CNS Drugs

, Volume 30, Issue 9, pp 845–867 | Cite as

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

Review Article

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.

Keywords

Risperidone Olanzapine Quetiapine Aripiprazole Modafinil 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Key Points

With the exception of paliperidone, all antipsychotics caused significantly higher rates of somnolence relative to placebo in schizophrenia and/or bipolar disorder, although the magnitude of differences between active treatments and placebo varied widely.

Based on studies in schizophrenia, bipolar mania, and bipolar depression, antipsychotics can be divided into at least three groups: high somnolence (clozapine), moderate somnolence (olanzapine, perphenazine, quetiapine, risperidone, ziprasidone), and low somnolence (aripiprazole, asenapine, haloperidol, lurasidone, paliperidone, and cariprazine).

Overall, patients with schizophrenia were less likely to report experiencing somnolence than patients with bipolar disorder. However, the majority of antipsychotics used in schizophrenia were studied with fixed dosing schedules, which are more likely to cause side effect(s) than a flexible dosing schedule.

Blockade of histamine 1 receptors and α1 receptors is more likely than other mechanisms to be related to antipsychotic-induced somnolence.

Educating patients about healthy sleep hygiene, choosing an antipsychotic with a lower risk for somnolence, starting with a low dose and slow titration, avoiding concurrent somnolence-prone medication, and waiting for the development of tolerance are strategies for reducing the severity of somnolence and the risk for discontinuation due to somnolence.

Using an antipsychotic with a higher risk for somnolence and starting at a higher dose with faster titration may be necessary for patients with acute psychosis, mania, agitation and/or insomnia.

1 Introduction

Somnolence is a common side effect of antipsychotics. This side effect may be beneficial to patients with acute psychosis, mania, agitation, or insomnia; however, it can be harmful to patients who cannot tolerate it. Severe somnolence, especially in outpatient settings, can lead to accidents, loss of employment, failure at school, interpersonal problems, and/or neglect of self or others. Our previous systematic reviews on sensitivity to and tolerability of antipsychotics in different psychiatric conditions found that somnolence was one of the most common side effects causing premature discontinuation during the acute treatment of bipolar depression, major depressive disorder, and generalized anxiety disorder [1, 2, 3], but that antipsychotics did not have a significantly higher rate of premature discontinuation due to somnolence relative to placebo in acute schizophrenia or mania [1, 2].

The rates of somnolence vary widely among the antipsychotics, and the relative risk for somnolence of each individual antipsychotic also differed in different psychiatric conditions [1, 2, 3, 4]. Knowing the risks for antipsychotic-induced somnolence in different psychiatric conditions and how to manage these risks is essential to reduce premature discontinuation and non-adherence, to avoid accident(s), and to improve patients’ quality of life. In this review, we focus on the incidence, mechanism, and management of antipsychotic-induced somnolence. Since only quetiapine-extended release (XR) has been studied in major depressive disorder and generalized anxiety disorder as monotherapy [2], we prioritized studies of antipsychotics in schizophrenia, bipolar mania, and bipolar depression.

2 Methods

2.1 Incidence

We initially searched the English-language literature published from January 1966 to December 2015 cited in MEDLINE using combinations of “antipsychotic” plus “schizophrenia”, “bipolar mania”, or “bipolar depression” plus “placebo-or active controlled” plus “somnolence or sedation” plus “trial”. We focused a second search on atypical antipsychotics with combinations of “atypical antipsychotic”, “clozapine (Clozaril)”, “olanzapine (Zyprexa)”, “risperidone (Risperdal)”, “paliperidone (Invega)”, “quetiapine (Seroquel)”, “ziprasidone (Geodon)”, “aripiprazole (Abilify)”, “iloperidone (Fanapt)”, “asenapine (Saphris)”, “lurasidone (Latuda)”, “cariprazine”, “amisulpride”, “blonanserin”, “carpipramine”, “melperone”, “perospirone”, “sertindole”, or “zotepine” plus “schizophrenia”, “bipolar depression”, “mania”, or “bipolar disorder” plus “placebo- or active-controlled”, and plus “trial”. We also conducted a manual search through the lists of references in identified publications.

Studies that met the following criteria were carefully reviewed for inclusion in our analysis: (1) adult patients (aged 18–65 or ≥18 years) enrolled in a study of the acute or maintenance treatment of schizophrenia, acute mania, acute bipolar depression, or bipolar disorder; (2) randomized, double-blind, placebo- or active-controlled design; (3) investigating any antipsychotic monotherapy; and (4) including data on self-reported somnolence. We included studies of oral drug administration with either immediate release (IR) or extended release (ER or XR) formulations but excluded studies of intramuscular injection or adjunctive therapy to a mood stabilizer(s). Somnolence was not a primary outcome in any studies published thus far. As a study with a small sample size would be more likely to produce unreliable results than one with a large sample size, we included only antipsychotics with a cumulative sample size of around ≥100 patients in each arm for analysis. We also excluded antipsychotics with limited clinical application worldwide, such as iloperidone and sertindole.

According to the US FDA, somnolence, drowsiness, sedation, and sleepiness are all terms that likely refer to the same event [5]. However, during a clinical trial, a patient can report experiencing somnolence, sedation, drowsiness, sleepiness, and/or other related side effects. Some studies group all these events into one category—somnolence—but others separate somnolence from sedation. For this review, we used studies with self-reported somnolence for comparison; for studies with both somnolence and sedation data, we only used the somnolence data. However, we excluded studies with sedation data alone.

To compare the difference between an antipsychotic and its placebo control or an active comparator, we extracted rates of somnolence from different studies and pooled them based on the doses of each antipsychotic in the same psychiatric condition. We estimated the absolute risk increase (ARI) and the number needed to harm (NNH) of an antipsychotic relative to placebo/active comparator. The type I error rate for significance tests between antipsychotics and their controls was set at α = 0.05 (two-tailed). The ARI and NNH were presented with mean and 95 % confidence interval (CIs) to reflect the magnitude of variance. For an antipsychotic versus placebo or an antipsychotic versus an active comparison, statistical significance was declared when a CI did not include zero. We hypothesized that all antipsychotics caused more incidences of somnolence than their controls; therefore, a positive value indicated ARI and NNH and a negative value indicated a decrease in risk and a benefit relative to the control.

2.2 Mechanism

For the mechanisms of antipsychotic-induced somnolence (see Sect. 3), we review the neurobiology and neurochemistry of wakefulness and sleep and then compare the pharmacological profiles of some commonly used antipsychotics. Neurotransmitters and their receptors that are potentially involved in antipsychotic-induced somnolence are discussed with an emphasis on interactions among them.

2.3 Management

For the management of antipsychotic-induced somnolence (see Sect. 4), we propose strategies based on the incidence of antipsychotic-induced somnolence in different psychiatric conditions, acute versus long-term treatment, lower versus higher doses, and potential neurochemicals involved in the wake–sleep cycle. Results from previous studies related to this topic are integrated. We discuss the importance of education on sleep hygiene.

3 Incidence of Antipsychotic-Induced Somnolence

3.1 Incidence of Antipsychotic-Induced Somnolence in Schizophrenia

3.1.1 Acute and Maintenance Active Treatment Versus Placebo

Our search identified 36 randomized, double-blinded, placebo-controlled studies of antipsychotics in the acute or maintenance treatment of schizophrenia. The rates of somnolence induced by blonanserin, chlorpromazine, iloperidone, sertindole, and zotepine relative to placebo were not compared because of their limited applications worldwide or small sample sizes [6, 7, 8, 9, 10, 11]. The study of cariprazine only reported sedation, so this study was also excluded [12].

In the acute treatment of schizophrenia with the remaining antipsychotics [11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39] (Table 1), the magnitude of difference in rates of somnolence between an antipsychotic and placebo varied widely from insignificant differences relative to placebo (aripiprazole, brexpiprazole, and paliperidone) to significant differences (asenapine, haloperidol, lurasidone, olanzapine, quetiapine-IR or XR, risperidone, and ziprasidone). Among the antipsychotics with significant differences, risperidone had the smallest ARI of 4.5 % and the largest NNH of 22, and olanzapine had the largest ARI of 11.1 % and the smallest NNH of 9 (Table 1).
Table 1

Incidence, absolute risk increase, and number needed to harm of antipsychotic-induced somnolence of active treatment versus placebo in schizophrenia

Agents and trials

Treatment arms

Duration (weeks)

Reported somnolence

Total N

No. (%) of cases

ARIa,b (95 % CI)

NNHa,b (95 % CI)

Acute treatment of schizophrenia

 Aripiprazole [15]

Aripiprazole 10 mg/d

6

105

7 (6.7)

1.1 (−5.9, ∞, 8.2)

94 (12, ∞, −17)

PL

107

6 (6.6)

 Aripiprazole [13, 15]

Aripiprazole 15 mg/d

4–6

207

17 (8.2)

3.5 (−1.4, ∞, 8.5)

29 (12, ∞, −74)

PL

211

10 (4.7)

 Aripiprazole [14, 15]

Aripiprazole 20 mg/d

4–6

199

14 (7.0)

−1.1 (−6.4, ∞, 4.3)

−94 (23, ∞, −16)

PL

210

17 (8.1)

 Aripiprazole [13]

Aripiprazole 30 mg/d

4

101

10 (9.9)

6.1 (−1.1, ∞, 13.8)

17 (7, ∞, −90)

PL

104

4 (3.9)

 Aripiprazole [ 13, 14 ]

Aripiprazole 10–30 mg/d

4–6

712

67 (9.4)

2.7 (1.1, ∞, 6.0)

37 (17, ∞,89)

PL

314

21 (6.7)

 Asenapine [16, 17]

Asenapine 10 mg/d

6

170

21 (12.4)

7.5 (1.7–13.7)

13 (7–60)

PL

185

9 (4.9)

 Asenapine [17]

Asenapine 20 mg/d

6

106

8 (7.6)

6.7 (1.6–13.4)

15 (7–64)

PL

123

1 (0.8)

 Asenapine [ 16, 17 ]

Asenapine 10–20 mg/d

6

276

29 (10.5)

5.6 (0.5–10.4)

18 (10–204)

PL

185

9 (4.9)

 Brexpiprazole [19]

Brexpiprazole 0.25 mg/d

6

90

0 (0)

−2.7 (−6.2, ∞, 1.7)

−37 (60, ∞, −16)

PL

184

5 (2.7)

 Brexpiprazole [18]

Brexpiprazole 1 mg/d

6

120

2 (1.7)

−1.1 (−4.7, ∞, 3.4)

−95 (29, ∞, −21)

PL

184

5 (2.7)

 Brexpiprazole [18, 19]

Brexpiprazole 2 mg/d

6

368

6 (1.6)

−1.1 (−3.5, ∞, 1.2)

−92 (86, ∞, −29)

PL

368

10 (2.7)

 Brexpiprazole [18, 19]

Brexpiprazole 4 mg/d

6

364

12 (3.3)

−0.6 (−2.0, ∞, 3.3)

173 (31, ∞, −49)

PL

368

10 (2.7)

 Brexpiprazole [ 18, 19 ]

Brexpiprazole 0.25–4 mg/d

6

942

20 (2.1)

0.6 (2.9, ∞, 1.1)

168 (92, ∞, −34)

PL

368

10 (2.7)

 Haloperidol [10]

Haloperidol 4–8 mg/d

8

138

13 (9.4)

−9.8 (−20.9, −0.2)

−10 (−465, −5)

PL

73

14 (19.2)

 Haloperidol [17]

Haloperidol 8 mg/d

6

115

2 (1.7)

0.9 (−2.9, ∞, 5.4)

108 (19, ∞, −34)

PL

123

1 (0.8)

 Haloperidol [9, 13]

Haloperidol 10 mg/d

4–6

163

15 (9.2)

5.6 (2.9–11.4)

18 (9–351)

PL

168

6 (3.4)

 Haloperidol [11]

Haloperidol 15 mg/d

6

118

8 (6.8)

4.4 (0.7–10.5)

23 (10–137)

PL

587

14 (2.6)

 Haloperidol [20]

Haloperidol 15 ± 5 mg/d

6

69

24 (34.8)

18.6 (4.0–32.3)

5 (3–25)

PL

68

11 (16.2)

 Haloperidol [ 9 11, 13, 17, 20 22 ]

Haloperidol 10–20 mg/d

4–8

472

67 (14.2)

8.3 (4.9–12.0)

12 (8–20)

PL

800

47 (5.9)

 Lurasidone [24, 25, 27]

Lurasidone 40 mg/d

6

293

29 (9.9)

5.1 (0.9–9.5)

20 (11–114)

PL

293

14 (4.8)

 Lurasidone [23, 25, 26]

Lurasidone 80 mg/d

6

336

27 (8.0)

4.8 (1.3–8.5)

21 (12–77)

PL

338

11 (3.3)

 Lurasidone [24, 26, 27]

Lurasidone 120 mg/d

6

291

41 (14.1)

9.3 (4.7–14.2)

11 (7–22)

PL

293

14 (4.8)

 Lurasidone [26]

Lurasidone 160 mg/d

6

121

8 (6.6)

5.8 (0.9–11.7)

17 (9–115)

PL

121

1 (0.8)

 Lurasidone [ 23 27 ]

Lurasidone 40, 80, 120, or 160 mg/d

6

1041

105 (10.1)

6.5 (3.9–8.9)

15 (11–26)

PL

504

18 (3.6)

 Olanzapine [20]

Olanzapine 5 ± 2.5 mg/d

6

65

13 (20.0)

3.8 (−9.3, ∞, 17.0)

26 (6, ∞, −11)

Olanzapine 10 ± 2.5 mg/d

64

19 (29.7)

13.5 (−0.9, ∞, 27.4)

7 (4, ∞, −118)

Olanzapine 15 ± 2.5 mg/d

69

27 (39.1)

23.0 (8.0–36.6)

4 (3–13)

PL

68

11 (16.2)

  

 Olanzapine [29, 30, 31]

Olanzapine 10 mg/d

6

414

76 (18.4)

10.5 (5.9–15.1)

10 (7–17)

PL

405

32 (7.9)

 Olanzapine [22, 24]

Olanzapine 15 mg/d

6

199

19 (9.6)

4.9 (−0.3, ∞, 10.2)

20 (10, ∞, −330)

PL

193

9 (4.7)

 Olanzapine [ 20, 22, 24, 29 31 ]

Olanzapine 7.5–17.5 mg/d

6

746

14 1 (18.9)

11.1 (7.6–14.6)

9 (7–13)

PL

666

52 (7.8)

 Paliperidone [32]

Paliperidone 10.4 ± 1.7 mg/d

2

158

14 (8.7)

7.6 (1.1–13.2)

13 (8–92)

PL

80

1 (1.3)

 Paliperidone [29]

Paliperidone 3 mg/d

6

127

4 (3.2)

−5.0 (−11.5, ∞, 1.0)

−20 (105, ∞, −9)

PL

123

10 (8.1)

 Paliperidone [30, 31]

Paliperidone 6 mg/d

6

235

20 (8.5)

−0.5 (−5.8, ∞, 4.7)

−185 (21, ∞, −17)

PL

232

21 (9.1)

 Paliperidone [29, 30]

Paliperidone 9 mg/d

6

246

15 (6.1)

−0.7 (−5.2, ∞, 3.8)

−137 (27, ∞, −19)

PL

249

17 (6.8)

 Paliperidone [30, 31]

Paliperidone 12 mg/d

6

242

25 (10.3)

1.3 (−4.2, ∞, 6.7)

78 (15, ∞, −24)

PL

232

21 (9.1)

 Paliperidone [29]

Paliperidone 15 mg/d

6

113

16 (14.2)

6.0 (−2.1, ∞, 14.5)

17 (7, ∞, −48)

PL

123

10 (8.1)

 Paliperidone [ 29 31 ]

Paliperidone 3–15 mg/d

6

963

86 (8.9)

1.9 (1.7, ∞, 4.9)

53 (21, ∞,60)

PL

355

25 (7.0)

 Quetiapine-IR [32]

Quetiapine-IR 600–800 mg/d

2

159

19 (12.0)

10.7 (3.8–16.8)

9 (6–26)

PL

80

1 (1.3)

 Quetiapine-IR [21, 33]

Quetiapine-IR ≤250 mg/d

6

196

26 (13.3)

1.0 (−6.5, ∞, 8.1)

98 (12, ∞, −15)

PL

147

18 (12.2)

 Quetiapine-IR [36]

Quetiapine-IR 300 mg/d

6

90

12 (13.3)

6.2 (−3.2, ∞, 15.6)

16 (6, ∞, −31)

PL

84

6 (7.1)

 Quetiapine-IR [35]

Quetiapine-IR 400 mg/d

6

123

9 (7.3)

5.6 (0.2–11.8)

18 (9–678)

PL

118

2 (1.7)

 Quetiapine-IR [36]

Quetiapine-IR 600 mg/d

6

86

9 (10.5)

3.3 (−5.7, ∞, 12.4)

30 (8, ∞, −18)

PL

84

6 (7.1)

 Quetiapine-IR [34]

Quetiapine-IR 600 or 800 mg/d

6

156

16 (10.3)

7.5 (−0.2, ∞, 13.6)

13 (7, ∞, −461)

PL

73

2 (2.7)

 Quetiapine-IR [21, 33, 34, 35, 36]

Quetiapine-IR 300–800 mg/d

6

551

68 (12.3)

8.4 (4.0–12.0)

12 (8–25)

PL

202

8 (4.0)

 Quetiapine-XR [36]

Quetiapine-XR 300 mg/d

6

91

7 (7.7)

0.6 (−8.0, ∞, 8.8)

182 (11, ∞, −13)

PL

84

6 (7.1)

 Quetiapine-XR [35]

Quetiapine-XR 400 mg/d

6

113

8 (7.1)

5.4 (−0.1, ∞, 11.8)

19 (8, ∞, −927)

PL

118

2 (1.7)

 Quetiapine-XR [26, 36]

Quetiapine-XR 600 mg/d

6

324

40 (12.4)

9.6 (5.6–13.8)

10 (7–18)

PL

323

9 (2.8)

 Quetiapine-XR [35, 36]

Quetiapine-XR 800 mg/d

6

210

22 (10.5)

6.5 (1.5–11.8)

15 (9–67)

PL

202

8 (4.0)

 Quetiapine-XR [ 26, 35, 36 ]

Quetiapine-XR 300–800 mg/d

6

738

77 (10.4)

7.7 (4.5–10.4)

13 (10–22)

PL

323

9 (2.8)

 Risperidone [34]

Risperidone 4–6 mg/d

2

153

4 (2.6)

0.1 (−7.0, ∞, 4.3)

−798 (23, ∞, −14)

PL

73

2 (2.7)

 Risperidone [14, 16]

Risperidone 6 mg/d

4–6

158

23 (14.6)

2.9 (−4.6, ∞, 10.4)

34 (10, ∞, −22)

PL

165

19 (11.7)

 Risperidone [11]

Risperidone 4–8 mg/d

6

306

18 (7.6)

5.2 (2.1–9.5)

19 (11–48)

PL

587

14 (2.4)

 Risperidone [ 11, 14, 16 ]

Risperidone 4–8 mg/d

4–6

464

41 (8.8)

4.5 (1.6–7.6)

22 (13–62)

PL

752

33 (4.4)

 Ziprasidone [37]

Ziprasidone 40 mg/d

4

44

3 (6.8)

−1.5 (−13.6, ∞, 11.0)

−66 (9, ∞, −7)

PL

48

4 (8.3)

 Ziprasidone [39]

Ziprasidone 80 mg/d

6

106

20 (18.9)

13.4 (4.3–22.5)

7 (4–23)

PL

92

5 (5.4)

 Ziprasidone [37]

Ziprasidone 120 mg/d

4

47

4 (8.5)

0.2 (−12.2, ∞, 12.7)

564 (8, ∞, −8)

PL

48

4 (8.3)

 Ziprasidone [38, 39]

Ziprasidone 160 mg/d

4–6

254

29 (11.4)

8.5 (4–13.2)

12 (8–25)

PL

239

7 (2.9)

 Ziprasidone [ 37 39 ]

Ziprasidone 40–160 mg/d

4–6

451

56 ( 12.4)

8.6 (4.6–12.3)

12 (8–22)

PL

287

11 ( 3.8 )

Maintenance treatment of schizophrenia

 Aripiprazole [40]

Aripiprazole 15 mg/d

26

153

5 (3.3)

1.3 (−2.8, ∞, 5.7)

77 (18, ∞, −36)

PL

153

3 (2.0)

 Asenapine [41]

Asenapine 10–20 mg/d

26

194

1 (0.5)

−0.5 (−3.2, ∞, 1.9)

−190 (52, ∞, −31)

PL

192

2 (1.0)

Rows formatted in bold and italics after each drug are the summaries of all studies for that drug

ARI absolute risk increase, CI confidence interval, IR immediate release, No. number, NNH number needed to harm, PL placebo, XR extended release, ∞ indicates indefinite

aPositive value indiciates an increased risk for somnolence and a number needed to harm relative to placebo; negative value indicates a decreased risk for somnolence and a number needed to treat to benefit relative to placebo. The type I error rate for significance tests between antipsychotics and their controls was set at α = 0.05 (two-tailed)

bData are presented as mean (95 % confidence interval)

A positive correlation between the dose of antipsychotic and the rate of somnolence was observed in an olanzapine study (Table 1) [20]. Similar correlations were also observed in most other antipsychotics (data not shown). However, with the exception of quetiapine-XR and risperidone, there were no consistent patterns of dose-dependent effect when pooling all data for other antipsychotics at the same dose together (Table 1). The ziprasidone studies [37, 38, 39] indicated that somnolence rates were positively correlated to study durations. However, the paliperidone studies did not show a similar correlation between somnolence rates and paliperidone treatment duration [29, 30, 31, 32]. Two maintenance studies [40, 41] showed no significant differences in somnolence rates between antipsychotics and placebo (Table 1).

3.1.2 Acute and Maintenance Active Treatment Versus an Active Comparator

To determine the assay sensitivity of a trial, some FDA-approved antipsychotics were used as an active control in double-blind, placebo-controlled trials during the development of a new drug. Head-to-head comparisons between or among antipsychotics were also conducted in effectiveness clinical trials. We identified 20 studies with active head-to-head comparisons. We excluded three studies because of small sample sizes [6, 16, 20] and one study because of no self-reported somnolence [12]. We used the remaining 16 studies for active head-to-head comparisons (Table 2).
Table 2

Incidence, absolute risk increase, and number needed to harm of antipsychotic-induced somnolence of active versus active comparator in schizophrenia

Agents and trials in the acute treatment of schizophrenia

Treatment arms

Duration (weeks)

Reported somnolence

Total no.

No. of cases (%)

ARIa,b (95 % CI)

NNHa,b (95 % CI)

Aripiprazole vs. risperidone [14]

Aripiprazole 20 mg/d

4

101

4 (4.0)

−10.2 (−18.7, −2.2)

4.5 (−5.6, ∞, 15.2)

−10 (−46, −5)

21 (7, ∞, −18)

Aripiprazole 30 mg/d

100

19 (19.0)

Risperidone 6 mg/d

99

14 (14.1)

Aripiprazole vs. risperidone [ 14 ]

Aripiprazole 20 or 30 mg/d

4

201

23 (11.4)

2.7 (11.7, ∞, 4.9)

3.7 (21, ∞,9)

Risperidone 6 mg/d

99

14 (14.1)

Aripiprazole vs. haloperidol [13]

Aripiprazole 15 mg/d

4

102

5 (4.9)

−7.7 (−16.0, ∞, 0.2)

−2.7 (−11.7, ∞, 6.2)

−13 (498, ∞, −6)

−37 (16, ∞, −9)

Aripiprazole 30 mg/d

101

10 (9.9)

Haloperidol 10 mg/d

103

13 (12.6)

Aripiprazole vs. haloperidol [ 13 ]

Aripiprazole 15 or 30 mg/d

4

203

15 (7.4)

5.2 (13.5, ∞, 1.5)

19 (65, ∞,7)

Haloperidol 10 mg/d

103

13 (12.6)

Asenapine vs. haloperidol [17]

Asenapine 10 mg/d

6

111

10 (9.0)

7.3 (1.3–14.2)

5.8 (0.1–12.6)

14 (7–76)

17 (8–1101)

Asenapine 20 mg/d

106

8 (7.6)

Haloperidol 8 mg/d

115

2 (1.7)

Asenapine vs. haloperido l [ 17 ]

Asenapine 10–20 mg/d

6

217

18 (8.3)

6.6 (1.3–11.2)

15 (9–80)

Haloperidol 8 mg/d

115

2 (1.7)

Clozapine vs. risperidone [43]

Clozapine 600 mg/d

12

136

33 (24.3)

10.1 (0.7–19.3)

10 (5–155)

Risperidone 6 mg/d

134

19 (14.2)

Risperidone vs. clozapine [42]

Risperidone 6.4 mg/d

8

43

13 (30.2)

−19.8 (−38.6–1.2)

−5 (82, −3)

Clozapine 291.2 mg/d

43

20 (50.0)

Clozapine vs. risperidone [ 42, 43 ]

Clozapine 291.2–600 mg/d

8–12

179

53 (29.6)

11.5 (2.7–20.2)

9 (5–37)

Risperidone 6–6.4 mg/d

177

32 (18.1)

Lurasidone vs. quetiapine-XR [26]

Lurasidone 80 mg/d

6

125

5 (4.0)

−9.5 (−17.1, −2.4)

−6.8 (−14.8, ∞, 0.9)

−11 (−42, −6)

−15 (112, ∞, −7)

Lurasidone 160 mg/d

121

8 (6.6)

Quetiapine–XR 600 mg/d

119

16 (13.5)

Lurasidone vs. quetiapine-XR [ 26 ]

Lurasidone 80 or 160 mg/d

6

246

13 (5.3)

8.2 (15.8,2.0)

12 (49,6)

Quetiapine–XR 600 mg/d

119

16 (13.5)

Lurasidone vs. olanzapine [24]

Lurasidone 40 mg/d

6

119

12 (10.1)

1.1 (−6.6, ∞, 8.8)

6.2 (−2.3, ∞, 14.8)

94 (11, ∞, −15)

16 (7, ∞, −47)

Lurasidone 120 mg/d

118

18 (15.3)

Olanzapine 15 mg/d

122

11 (9.0)

Lurasidone vs. olanzapine [ 24 ]

Lurasidone 40 or 120 mg/d

6

237

30 (12.7)

3.6 (3.7, ∞, 9.9)

27 (10, ∞,27)

Olanzapine 15 mg/d

122

11 (9)

Paliperidone vs. olanzapine [29]

Paliperidone–ER 3 mg/d

6

127

7 (5.5)

−11.8 (−19.8, −4.0)

−8 (−25, −5)

Olanzapine 10 mg/d

127

22 (17.3)

Paliperidone vs. olanzapine [30, 31]

Paliperidone–ER 6 mg/d

6

235

20 (8.5)

−11.7 (−17.9, −5.4)

−9 (−19, −6)

Olanzapine 10 mg/d

238

48 (20.2)

Paliperidone vs. olanzapine [29, 30]

Paliperidone–ER 9 mg/d

6

244

24 (9.8)

−5.9 (−11.7, ∞, 0.1)

−17 (2020, ∞, −9)

Olanzapine 10 mg/d

255

40 (15.7)

Paliperidone vs. olanzapine [30, 31]

Paliperidone–ER 12 mg/d

6

241

25 (10.4)

−9.8 (−16.2, −3.4)

−10 (−30, −6)

Olanzapine 10 mg/d

238

48 (20.2)

Paliperidone vs. olanzapine [29]

Paliperidone–ER 15 mg/d

6

113

10 (8.9)

−8.5 (−17.0, ∞, 0.2)

−12 (419, ∞, −6)

Olanzapine 10 mg/d

127

22 (17.3)

Paliperidone vs. olanzapine [ 20 31 ]

Paliperidone 3–15 mg/d

6

963

86 (8.9)

−7.5 (−12.0, −3.5)

−13 (−28, −8)

Olanzapine 10 mg/d

365

60 (16.4)

Paliperidone vs. quetiapine [32]

Paliperidone 9–12 mg/d

2

158

14 (8.9)

−3.1 (−10.0, ∞, 3.9)

−32 (26, ∞, −10)

Quetiapine 600–800 mg/d

159

19 (12.0)

Quetiapine vs. risperidone [44]

Quetiapine 200–800 mg/d

8

338

89 (26.3)

6.6 (0.2–12.9)

15 (8–512)

Risperidone 2–8 mg/d

334

66 (19.8)

Risperidone vs. quetiapine [34]

Risperidone 4 or 6 mg/d

2

153

4 (2.6)

−7.6 (−13.6, −2.2)

−13 (−46, −7)

Quetiapine 600 or 800 mg/d

156

16 (10.3)

Haloperidol, risperidone vs. ziprasidone [11]

Haloperidol 15 mg/d

4–6

118

8 (6.8)

0.8 (−5.2, ∞, 7.4)

−0.1 (−5.6–4.2)

128 (13, ∞, −19)

−850 (24, ∞, −18)

Risperidone 4–8 mg/d

306

18 (5.9)

Ziprasidone 160 mg

150

9 (6.0)

Olanzapine, perphenazine, quetiapine, risperidone vs. ziprasidone [45]

Olanzapine 20.1 mg/d

18 months

336

104 (31.0)

6.6 (−1.5, ∞, 14.2)

4.0 (−4.4, ∞, 12.1)

6.2 (−1.9, ∞, 13.8)

3.8 (−4.2, ∞, 11.4)

15 (7, ∞, −65)

25 (8, ∞, −23)

16 (7, ∞, −53)

26 (9, ∞, −24)

Perphenazine 20.8 mg/d

261

74 (28.4)

Quetiapine 543.4 mg/d

337

103 (30.7)

Risperidone 3.9 mg/d

341

96 (28.2)

Ziprasidone 112.8 mg/d

185

45 (24.3)

Clozapine vs. olanzapine [46]

Clozapine 274.2 ± 155 mg/d

24 months

479

220 (46.0)

21.2 (15.2–27.0)

5 (4–7)

Olanzapine 16.6 ± 6.4 mg/d

477

118 (24.7)

Rows formatted in bold and italics after each drug are the summaries of all studies for that drug

ARI absolute risk increase, CI confidence interval, ER extended release, No. number, NNH number needed to harm, XR extended release, ∞ indicates indefinite

aPositive value indiciates an increased risk for somnolence and an NNH relative to an active comparator; a negative value indicates a decreased risk for somnolence and a number needed to benefit relative to an active comparator. The type I error rate for significance tests between antipsychotics and their controls was set at α = 0.05 (two-tailed)

bData are presented as mean (95 % confidence interval)

The largest difference was clozapine versus olanzapine in a 24-month study (ARI 21.2 %, NNH 5) [46]. In a 12-week study, clozapine also had a significantly higher rate of somnolence than risperidone (ARI 10.1 %, NNH 10) [43] (Table 2). Significantly higher rates of somnolence were observed with asenapine relative to haloperidol (ARI 6.6 %), quetiapine relative to lurasidone (ARI 8.2 %), olanzapine relative to paliperidone (ARI of 7.5 %), and quetiapine relative to risperidone (ARI 6.6–7.6 %) (Table 2). Aripiprazole and lurasidone studies indicated that there were dose-dependent differences between a studied antipsychotic and its active comparator (Table 2).

The CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study was the only one that compared multiple drugs simultaneously [45]. In this 18-month study, the rates of hypersomnia and sleepiness were 31.0 % for olanzapine, 30.7 % for quetiapine, 28.4 % for perphenazine, 28.2 % for risperidone, and 24.3 % for ziprasidone. There were no significant differences among these five antipsychotics (Table 2).

3.2 Incidence of Antipsychotic-Induced Somnolence in Acute Mania

3.2.1 Acute Active Treatment Versus Placebo

All antipsychotics studied in mania caused higher rates of somnolence than placebo [47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65], but the somnolence rates with haloperidol 2–8 mg/day in one study and paliperidone 3–12 mg/day were not significantly higher than those with placebo (Table 3). Aripiprazole and risperidone caused significantly higher rates of somnolence with similar ARIs relative to placebo as quetiapine and ziprasidone (Table 3).
Table 3

Incidence, absolute risk increase, and number needed to harm of antipsychotic-induced somnolence in bipolar mania

Agents and trials

Treatment arms

Duration

Reported somnolence

Total no.

No. of cases (%)

ARIa,b (95 % CI)

NNHa,b (95 % CI)

Acute treatment of mania: active vs. placebo

 Aripiprazole [47, 48]

Aripiprazole 15–30 mg/d

3 weeks

263

53 (20.2)

12.5 (6.6–18.4)

8 (5–15)

Placebo

 

260

20 (7.7)

 Asenapine [49, 50]

Asenapine 10–20 mg/d

3 weeks

379

39 (10.3)

7.8 (3.7–11.6)

13 (9–27)

Placebo

 

203

5 (2.5)

 Cariprazine [51]

Cariprazine 3–12 mg/d

3 weeks

158

9 (5.7)

4.4 (0.1–9.3)

23 (11–702)

Placebo

 

154

2 (1.3)

 Haloperidol [52, 53, 54]

Haloperidol 2–12 mg/d

3 weeks

335

32 (9.6)

5.5 (1.7–9.5)

18 (11–59)

Placebo

 

324

13 (4.0)

 Haloperidol [55]

Haloperidol 2–8 mg/d

12 weeks

99

9 (9.1)

4.4 (–3.3, ∞, 12.0)

24 (8, ∞, −30)

Placebo

 

101

5 (5.0)

 Olanzapine [49, 50, 51, 52, 53, 56, 58]

Olanzapine 5–20 mg/d

3–4 weeks

839

121 (14.4)

9.2 (6.0–21.1)

11 (8–17)

Placebo

 

533

28 (5.3)

 Paliperidone [59]

Paliperidone 3–12 mg/d

3 weeks

194

19 (9.8)

6.0 (–0.6, ∞, 11.5)

17 (9, ∞, −176)

Placebo

 

105

4 (3.8)

 Quetiapine-IR [60]

Quetiapine–IR 400–800 mg/d

12 weeks

209

34 (16.3)

12.2 (6.5–18.2)

8 (6–15)

Placebo

 

198

8 (4.0)

 Quetiapine-XR [61]

Quetiapine–XR 400–800 mg/d

3 weeks

151

25 (16.6)

12.2 (5.5–19.3)

8 (5–18)

Placebo

 

160

7 (4.4)

 Risperidone [52, 62]

Risperidone 1–6 mg/d

3 weeks

288

45 (15.6)

11.5 (6.6–16.5)

9 (6–15)

Placebo

 

265

11 (4.2)

 Ziprasidone [63, 64, 65]

Ziprasidone 80–160 mg/d

3 weeks

457

84 (18.4)

11.2 (6.0–15.9)

9 (6–17)

Placebo

 

224

16 (7.1)

Maintenance treatment of bipolar disorder with index episode of mania

 Aripiprazole [66]

Aripiprazole 15–30 mg/d

26 weeks

77

4 (5.2)

−2.0 (6.3, ∞, −10.3)

−49 (16, ∞, −10)

Placebo

 

83

6 (7.2)

 Olanzapine [67]

Olanzapine 5–20 mg/d

18 mo

131

16 (12.2)

9.3 (2.9–16.2)

11 (6–34)

Placebo

 

135

4 (3.0)

 Olanzapine [68]

Olanzapine 5–20 mg/d

48 weeks

225

6 (2.7)

1.2 (−2.8, ∞, 4.4)

84 (23, ∞, −36)

Placebo

 

136

2 (1.5)

 Paliperidone-ER [69]

Paliperidone 3–12 mg/d

24 mo

149

5 (3.4)

3.4 (0.2–7.6)

1.2 (−1.5, ∞,6.5)

30 (13–588)

83 (15, ∞, −65)

Olanzapine 5–20 mg/d

 

83

1 (1.2)

Placebo

 

147

0 (0)

 Quetiapine-IR [70]

Quetiapine 400–800 mg/d

104 weeks

404

27 (6.7)

2.5 (–0.7, ∞, 5.7)

40 (17, ∞, −143)

Placebo

 

404

17 (4.2)

Acute treatment of mania: active vs. active

 Asenapine vs. olanzapine [50, 51]

Asenapine 10–20 mg/d

3 weeks

379

39 (10.3)

0.9 (−3.3, ∞, 5.2)

111 (19, ∞, −30)

Olanzapine 5–20 mg/d

 

394

37 (9.4)

 Asenapine vs. olanzapine [50, 51]

Asenapine 10–20 mg/d

12 weeks

181

21 (11.6)

−2.8 (−9.3, ∞, 4.0)

−36 (25, ∞, −11)

Olanzapine 5–20 mg/d

 

229

33 (14.4)

 Olanzapine vs. haloperidol [53]

Olanzapine 5–20 mg/d

3 weeks

105

20 (19.1)

4.1 (–18.0, ∞, 17.0)

25 (6, ∞, −6)

Haloperidol 2.5–10 mg/d

 

20

3 (15.0)

 Olanzapine vs. haloperidol [71]

Olanzapine 5–20 mg/d

12 weeks

234

35 (15.0)

6.3 (0.3–12.3)

16 (8–361)

Halperidol 3–15 mg/d

 

219

19 (8.7)

 Paliperidone-ER vs. quetiapine [59]

Paliperidone–ER 3–12 mg/d

3 weeks

194

19 (9.8)

−8.4 (−15.4, −1.5)

−12 (−67, −6)

Quetiapine 400–800 mg/d

 

192

35 (18.2)

 Paliperidone-ER vs. quetiapine [59]

Paliperidone–ER 3–12 mg/d

12 weeks

194

19 (9.8)

−11.6 (−18.8, −4.4)

−9 (−23, −5)

Quetiapine 400–800 mg/d

 

192

41 (21.4)

 Quetiapine vs. haloperidol [55]

Quetiapine up to 800 mg/d

12 weeks

102

13 (12.8)

3.7 (−5.3, ∞, 12.6)

29 (8, ∞, −19)

Haloperidol up to 8 mg/d

 

99

9 (9.1)

 Risperidone vs. haloperidol [52]

Risperidone 1–6 mg/d

3 weeks

154

7 (4.6)

1.1 (−3.9, ∞, 6.0)

93 (17, ∞, −26)

Haloperidol 2–12 mg/d

 

144

5 (3.5)

 Risperidone vs. haloperidol [52]

Risperidone 1–6 mg/d

12 weeks

154

15 (9.7)

4.2 (−2.1, ∞, 10.5)

24 (10, ∞, −48)

Haloperidol 2–12 mg/d

 

144

8 (5.6)

 Ziprasidone vs. haloperidol [65]

Ziprasidone 80–160 mg/d

3 weeks

178

19 (10.7)

−4.5 (−11.7, ∞, 2.6)

–22 (39, ∞, −9)

Haloperidol 8–30 mg/d

 

171

26 (15.2)

 Ziprasidone vs. haloperidol [65]

Ziprasidone 80–160 mg/d

12 weeks

178

25 (14.0)

−2.3 (−10.0, ∞, 5.3)

−43 (19, ∞, −10)

Haloperidol 4–30 mg/d

 

171

28 (16.4)

ARI absolute risk increase, CI confidence interval, ER extended release, IR immediate release, no. number, NNH number needed to harm, XR extended release, ∞ indicates indefinite

aPositive value indicates an increased risk for somnolence and a number needed to harm relative to placebo; negative value indicates a decreased risk for somnolence and a number needed to benefit relative to placebo. The type I error rate for significance tests between antipsychotics and their controls was set at α = 0.05 (two-tailed)

bData are presented as mean (95 % CI)

3.2.2 Maintenance Active Treatment Versus Placebo in Patients with an Index Episode of Mania

Although aripiprazole and quetiapine-XR had significantly higher rates of somnolence relative to placebo in acute mania [47, 48, 61], the somnolence rates with these two agents during maintenance treatment were not significantly different from those with placebo (Table 3). In three studies of olanzapine [67, 68, 69], only one study showed that olanzapine had a significantly higher rate of somnolence than placebo (ARI 9.3 %, NNH of 11; 95 % CI 6–34), which is similar to that in acute mania [49, 50, 53, 56, 57, 58]. Paliperidone-ER had a small but significantly higher rate of somnolence relative to placebo (NNH 30; 95 % CI 13–588) (Table 3).

3.2.3 Acute Active Treatment Versus an Active Comparator

As in schizophrenia, some studies in mania used an FDA-approved antipsychotic as an active control during the development of a new drug. Eight studies were available for active-to-active comparisons (Table 3). Olanzapine had a significantly higher rate of somnolence than haloperidol in a 12-week study (ARI 6.3 %, NNH 16) [71], but not in a 3-week study [53]. However, quetiapine had a significantly higher rate of somnolence than paliperidone in a study at week 3 (ARI 8.4 %, NNH 12) and at week 12 (ARI 11.6 %, NNH 9) [59]. No significant differences were observed between asenapine and olanzapine or between quetiapine and risperidone or ziprasidone and haloperidol (Table 3).

3.3 Incidence of Antipsychotic-Induced Somnolence in Bipolar Depression

3.3.1 Acute Active Treatment Versus Placebo

Among six second-generation antipsychotics in the acute treatment of bipolar depression [72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82], three had significantly higher rates of somnolence relative to placebo; quetiapine-XR had the highest rate of somnolence (29.2 %) [81], the largest ARI (23.4 %), and the smallest NNH (4; 95 % CI 3–7) (Table 4). The rates of somnolence from ziprasidone were positively correlated to dosing [82]. However, quetiapine-IR 300 and 600 mg/day had a similar ARI and the same NNH [77, 78, 79, 80]. Comparing the 8-week and the 6-week study of olanzapine [75, 76], the ARI in the 8-week study was larger relative to placebo (Table 4).
Table 4

Incidence, absolute risk increase, and number needed to harm of antipsychotic-induced somnolence in bipolar depression

Agents and trials

Treatment arms

Duration (weeks)

Reported somnolence

Total no.

No. of cases (%)

ARIa,b (95 % CI)

NNHa,b (95 % CI)

Acute treatment of bipolar depression

 Aripiprazole [72]

Aripiprazole 5–30 mg/d

Placebo

8

360

27 (7.5)

3.4 (0.0–7.0)

29 (14, ∞, −6789)

367

15 (4.1)

 Cariprazine [73]

Cariprazine 0.75 mg/d

Cariprazine 1.5 mg/d

Cariprazine 3.0 mg/d

Placebo

8

141

6 (4.3)

0.1 (−5.0, ∞, 5.3)

2.0 (−3.4, ∞, 7.6)

2.7 (−2.8, ∞, 8.5)

852 (19, −20)

49 (13, −29)

37 (13, −29)

146

9 (6.2)

146

10 (6.8)

145

6 (4.1)

 Cariprazine [ 73 ]

Cariprazine 0.75-3.0 mg/d

Placebo

8

408

25 ( 5.6 )

1.6 (3.3–5.1)

61 (20,30)

145

6 ( 4.1 )

 Lurasidone [74]

Lurasidone 20–60 mg/d

Lurasidone 80–120 mg/d

Placebo

6

164

7 (4.3)

0.1 (−4.6, ∞, 4.9)

2.4 (−2.7, ∞, 7.7)

984 (20, ∞, −22)

41 (13, ∞, −38)

167

11 (6.6)

168

7 (4.2)

 Lurasidone [ 74 ]

Lurasidone 20–120 mg/d

Placebo

6

313

18 (5.4)

1.3 (3.4–5.0)

79 (20,30)

168

7 (4.2)

 Olanzapine [75]

Olanzapine 5–20 mg/d

Placebo

8

370

104 (28.1)

15.6 (9.9–21.3)

6 (5–10)

377

47 (12.5)

 Olanzapine [76]

Olanzapine 5–20 mg/d Placebo

6

343

59 (16.3)

10.8 (4.8–15.9)

9 (6–21)

171

11 (6.4)

 Olanzapine [ 75, 76 ]

Olanzapine 5–20 mg/d Placebo

6–8

780

163 (20.9)

10.3 (6.4–14.1)

10 (7–16)

548

58 (10.6)

 Quetiapine-IR c [ 77 80 ]

Quetiapine-IR 300 mg/d

Quetiapine-IR 600 mg/d

Placebo

8

853

188 (22.0)

14.1 (10.5–17.5)

14.3 (10.4–17.5)

7 (6–10)

7 (6,10)

859

189 (22.0)

602

48 (8.0)

 Quetiapine-XRc [81]

Quetiapine-XR 300 mg/d

Placebo

8

137

40 (29.2)

23.5 (14.8–32.1)

4 (3–7)

140

8 (5.7)

 Ziprasidone [82]

Ziprasidone 40–80 mg/d

Ziprasidone120–160 mg/d

Placebo

6

288

39 (13.5)

10.0 (5.7–14.6)

14.1 (9.1–19.7)

10 (7–17)

7 (5–11)

232

41 (17.7)

364

13 (3.6)

 Ziprasidone [ 82 ]

Ziprasidone 40–160 mg/d

Placebo

6

520

80 (15.4)

11.8 (8.1–15.5)

8 (6–12)

364

13 (3.6)

Maintenance treatment of bipolar disorder with index episode of depression

 Quetiapine-IR [83]

Quetiapine 300 mg/d

Quetiapine 600 mg/d

Placebo

52

141

9 (6.4)

2.3 (−1.9, ∞, 7.9)

2.6 (−1.6, ∞, 8.0)

43 (13, ∞, −53)

39 (12, ∞, −62)

150

10 (6.7)

294

12 (4.1)

A row with bold font and italic after each drug is the summary of all doses

ARI absolute risk increase, CI confidence interval, IR immediate release, no. number, NNH number needed to harm, XR extended release, ∞ indicates indefinite

aPositive value indicates an increased risk for somnolence and a number needed to harm relative to placebo; negative value indicates a decreased risk for somnolence and a number needed to benefit relative to placebo. The type I error rate for significance tests between antipsychotics and their controls was set at α = 0.05 (two-tailed)

bData are presented as mean (95 % CI)

cStudies included patients with bipolar I or II depression

3.3.2 Maintenance Active Treatment Versus Placebo in Patients with an Index Episode of Depression

Quetiapine-IR was the only antipsychotic studied for maintenance treatment with a study index episode of depression [83]. The rates of somnolence for quetiapine-IR 300 mg, 600 mg/d, and placebo were similar (6.4, 6.7, and 4.1 %, respectively; Table 4).

3.4 Classification of Antipsychotics According to the Risk for Somnolence

According to the incidence of antipsychotic-induced somnolence relative to that of placebo in schizophrenia, antipsychotics may be classified into at least three groups, i.e., high, moderate, and low somnolence. Clozapine is included in the high somnolence group because it had significantly higher rates of somnolence than olanzapine and risperidone (Table 2). The moderate group includes haloperidol, olanzapine, perphenazine, quetiapine-IR, quetiapine-XR, risperidone, and ziprasidone. Although the ARI of risperidone relative to placebo in schizophrenia was relatively smaller than those of other antipsychotics in this group (Fig. 1), the CATIE study found the rate of somnolence from risperidone to be similar to those from olanzapine and quetiapine-IR, supporting the inclusion of risperidone in this group. The low somnolence group includes aripiprazole, asenapine, lurasidone, and paliperidone, although only a few significant differences were found during active head-to-head comparisons between these drugs and some antipsychotics in the moderate somnolence group (Table 2).
Fig. 1

Cumulative mean absolute risk increase of antipsychotic-induced somnolence relative to placebo in acute treatment of schizophrenia, bipolar mania, or bipolar depression

However, in acute mania, aripiprazole appeared to belong with olanzapine, quetiapine, risperidone, and ziprasidone, whereas haloperidol appeared to belong to the low somnolence group (Table 3). Aripiprazole did not have a significantly higher rate of somnolence in bipolar depression (Table 4). Considering these results all together, aripiprazole and haloperidol can be included in the low somnolence group, but the order for this group from high to low somnolence should be haloperidol, asenapine, aripiprazole, lurasidone, paliperidone, and cariprazine (Tables 1, 2, 3). The overall magnitude of difference between brexpiprazole and placebo or an active comparator(s) for somnolence needs further investigation.

3.5 Interpretation and Limitations of Somnolence Data

3.5.1 Measurement of Somnolence

Until recently [84], data on antipsychotic-induced somnolence were commonly collected via questions related to somnolence or sedation on an adverse event form for a study, which usually provided three choices—mild, moderate, or severe—by which to rate the severity of somnolence or sedation. A report of somnolence at any visit during the entire study period would be recorded as an adverse event. Most published studies had available only rates of somnolence without data on how severe the somnolence was and when the event occurred. Therefore, the data of such “one-time-snapshot” measurement might not reflect the entire picture of antipsychotic-induced somnolence.

In a post-hoc analysis, Loebel et al. [84] used the Epworth Sleepiness Scale to measure change in daytime sleepiness and found that lurasidone 80 or 160 mg/day was associated with a reduction in daytime sleepiness similar to placebo, but quetiapine-XR was associated with a significant increase in daytime sleepiness compared with both lurasidone and placebo. However, based on the incidence analysis of our current review, lurasidone 80 and 160 mg/day in schizophrenia had significantly higher rates of somnolence relative to placebo (Table 1) [23, 24, 25, 26, 27]. The variation between lurasidone-induced somnolence relative to placebo when measured using the rate and using the Epworth Sleepiness Scale suggests that a similar disagreement might have also occurred for other antipsychotics in previous studies if both measurements were used. Future studies should use rating scales to monitor antipsychotic-induced somnolence at each study visit.

3.5.2 Effect of Study Design on the Incidence of Antipsychotic-Induced Somnolence

In addition to the methods of measurement, other factors could also affect the interpretation of antipsychotic-induced somnolence. All of the phase II and III efficacy studies have used stringent inclusion and exclusion criteria to only allow patients with relatively “pure” schizophrenia, mania, or bipolar depression to enroll in a study. Patients with a current substance use disorder(s) and/or a severe medical problem(s) were commonly excluded. Therefore, the data from most studies reviewed here may not be generalizable to clinical practice. Because the eligibility in each study varied according to study sponsor, the results from different studies of an antipsychotic, even when studied in the same psychiatric condition, such as schizophrenia, were not comparable. Haloperidol and olanzapine were studied by different sponsors (Table 1, 3); therefore, the cumulative results of these two medications may be more accurate and generalizable. In contrast, the result of quetiapine-XR in bipolar depression may not be generalizable because it was only investigated in one study (Table 4).

Moreover, all efficacy studies used a relatively short duration. These short-term studies may underestimate the incidence of antipsychotic-induced somnolence (Tables 1, 3, 4), and the findings of the CATIE study support this assumption. In the CATIE study, patients were observed for up to 18 months. The rates of somnolence from risperidone, olanzapine, quetiapine, and ziprasidone were much higher than the rates of these drugs in the acute treatment of schizophrenia (Tables 1, 2).

The interpretation of the lower rates of somnolence in maintenance studies should be viewed cautiously (Tables 1, 3, 4). All maintenance studies used a relapse-prevention design, in which only patients who reached stabilization and tolerated a study medication entered a randomized, doubled-blind phase [84]. The lower rates in the maintenance studies could be due to the resolution of somnolence and/or the discontinuation of patients who could not tolerate a study drug, especially because of somnolence during an acute open-label phase before randomization.

3.5.3 Effect of Dosing and Dosage on the Incidence of Somnolence

In clinical trials, study medications can be given as fixed or flexible doses. Fixed dosing is believed to be more likely to detect an efficacy signal between an active drug and placebo. Meanwhile, a studied drug with fixed-dosing schedules is found to be more likely to cause side effect(s) and/or discontinuation due to adverse events than with flexible dosing. The majority of studies in schizophrenia used fixed dosing (Table 1), but the majority of studies in bipolar disorder used flexible dosing (Table 3, 4). In clinical practice, flexible dosing is routine.

The dosage of a studied drug can also affect the incidence of somnolence, although a dose-effect relationship is difficult to establish (Table 1). In most cases, pharmaceutical companies are not interested in finding a dose–effect curve for efficacy or side effect(s), rather, they are interested in finding a dose(s) that is superior to placebo in reducing targeted symptoms with an acceptable side-effect profile. Commonly, the doses used in a study are already above a minimal effective dose. In the studies of schizophrenia (Table 1), all doses of aripiprazole, asenapine, olanzapine, paliperidone, and quetiapine-IR or XR studied were superior to placebo in reducing psychotic symptoms. