Antipsychotic Drug-Induced Somnolence: Incidence, Mechanisms, and Management

Abstract

Somnolence is a common side effect of antipsychotics. To assess the incidence of this side effect, we performed a MEDLINE search for randomized, double-blinded, placebo- or active-controlled studies of adult patients treated with antipsychotics for schizophrenia, mania, bipolar depression, or bipolar disorder. We extracted rates of somnolence from original publications and pooled them based on the dose of each antipsychotic in the same psychiatric condition, then estimated the absolute risk increase (ARI) and the number needed to harm (NNH) of an antipsychotic relative to placebo or an active comparator in the same psychiatric condition. According to the ARI in acute schizophrenia, bipolar mania, and bipolar depression, antipsychotics can be classified as high somnolence (clozapine), moderate somnolence (olanzapine, perphenazine, quetiapine, risperidone, ziprasidone), and low somnolence (aripiprazole, asenapine, haloperidol, lurasidone, paliperidone, cariprazine). The risk of somnolence with blonanserin, brexpiprazole, chlorpromazine, iloperidone, sertindole, and zotepine needs further investigation. The rates of somnolence were positively correlated to dose and duration for some antipsychotics, but not for others. Many factors, including antipsychotic per se, the method used to measure somnolence, patient population, study design, and dosing schedule, might affect the incidence of antipsychotic-induced somnolence. The mechanisms of antipsychotic-induced somnolence are likely multifactorial, although the blockade of histamine 1 receptors and α1 receptors may play a major role. The management of antipsychotic-induced somnolence should include sleep hygiene education, choosing an antipsychotic with a lower risk for somnolence, starting at a lower dose with a slower titration based on psychiatric diagnoses, adjusting doses when necessary, and minimizing concurrent somnolence-prone agents. Since most cases of somnolence were mild to moderate, allowing tolerance to develop over at least 4 weeks is reasonable before discontinuing an antipsychotic.

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References

  1. 1.

    Gao K, Ganocy SJ, Gajwani P, Muzina DJ, Kemp DE, Calabrese JR. A review of sensitivity and tolerability of antipsychotics in patients with bipolar disorder or schizophrenia: focus on somnolence. J Clin Psychiatry. 2008;69:302–9.

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Gao K, Kemp DE, Fein E, Wang Z, Fang Y, Ganocy SJ, et al. Number needed to treat to harm for discontinuation due to adverse events in the treatment of bipolar depression, major depressive disorder, and generalized anxiety disorder with atypical antipsychotics. J Clin Psychiatry. 2011;72:1063–71.

    PubMed  Article  Google Scholar 

  3. 3.

    Gao K, Yuan C, Wu R, Chen J, Wang Z, Fang Y, et al. Important clinical features of atypical antipsychotics in acute bipolar depression that inform routine clinical care: a review of pivotal studies with number needed to treat. Neurosci Bull. 2015;31(5):572–88.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Wang Z, Kemp DE, Chan PK, Fang Y, Ganocy SJ, Calabrese JR, et al. Comparisons of the tolerability and sensitivity of quetiapine-XR in the acute treatment of schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder. Int J Neuropsychopharmacol. 2011;14(1):131–42.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Food and Drug Administration Center for Drug Evaluation and Research (CDER). Review guidance: conducting a clinical safety review of a new product application and preparing a report on the review. Good Review Practices, 2005. Rockville: Food and Drug Administration; 2005.

  6. 6.

    Cooper SJ, Tweed J, Raniwalla J, Butler A, Welch C. A placebo-controlled comparison of zotepine versus chlorpromazine in patients with acute exacerbation of schizophrenia. Acta Psychiatr Scand. 2000;101:218–25.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    van Kammen DP, McEvoy JP, Targum SD, Kardatzke D, Sebree TB. A randomized, controlled, dose-ranging trial of sertindole in patients with schizophrenia. Psychopharmacol (Berl). 1996;124:168–75.

    Article  Google Scholar 

  8. 8.

    Cooper SJ, Butler A, Tweed J, Welch C, Raniwalla J. Zotepine in the prevention of recurrence: a randomised, double-blind, placebo-controlled study for chronic schizophrenia. Psychopharmacol (Berl). 2000;150:237–43.

    CAS  Article  Google Scholar 

  9. 9.

