, compared Although dosage and affi nity for hista- with 95% in nonpsychiatric controls. mine H1 receptors play important roles in Because of these differences in sleep the sedative effect of a medication, what patterns, patients with schizophrenia often ultimately determines sedative effect is the experience inadequate sleep. combination of histamine H1 affi nity and the amount of drug reaching the histamine Antipsychotic eff ects on sleep patterns. H1 receptors in the CNS. Your choice of an antipsychotic also can For example, the SGA quetiapine— affect the patient’s sleep. In a study of which has moderate affi nity for hista- sleep measures in patients with schizo- mine H1 receptors14—also has relatively phrenia treated with risperidone or halo- low affi nity for dopamine D2 receptors. peridol, Yamashita et al17 reported a sig- Higher dosages of quetiapine are there- nificant difference in the time each group fore required to produce antipsychotic spent in slow-wave sleep (27% with effects compared with other SGAs—such risperidone vs 20% with haloperidol). as risperidone, ziprasidone, and aripip- The authors suggested that risperidone razole—that have higher affi nities for the might lengthen the amount of slow-wave dopamine D2 receptors. sleep because of its higher affinity for se- Because of higher dosing, higher rotonin 5-HT2 receptors compared with amounts of quetiapine are assumed to be haloperidol. reaching the histamine H1 receptors in the Salin-Pascual et al18 found that olanzap- CNS. This is why quetiapine causes more ine improved total sleep time and sleep sedation in clinical use than does risperi- effi cacy, reduced stage 1 sleep, and signifi - done, even though risperidone has greater cantly enhanced stage 2 and slow-wave Current Psychiatry 44 August 2007 affi nity for the histamine H1 receptor. (delta) sleep. Figure Managing sedation in patients with schizophrenia pSYCHIATRY

CurrentPsychiatry.com Persistent sedation

Give most of antipsychotic dose at bedtime

If clinically indicated, Review medications for reduce or eliminate other sedative agents offending medication(s)

Consider reducing Gradually reduce dosage antipsychotic dosage with close monitoring

Clinical Point Consider switching to less sedating antipsychotic -type (such as aripiprazole or could ziprasidone) worsen psychosis, so their use in

Consider adding modafi nil Consider adding a patients with persistent sedation

Monitor closely is controversial for worsening psychosis

Serotonin 5-HT2 receptors have been re- Review the patient’s medication list to ported to be involved in controlling sleep determine if other potentially sedating quality.19 Similar to risperidone and olan- medications can be reduced or eliminat- zapine, the other SGAs also have a higher ed. Psychotropics that can cause sedation affi nity than haloperidol for serotonin include: 5-HT2 receptors (Table 2, page 43). Thus, • such as the although antipsychotics’ sedative effects and may adversely affect patients, SGAs may • mood stabilizers (particularly valproic have the potential to improve sleep quality acid, but also , lithium, in individuals with schizophrenia. SGAs and ). increase slow-wave sleep, and patients feel Also consider gradually reducing the more rested after awakening. patient’s antipsychotic dose, and closely monitor for worsening of psychosis. If sedation persists despite these inter- Managing excessive sedation ventions, consider switching the patient Take steps to minimize bothersome se- to a less sedating antipsychotic such as dation in patients taking antipsychotics ziprasidone or aripiprazole. If these ef- (Figure). To reduce daytime sedation, in- forts also are ineffective, or off- struct the patient to take all or most of the label —75 to 100 mg once in antipsychotic dose at bedtime. Also rule the morning or up to twice daily—might out medical conditions that can produce help the patient feel more alert. Many pa- fatigue and sedation, such as hypothyroid- tients taking antipsychotics drink several ism, obstructive sleep apnea (OSA), and cups of coffee every morning to feel less Current Psychiatry . sedated. Vol. 6, No. 8 45 continued Table 4 psychotics.22 A later double-blind, placebo- to treat insomnia controlled trial by Sevy et al23 found that in patients with schizophrenia modafi nil and placebo were associated with similar, signifi cant improvement in Common bedtime fatigue over time. Narendran24 reported a Medication dose range* case in which modafi nil might have exac- erbated psychosis in a patient with schizo- Sedation 1 to 2 mg phrenia who was taking 200 mg qid. 15 to 30 mg 7.5 to 30 mg 0.125 to 0.25 mg Managing chronic insomnia Schizophrenia patients with chronic in- 2 to 3 mg somnia usually require education about 5 to 10 mg appropriate sleep habits, combined with 5 to 10 mg additional treatments. Zolpidem CR 6.25 to 12.5 mg

Clinical Point receptor agonist Sleep hygiene. Instruct patients to: Caff eine might help 8 mg • Wake up at the same time every day, regardless of when they went to sleep. the patient feel more H1 • Maintain a consistent bedtime. alert; many patients Diphenhydramine 25 to 50 mg • Exercise regularly, preferably in the 50 to 100 mg taking antipsychotics late afternoon but not within 2 to 4 drink several cups of Antidepressants hours of bedtime. coff ee every morning Mirtazapine 15 to 30 mg • Perform relaxing activities before bed. 50 to 200 mg • Keep the bedroom quiet and cool * No dosage adjustment is required in this patient population (extreme temperatures compromise sleep). • Do not watch the clock at night. Stimulants. A consensus guideline on • Avoid caffeine and for at least treating schizophrenia20 recommends pre- 6 hours before bedtime. scribing amphetamine-related stimulants • Drink only in moderation, and for patients who are persistently sedated, avoid use for at least 4 hours before but this practice is highly controversial. bedtime. Many stimulants increase dopamine re- • Avoid napping; it may interfere with lease in the CNS, which theoretically can the ability to fall asleep at night. worsen psychosis. A clinician could be held liable for the actions of patients medi- Medications. The consensus guideline on cated with stimulants. treating schizophrenia20 offers the option of Modafi nil is a nonamphetamine CNS switching the patient with chronic insomnia stimulant approved for use in disorders of to one of the more sedating antipsychotics, excessive sleep such as narcolepsy, OSA, such as olanzapine, quetiapine, or clozap- shift work sleep disorder, and fatigue re- ine. Sedation alone should not be the reason lated to multiple sclerosis. Its mechanism to switch to clozapine, however. of action in promoting wakefulness in You could consider adding a bedtime these disorders is not fully understood; it sedative to the patient’s medications (Table may activate projections in 4). FDA-approved sedatives include non- the frontal cortex from the tuberomammil- benzodiazepines such as zolpidem, zolpi- lary nucleus, which plays a major role in dem extended-release, zaleplon, or eszopi- maintaining wakefulness.21 clone, and the agonist Modafi nil, 200 mg in the morning, has ramelteon. Although not approved as seda- been reported to reduce total sleep time tives, some antidepressants such as trazo- without adverse effects in 3 patients ex- done or mirtazapine and antihistamines Current Psychiatry 46 August 2007 periencing sedation associated with anti- such as diphenhydramine and hydroxyzine continued on page 51 continued from page 46 are used to promote sleep. Benzodiazepines Related Resources can be helpful but require caution when pSYCHIATRY prescribed to patients with comorbid sub- • Miller DD. Atypical antipsychotics: sleep, sedation, and effi cacy. Prim Care Companion J Clin Psychiatry 2004;6(suppl CurrentPsychiatry.com stance abuse disorders. 2):3-7. Sedatives have been studied extensively • Benca RM, Diagnosis and treatment of chronic insomnia: a in general populations with insomnia but review. Psychiatr Serv 2005;56(3):332-43. not in patients receiving antipsychotics. Drug Brand Names Combining antipsychotics and sedatives can Aripiprazole • Abilify Mirtazapine • Remeron Bupropion • Wellbutrin Modafi nil • Provigil produce daytime drowsiness and sedation. Carbamazepine • Tegretol Olanzapine • Zyprexa Chlorpromazine • Thorazine Quetiapine • Seroquel References Clozapine • Clozaril Ramelteon • Rozerem 1. McQuade R, Burris KD, Jordan S, et al. Aripiprazole: a Diphenhydramine • Risperidone • Risperdal dopamine-serotonin system stabilizer [abstract no. P.3.W.080]. Estazolam • ProSom Temazepam • Restoril Int J Neuropsychopharmacol, 2002;5(suppl 1):S176. Eszopiclone • Lunesta Trazodone • Desyrel 2. Davis JM, Chen N, Glick ID. A meta-analysis of the effi cacy Fluphenazine • Prolixin Triazolam • Halcion of second-generation antipsychotics. Arch Gen Psychiatry Flurazepam • Dalmane Valproic acid • Depakote 2003;60(6):553-64. Haloperidol • Haldol Zaleplon • Sonata 3. Gardner DM, Baldessarini RJ, Waraich P. Modern Hydroxyzine • Vistaril, Atarax Ziprasidone • Geodon antipsychotic : a critical overview. Can Med Assoc J Lamotrigine • Lamictal Zolpidem • Ambien, 2005;172(13):1703-11. Ambien CR Clinical Point 4. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Disclosure Engl J Med 2005;353(12):1209-23. When used to Dr. Miller receives research support from Pfi zer Inc. and has 5. Andrezina R, Josiassen RC, Marcus RN, et al. Intramuscular manage insomnia, aripiprazole for the treatment of acute agitation in patients received honoraria from AstraZeneca, Bristol-Myers Squibb, with schizophrenia or schizoaffective disorder: a double- Janssen Pharmaceutica, and Pfi zer Inc. adding sedatives blind, placebo-controlled comparison with intramuscular haloperidol. Psychopharmacol (Berl) 2006;188(3):281-92. to antipsychotic 6. Brook S, Lucey JV, Gunn KP. Intramuscular ziprasidone compared with intramuscular haloperidol in the treatment therapy can result in of acute psychosis. Ziprasidone I.M. Study Group. J Clin 16. Benson KL, Zarcone VP Jr. Rapid eye movement sleep eye Psychiatry 2000;61(12):933-41. movements in schizophrenia and depression. Arch Gen daytime drowsiness 7. Agid O, Kapur S, Arenovich T, Zipursky RB. Delayed-onset Psychiatry 1993;50(6):474-82. hypothesis of antipsychotic action: a hypothesis tested and 17. Yamashita H, Morinobu S, Yamawaki S, et al. Effect of and sedation rejected. Arch Gen Psychiatry 2003;60(12):1228-35. risperidone on sleep in schizophrenia: a comparison with 8. Leucht S, Busch R, Hamann J, et al. Early-onset hypothesis of haloperidol. Psychiatry Res 2002;109(2):137-42. antipsychotic drug action: a hypothesis tested, confi rmed and 18. Salin-Pascual RJ, Herrera-Estrella M, Galicia-Polo L, extended. Biol Psychiatry 2005;57(12):1543-9. Laurrabaquio MR. Olanzapine acute administration in 9. Jibson MD, Tandon, R. An overview of antipsychotic schizophrenic patients increases delta sleep and sleep medications. CNS News 2001;3:49-54. effi ciency. Biol Psychiatry 1999;46(1):141-3. 10. Collaborative Working Group on Evaluations. 19. Idzikowski C, Mills FJ, Glennard R. 5-Hydroxytryptamine- Treatment of special populations with the atypical 2 antagonist increases human slow wave sleep. Brain Res antipsychotics. J Clin Psychiatry 1998;59(suppl 12):46-52. 1986;378(1):164-8. 11. El-Sayeh HG, Morganti C. Aripiprazole for schizophrenia. 20. Expert Consensus Guideline Series. Treatment of Cochrane Database Syst Rev 2004(2):CD004578. schizophrenia. J Clin Psychiatry 1999;60(suppl 11):1-80. 12. Tandon R, Jibson MD. Effi cacy of newer generation 21. Scammell TE, Estabrooke IV, McCarthy MT, et al. antipsychotics in the treatment of schizophrenia. Hypothalamic arousal regions are activated during modafi nil- Psychoneuroendocrinol 2003;28(suppl 1):9-26. induced wakefulness. J Neurosci 2000;20(22):8620-8. 13. Tandon R. Safety and tolerability: how do newer generation 22. Makela EH, Miller K, Cutlip WD 2nd. Three case reports of ”atypical” antipsychotics compare? Psychiatr Q 2002;73(4):297- modafi nil use in treating sedation induced by antipsychotic 311. medications. J Clin Psychiatry 2003;64(4):485-6. 14. Richelson E, Souder T. Binding of antipsychotic drugs to 23. Sevy S, Rosenthal MH, Alvir J, et al. Double-blind, placebo- human brain receptors focus on newer generation compounds. controlled study of modafi nil for fatigue and cognition in Life Sci 2000;68(1):29-39. schizophrenia patients treated with psychotropic medications. 15. Tandon R, Shipley JE, Taylor S, et al. Electroencephalographic J Clin Psychiatry 2005;66(7):839-43. sleep abnormalities in schizophrenia. Relationship to positive/ 24. Narendran R, Young CM, Valenti AM, et al. Is psychosis negative symptoms and prior neuroleptic treatment. Arch Gen exacerbated by modafi nil? Arch Gen Psychiatry Psychiatry 1992;49(3):185-94. 2002;59(3):292-3.

Bottom Line All antipsychotics are eff ective in reducing psychotic symptoms but vary in degree of sedation. For persistent sedation, consider nighttime dosing, rule out other sedating drugs or conditions, or switch antipsychotics. Consider adding a stimulant or modafi nil, but monitor for worsening psychosis. For persistent insomnia, provide Current Psychiatry sleep hygiene education and consider adding a bedtime sedative. Vol. 6, No. 8 51