    Garcia E, Robert M, Peris F, Nakamura H, Sato N, Terazawa Y. The efficacy and safety of blonanserin compared with haloperidol in acute-phase schizophrenia a randomized, double-blind, placebo-controlled, multicentre study. CNS Drugs. 2009;23:615–25.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Zimbroff DL, Kane JM, Tamminga CA, Daniel DG, Mack RJ, Wozniak PJ, et al. Controlled, dose-response study of sertindole and haloperidol in the treatment of schizophrenia, Sertindole Study Group. Am J Psychiatry. 1997;154:782–91.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Citrome L, Meng X, Hochfeld M, Stahl SM. Efficacy of iloperidone in the short-term treatment of schizophrenia: a post hoc analysis of pooled patient data from four phase III, placebo and active-controlled trials. Hum Psychopharmacol Clin Exp. 2012;27:24–32.

    CAS  Article  Google Scholar 

  12. 12.

    Durgam S, Starace A, Li D, Migliore R, Ruth A, Németh G, et al. An evaluation of the safety and efficacy of cariprazine in patients with acute exacerbation of schizophrenia: a phase II, randomized clinical trial. Schizophr Res. 2014;152(2–3):450–7.

    PubMed  Article  Google Scholar 

  13. 13.

    Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito GG, Zimbroff DL, et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry. 2002;63:763–71.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Potkin SG, Saha AR, Kujawa MJ, Carson WH, Ali M, Stock E, et al. Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry. 2003;60:681–90.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    McEvoy JP, Daniel DG, Carson WH Jr, McQuade RD, Marcus RN. A randomized, double-blind, placebo-controlled, study of the efficacy and safety of aripiprazole 10, 15 or 20 mg/day for the treatment of patients with acute exacerbations of schizophrenia. J Psychiatr Res. 2007;41:895–905.

    PubMed  Article  Google Scholar 

  16. 16.

    Potkin SG, Cohen M, Panagides J. Efficacy and tolerability of asenapine in acute schizophrenia: a placebo- and risperidone-controlled trial. J Clin Psychiatry. 2007;68:1492–500.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Kane JM, Cohen M, Zhao J, Alphs L, Panagides J. Efficacy and safety of asenapine in a placebo- and haloperidol-controlled trial in patients with acute exacerbation of schizophrenia. J Clin Psychopharmacol. 2010;30:106–15.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Kane JM, Skuban A, Ouyang J, Hobart M, Pfister S, McQuade RD, et al. A multicenter, randomized, double-blind, controlled phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophrenia. Schizophr Res. 2015;164:127–35.

    PubMed  Article  Google Scholar 

  19. 19.

    Correll CU, Skuban A, Ouyang J, Hobart M, Pfister S, McQuade RD, et al. Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 2015;172(9):870–80.

    PubMed  Article  Google Scholar 

  20. 20.

    Beasley CM Jr, Tollefson G, Tran P, Satterlee W, Sanger T, Hamilton S. Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology. 1996;14:111–23.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    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;42:233–46.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Shen JH, Zhao Y, Rosenzweig-Lipson S, Popp D, Williams JB, Giller E, et al. A 6-week randomized, double-blind, placebo-controlled, comparator referenced trial of vabicaserin in acute schizophrenia. J Psychiatr Res. 2014;53:14–22.

    PubMed  Article  Google Scholar 

  23. 23.

    Nakamura M, Ogasa M, Guarino J, Phillips D, Severs J, Cucchiaro J, et al. Lurasidone in the treatment of acute schizophrenia: a double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70:829–36.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Meltzer HY, Cucchiaro J, Silva R, Ogasa M, Phillips D, Xu J, et al. Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and olanzapine-controlled study. Am J Psychiatry. 2011;168:957–67.

    PubMed  Article  Google Scholar 

  25. 25.

    Nasrallah HA, Silva R, Phillips D, Cucchiaro J, Hsu J, Xu J, et al. Lurasidone for the treatment of acutely psychotic patients with schizophrenia: a 6-week, randomized, placebo-controlled study. J Psychiatr Res. 2013;47:670–7.

    PubMed  Article  Google Scholar 

  26. 26.

    Loebel A, Cucchiaro J, Sarma K, Xu L, Hsu C, Kalali AH, et al. Efficacy and safety of lurasidone 80 mg/day and 160 mg/day in the treatment of schizophrenia: a randomized, double-blind, placebo- and active-controlled trial. Schizophr Res. 2013;145:101–9.

    PubMed  Article  Google Scholar 

  27. 27.

    Ogasa M, Kimura T, Nakamura M, Guarino J. Lurasidone in the treatment of schizophrenia: a 6-week, placebo-controlled study. Psychopharmacol (Berl). 2013;225:519–30.

    CAS  Article  Google Scholar 

  28. 28.

    Beasley CM Jr, Sanger T, Satterlee W, Tollefson G, Tran P, Hamilton S. Olanzapine HGAP Study Group. Olanzapine versus placebo: results of a double-blind, fixed-dose olanzapine trial. Psychopharmacology. 1996;124:159–67.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Davidson M, Emsley R, Kramer M, Ford L, Pan G, Lim P, et al. Efficacy, safety and early response of paliperidone extended-release tablets (paliperidone ER): results of a 6-week, randomized, placebo-controlled study. Schizophr Res. 2007;93:117–30.

    PubMed  Article  Google Scholar 

  30. 30.

    Kane J, Canas F, Kramer M, Ford L, Gassmann-Mayer C, Lim P, et al. Treatment of schizophrenia with paliperidone extended-release tablets: a 6-week placebo-controlled trial. Schizophr Res. 2007;90:147–61.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Marder SR, Kramer M, Ford L, Eerdekens E, Lim P, Eerdekens M, et al. Efficacy and safety of paliperidone extended-release tablets: results of a 6-week, randomized, placebo-controlled study. Biol Psychiatry. 2007;62:1363–70.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Canuso CM, Dirks B, Carothers J, Kosik-Gonzalez C, Bossie CA, Zhu Y, et al. Randomized, double-blind, placebo-controlled study of paliperidone extended-release and quetiapine in inpatients with recently exacerbated schizophrenia. Am J Psychiatry. 2009;166:691–701.

    PubMed  Article  Google Scholar 

  33. 33.

    Small JG, Hirsch SR, Arvanitis LA, Miller BG, Link CG. Quetiapine in patients with schizophrenia. A high- and low-dose double-blind comparison with placebo. Seroquel Study Group. Arch Gen Psychiatry. 1997;54:549–57.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Potkin SG, Gharabawi GM, Greenspan AJ, Mahmoud R, Kosik-Gonzalez C, Rupnow MF, et al. A double-blind comparison of risperidone, quetiapine and placebo in patients with schizophrenia experiencing an acute exacerbation requiring hospitalization. Schizophr Res. 2006;85:254–65.

    PubMed  Article  Google Scholar 

  35. 35.

    Kahn RS, Schulz SC, Palazov VD, Reyes EB, Brecher M, Svensson O, et al. Efficacy and tolerability of once-daily extended release quetiapine fumarate in acute schizophrenia: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2007;68:832–42.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Lindenmayer JP, Brown D, Liu S, Brecher M, Meulien D. The efficacy and tolerability of once-daily extended release quetiapine fumarate in hospitalized patients with acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled study. Psychopharmacol Bull. 2008;41:11–35.

    PubMed  Google Scholar 

  37. 37.

    Keck P Jr, Buffenstein A, Ferguson J, Feighner J, Jaffe W, Harrigan EP, et al. Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 4-week placebo-controlled trial. Psychopharmacol (Berl). 1998;140:173–84.

    CAS  Article  Google Scholar 

  38. 38.

    Cutler AJ, Kalali AH, Weiden PJ, Hamilton J, Wolfgang CD. Four-week, double-blind, placebo- and ziprasidone-controlled trial of iloperidone in patients with acute exacerbations of schizophrenia. J Clin Psychopharmacol. 2008;2(8):S20–8.

    Article  CAS  Google Scholar 

  39. 39.

    Daniel DG, Zimbroff DL, Potkin SG, Reeves KR, Harrigan EP, Lakshminarayanan M. Ziprasidone 80 mg/day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebo-controlled trial. Ziprasidone Study Group. Neuropsychopharmacology. 1999;20:491–505.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Pigott TA, Carson WH, Saha AR, Torbeyns AF, Stock EG, Ingenito GG. Aripiprazole for the prevention of relapse in stabilized patients with chronic schizophrenia: a placebo-controlled 26-week study. J Clin Psychiatry. 2003;64:1048–56.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Kane JM, Mackle M, Snow-Adami L, Zhao J, Szegedi A, Panagides J. A randomized placebo-controlled trial of asenapine for the prevention of relapse of schizophrenia after long-term treatment. J Clin Psychiatry. 2011;72:349–55.

    PubMed  Article  Google Scholar 

  42. 42.

    Bondolfi G, Dufour H, Patris M, May JP, Billeter U, Eap CB, et al. Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. The Risperidone Study Group. Am J Psychiatry. 1998;155(4):499–504.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Azorin JM, Spiegel R, Remington G, Vanelle JM, Péré JJ, Giguere M, et al. A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia. Am J Psychiatry. 2001;158(8):1305–13.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Zhong KX, Sweitzer DE, Hamer RM, Lieberman JA. A double-blind comparison of risperidone, quetiapine and placebo in patients with schizophrenia experiencing an acute exacerbation requiring hospitalization. Schizophr Res. 2006;85(1–3):254–65.

    Google Scholar 

  45. 45.

    Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209–23.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, Bertoldi A, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003;60(1):82–9.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Keck PE Jr, Marcus R, Tourkodimitris S, Ali M, Liebeskind A, Saha A, et al. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry. 2003;160:1651–8.

    PubMed  Article  Google Scholar 

  48. 48.

    Sachs G, Sanchez R, Marcus R, Stock E, McQuade R, Carson W, et al. Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study. J Psychopharmacol. 2006;20:536–46.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    McIntyre RS, Cohen M, Zhao J, Alphs L, Macek TA, Panagides J. A 3-week, randomized, placebo-controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states. Bipolar Disord. 2009;11:673–86.

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    McIntyre RS, Cohen M, Zhao J, Alphs L, Macek TA, Panagides J. Asenapine in the treatment of acute mania in bipolar I disorder: a randomized, double-blind, placebo-controlled trial. J Affect Disord. 2010;122:27–38.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Sachs GS, Greenberg WM, Starace A, Lu K, Ruth A, Laszlovszky I, et al. Cariprazine in the treatment of acute mania in bipolar I disorder: a double-blind, placebo-controlled, phase III trial. J Affect Disord. 2015;174:296–302.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Smulevich AB, Khanna S, Eerdekens M, Karcher K, Kramer M, Grossman F. Acute and continuation risperidone monotherapy in bipolar mania: a 3-week placebo-controlled trial followed by a 9-week double-blind trial of risperidone and haloperidol. Eur Neuropsychopharmacol. 2005;15:75–84.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Katagiri H, Takita Y, Tohen M, Higuchi T, Kanba S, Takahashi M. Efficacy and safety of olanzapine in the treatment of Japanese patients with bipolar I disorder in a current manic or mixed episode: a randomized, double-blind, placebo- and haloperidol-controlled study. J Affect Disord. 2012;136:476–84.

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Vieta E, Ramey T, Keller D, English PA, Loebel AD, Miceli J. Ziprasidone in the treatment of acute mania: a 12-week, placebo-controlled, haloperidol-referenced study. J Psychopharmacol. 2010;24:547–58.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    McIntyre RS, Brecher M, Paulsson B, Huizar K, Mullen J. Quetiapine or haloperidol as monotherapy for bipolar mania: a 12-week, double-blind, randomised, parallel-group, placebo-controlled trial. Eur Neuropsychopharmacol. 2005;15:573–85.

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Tohen M, Sanger TM, McElroy SL, Tollefson GD, Chengappa KN, Daniel DG, et al. Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group. Am J Psychiatry. 1999;156:702–9.

    CAS  PubMed  Google Scholar 

  57. 57.

    Tohen M, Jacobs TG, Grundy SL, McElroy SL, Banov MC, Janicak PG, et al. Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. The Olanzipine HGGW Study Group. Arch Gen Psychiatry. 2000;57:841–9.

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Tohen M, Vieta E, Goodwin GM, Sun B, Amsterdam JD, Banov M, et al. Olanzapine versus divalproex versus placebo in the treatment of mild to moderate mania: a randomized, 12-week, double-blind study. J Clin Psychiatry. 2008;69:1776–89.

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Vieta E, Nuamah IF, Lim P, Yuen EC, Palumbo JM, Hough DW, et al. A randomized, placebo- and active-controlled study of paliperidone extended release for the treatment of acute manic and mixed episodes of bipolar I disorder. Bipolar Disord. 2010;12(3):230–43.

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Vieta E, Mullen J, Brecher M, Paulsson B, Jones M. Quetiapine monotherapy for mania associated with bipolar disorder: combined analysis of two international, double-blind, randomised, placebo-controlled studies. Curr Med Res Opin. 2005;21:923–34.

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Cutler AJ, Datto C, Nordenhem A, Minkwitz M, Acevedo L, Darko D. Extended-release quetiapine as monotherapy for the treatment of adults with acute mania: a randomized, double-blind, 3-week trial. Clin Ther. 2011;33:1643–58.

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Hirschfeld RM, Keck PE Jr, Kramer M, Karcher K, Canuso C, Eerdekens M, et al. Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, double-blind, placebo-controlled trial. Am J Psychiatry. 2004;161:1057–65.

    PubMed  Article  Google Scholar 

  63. 63.

    Keck PE Jr, Versiani M, Potkin S, West SA, Giller E, Ice K. Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Am J Psychiatry. 2003;160(4):741–8.

    PubMed  Article  Google Scholar 

  64. 64.

    Potkin SG, Keck PE Jr, Segal S, Ice K, English P. Ziprasidone in acute bipolar mania: a 21-day randomized, double-blind, placebo-controlled replication trial. J Clin Psychopharmacol. 2005;25:301–10.

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Vieta E, Ramey T, Keller D, English PA, Loebel AD, Miceli J. Ziprasidone in the treatment of acute mania: a 12-week, placebo-controlled, haloperidol-referenced study. J Psychopharmacol. 2010;24(4):547–58.

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Keck PE Jr, Calabrese JR, McQuade RD, Carson WH, Carlson BX, Rollin LM, et al. A randomized, double-blind, placebo-controlled 26-week trial of aripiprazole in recently manic patients with bipolar I disorder. J Clin Psychiatry. 2006;67:626–37.

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Vieta E, Montgomery S, Sulaiman AH, Cordoba R, Huberlant B, Martinez L, et al. A randomized, double-blind, placebo-controlled trial to assess prevention of mood episodes with risperidone long-acting injectable in patients with bipolar I disorder. Eur Neuropsychopharmacol. 2012;22:825–35.

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    Tohen M, Calabrese JR, Sachs GS, Banov MD, Detke HC, Risser R, et al. Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine. Am J Psychiatry. 2006;163:247–56.

    PubMed  Article  Google Scholar 

  69. 69.

    Berwaerts J, Melkote R, Nuamah I, Lim P. A randomized, placebo- and active-controlled study of paliperidone extended-release as maintenance treatment in patients with bipolar I disorder after an acute manic or mixed episode. J Affect Disord. 2012;138(3):247–58.

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Weisler RH, Nolen WA, Neijber A, Hellqvist A, Paulsson B, Trial 144 Study Investigators. Continuation of quetiapine versus switching to placebo or lithium for maintenance treatment of bipolar I disorder (Trial 144: a randomized controlled study). J Clin Psychiatry. 2011;72:1452–64.

    PubMed  Article  Google Scholar 

  71. 71.

    Tohen M, Goldberg JF, Gonzalez-Pinto Arrillaga AM, Azorin JM, Vieta E, Hardy-Bayle MC, Lawson WB, et al. A 12-week, double-blind comparison of olanzapine vs haloperidol in the treatment of acute mania. Arch Gen Psychiatry. 2003;60(12):1218–26.

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Thase ME, Jonas A, Khan A, Bowden CL, Wu X, McQuade RD, et al. Aripiprazole monotherapy in non-psychotic bipolar I depression results of 2 randomized, placebo-controlled studies. J Clin Psychopharmacol. 2008;28:13–20.

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Durgam S, Earley W, Lipschitz A, Guo H, Laszlovszky I, Németh G, Vieta E, Calabrese JR, Yatham LN. An 8-week randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of cariprazine in patients with bipolar I depression. Am J Psychiatry. 2015:appiajp201515020164 (Epub ahead of print).

  74. 74.

    Loebel A, Cucchiaro J, Silva R, Kroger H, Hsu J, Sarma K, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171:160–8.

    PubMed  Article  Google Scholar 

  75. 75.

    Tohen M, Vieta E, Calabrese J, Ketter TA, Sachs G, Bowden C, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60(11):1079–88.

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Tohen M, McDonnell DP, Case M, Kanba S, Ha K, Fang YR, et al. Randomised, double-blind, placebo-controlled study of olanzapine in patients with bipolar I depression. Br J Psychiatry. 2012;201:376–82.

    PubMed  Article  Google Scholar 

  77. 77.

    Calabrese JR, Keck PE Jr, Macfadden W, Minkwitz M, Ketter TA, Weisler RH, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162:1351–60.

    PubMed  Article  Google Scholar 

  78. 78.

    Thase ME, Macfadden W, Weisler RH, Chang W, Paulsson B, Khan A, et al. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study). J Clin Psychopharmacol. 2006;26:600–9.

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    McElroy SL, Weisler RH, Chang W, Olausson B, Paulsson B, Brecher M, et al. A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II). J Clin Psychiatry. 2010;71:163–74.

    CAS  PubMed  Article  Google Scholar 

  80. 80.

    Young AH, McElroy SL, Bauer M, Philips N, Chang W, Olausson B, et al. A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). J Clin Psychiatry. 2010;71:150–62.

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Suppes T, Datto C, Minkwitz M, Nordenhem A, Walker C, Darko D. Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression. J Affect Disord. 2010;121:106–15.

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Gao K, Pappadopulos E, Karayal ON, Kolluri S, Calabrese JR. Risk for adverse events and discontinuation due to adverse events of ziprasidone monotherapy relative to placebo in the acute treatment of bipolar depression, mania, and schizophrenia. J Clin Psychopharmacol. 2013;33:425–31.

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Young AH, McElroy SL, Olausson B, Paulsson B. A randomised, placebo-controlled 52-week trial of continued quetiapine treatment in recently depressed patients with bipolar I and bipolar II disorder. World J Biol Psychiatry. 2014;15:96–112.

    PubMed  Article  Google Scholar 

  84. 84.

    Loebel AD, Siu CO, Cucchiaro JB, Pikalov AA, Harvey PD. Daytime sleepiness associated with lurasidone and quetiapine XR: results from a randomized double-blind, placebo-controlled trial in patients with schizophrenia. CNS Spectr. 2014;19(2):197–205.

    PubMed  Article  Google Scholar 

  85. 85.

    Datta S, Maclean RR. Neurobiological mechanisms for the regulation of mammalian sleep-wake behavior: reinterpretation of historical evidence and inclusion of contemporary cellular and molecular evidence. Neurosci Biobehav Rev. 2007;31:775–824.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011;34:845–58.

    PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Uchida H, Takeuchi H, Graff-Guerrero A, Suzuki T, Watanabe K, Mamo DC. Dopamine D2 receptor occupancy and clinical effects: a systematic review and pooled analysis. J Clin Psychopharmacol. 2011;31:497–502.

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Matsui-Sakata A, Ohtani H, Sawada Y. Pharmacokinetic-pharmacodynamic analysis of antipsychotics-induced extrapyramidal symptoms based on receptor occupancy theory incorporating endogenous dopamine release. Drug Metab Pharmacokinet. 2005;20:187–99.

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Tashiro M, Duan X, Kato M, Miyake M, Watanuki S, Ishikawa Y, et al. Brain histamine H1 receptor occupancy of orally administered antihistamines, bepotastine and diphenhydramine, measured by PET with 11C-doxepin. Br J Clin Pharmacol. 2008;65(6):811–21.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Bigott-Hennkens HM, Dannoon S, Lewis MR, Jurisson SS. In vitro receptor binding assays: general methods and considerations. Q J Nucl Med Mol Imaging. 2008;52(3):245–53.

    CAS  PubMed  Google Scholar 

  91. 91.

    Sekine Y, Rikihisa T, Ogata H, Echizen H, Arakawa Y. Correlations between in vitro affinity of antipsychotics to various central neurotransmitter receptors and clinical incidence of their adverse drug reactions. Eur J Clin Pharmacol. 1999;55(8):583–7.

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P, et al. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology. 2003;28(3):519–26.

    CAS  PubMed  Article  Google Scholar 

  93. 93.

    Shahid M, Walker GB, Zorn SH, Wong EH. Asenapine: a novel psychopharmacologic agent with a unique human receptor signature. J Psychopharmacol. 2009;23:65–73.

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Ishibashi T, Horisawa T, Tokuda K, Ishiyama T, Ogasa M, Tagashira R, et al. Pharmacological profile of lurasidone, a novel antipsychotic agent with potent 5-hydroxytryptamine 7 (5-HT7) and 5-HT1A receptor activity. J Pharmacol Exp Ther. 2010;334:171–81.

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Church DS, Church MK. Pharmacology of antihistamines. World Allergy Organ J. 2011;4(3 Suppl):S22–7.

    PubMed  PubMed Central  Google Scholar 

  96. 96.

    Sagalés T, Erill S. Effects of central dopaminergic blockade with primozide upon the EEG stages of sleep in man. Psychopharmacologia. 1975;41(1):53–6.

    PubMed  Article  Google Scholar 

  97. 97.

    Monti JM. Serotonin control of sleep-wake behavior. Sleep Med Rev. 2011;15:269–81.

    PubMed  Article  Google Scholar 

  98. 98.

    van Laar M, Volkerts E, VerbatenM. Subchronic effects of the GABA-agonist lorazepam and the 5-HT2A/2C antagonist ritanserin on driving performance, slow wave sleep and daytime sleepiness in healthy volunteers. Psychopharmacology (Berl) 2001;154:189–97.

  99. 99.

    Berridge CW, Schmeichel BE, España RA. Noradrenergic modulation of wakefulness/arousal. Sleep Med Rev. 2012;16:187–97.

    PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    Berridge CW, España RA. Synergistic sedative effects of noradrenergic alpha(1)- and beta-receptor blockade on forebrain electroencephalographic and behavioral indices. Neuroscience. 2000;99:495–505.

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Yeomans JS. Muscarinic receptors in brain stem and mesopontine cholinergic arousal functions. Handb Exp Pharmacol. 2012;208:243–59.

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Wu Y, Blichowski M, Daskalakis ZJ, Wu Z, Liu CC, Cortez MA, et al. Evidence that clozapine directly interacts on the GABAB receptor. Neuroreport. 2011;22:637–41.

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Yamamura S, Ohoyama K, Hamaguchi T, Nakagawa M, Suzuki D, Matsumoto T, et al. Effects of zotepine on extracellular levels of monoamine, GABA and glutamate in rat prefrontal cortex. Br J Pharmacol. 2009;157:656–65.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Mori K, Kim J, Sasaki K. Electrophysiological effects of orexin-B and dopamine on rat nucleus accumbens shell neurons in vitro. Peptides. 2011;32:246–52.

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Liem-Moolenaar M, Rad M, Zamuner S, Cohen AF, Lemme F, Franson KL, et al. Central nervous system effects of the interaction between risperidone (single dose) and the 5-HT6 antagonist SB742457 (repeated doses) in healthy men. Br J Clin Pharmacol. 2011;71(6):907–16.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Gao K, Wang Z, Chen J, Kemp DE, Chan PK, Conroy CM, et al. Should an assessment of Axis I comorbidity be included in the initial diagnostic assessment of mood disorders? Role of QIDS-16-SR total score in predicting number of Axis I comorbidity. J Affect Disord. 2013;148(2–3):256–64.

    PubMed  Article  Google Scholar 

  107. 107.

    Kemp DE, Gao K, Chan P, Ganocy SJ, Findling RL, Calabrese JR. Mecial Comorbidity in bipolar disorder: relationship between illnesses of the endocrine/metabolic system and treament outcome. Bipolar Disord. 2010;12:404–13.

    PubMed  PubMed Central  Article  Google Scholar 

  108. 108.

    Casey DA, Rodriguez M, Northcott C, Vickar G, Shihabuddin L. Schizophrenia: medical illness, mortality, and aging. Int J Psychiatry Med. 2011;41(3):245–51.

    PubMed  Article  Google Scholar 

  109. 109.

    Gao K, Mackle M, Cazorla P, Zhao J, Szegedi A. Comparison of somnolence associated with asenapine, olanzapine, risperidone, and haloperidol relative to placebo in patients with schizophrenia or bipolar disorder. Neuropsychiatr Dis Treat. 2013;9:1145–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Lohr JB, Liu L, Caligiuri MP, Kash TP, May TA, Murphy JD, et al. Modafinil improves antipsychotic-induced parkinsonism but not excessive daytime sleepiness, psychiatric symptoms or cognition in schizophrenia and schizoaffective disorder: a randomized, double-blind, placebo-controlled study. Schizophr Res. 2013;150:289–96.

    PubMed  Article  Google Scholar 

  111. 111.

    Andrade C, Kisely S, Monteiro I, Rao S. Antipsychotic augmentation with modafinil or armodafinil for negative symptoms of schizophrenia: systematic review and meta-analysis of randomized controlled trials. J Psychiatr Res. 2015;60:14–21.

    PubMed  Article  Google Scholar 

  112. 112.

    Lindenmayer JP, Nasrallah H, Pucci M, James S, Citrome L. A systematic review of psychostimulant treatment of negative symptoms of schizophrenia: challenges and therapeutic opportunities. Schizophr Res. 2013;147:241–52.

    PubMed  Article  Google Scholar 

  113. 113.

    Saavedra-Velez C, Yusim A, Anbarasan D, Lindenmayer JP. Modafinil as an adjunctive treatment of sedation, negative symptoms, and cognition in schizophrenia: a critical review. J Clin Psychiatry. 2009;70:104–12.

    CAS  PubMed  Article  Google Scholar 

  114. 114.

    Freudenreich O, Henderson DC, Macklin EA, Evins AE, Fan X, Cather C, et al. Modafinil for clozapine-treated schizophrenia patients: a double-blind, placebo-controlled pilot trial. J Clin Psychiatry. 2009;70:1674–80.

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Lasser RA, Dirks B, Nasrallah H, Kirsch C, Gao J, Pucci ML, et al. Adjunctive lisdexamfetamine dimesylate therapy in adult outpatients with predominant negative symptoms of schizophrenia: open-label and randomized-withdrawal phases. Neuropsychopharmacology. 2013;38:2140–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Gao K, Wu R, Grunze H, Calabrese JR. Phamarcological treatment of acute bipolar depression. In: Yildiz A, Ruiz P, Nemeroff C, editors. Bipolar book: history, neurobiology, and treatment. New York: Oxford University Press; 2015. p. 281–98.

    Google Scholar 

  117. 117.

    Dell’Osso B, Ketter TA. Use of adjunctive stimulants in adult bipolar depression. Int J Neuropsychopharmacol. 2013;16(1):55–68.

    PubMed  Article  CAS  Google Scholar 

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Acknowledgments

The authors express their gratitude to Mrs. Mary Beth Serrano, MA, a research manager in the Mood Disorders Program of University Hospitals Case Medical Center/Case Western Reserve University for her proofreading of the manuscript.

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Correspondence to Zuowei Wang or Keming Gao.

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No sources of funding were used to conduct this study or prepare this manuscript.

Conflict of interest

Dr. Calabrese has received lecture honoraria thorough speaking engagements from AstraZeneca, Benecke, CME Outfitters, Dainippon Sumitomo Pharma, Elan, Forest, Health & Wellness Partners, Lundbeck, Medwiz, Otsuka, ProMedica, Spirant Communication Private Limited, Sunovion, Takeda, Teva, and Wenckebach Institute, American Foundation Suicide Prevention, University of Florida, and Western Psychiatric Institute. He has acted as consultant to Biomedical Development Corporation, Convergent Health Solutions, Dainippon Sumitomo Pharma, Elan, Forest, Health and Wellness Partners, Lilly, Lundbeck, Otsuka, Scientia, Takeda, and Teva. He has received research support from the US National Institutes of Health (NIH). Dr. Gao has received grant support from AstraZeneca, the Brain and Behavior Research Foundation, and the Cleveland Foundation and has been on a speakers’ bureau for Sunovion. Dr. Wang has received grant support from the National Natural Science Foundation of China (grant number 81301159); Shanghai Key Medicine Specialties Program (grant number ZK2012A12); and the Training Plan for Excellent Academic Leaders of Shanghai Health System (grant number XBR2013087). Drs. Fang, Sun, and Ren have no conflicts of interest to disclose.

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F. Fang and H. Sun contributed equally.

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Fang, F., Sun, H., Wang, Z. et al. Antipsychotic Drug-Induced Somnolence: Incidence, Mechanisms, and Management. CNS Drugs 30, 845–867 (2016). https://doi.org/10.1007/s40263-016-0352-5

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Keywords

  • Risperidone
  • Olanzapine
  • Quetiapine
  • Aripiprazole
  • Modafinil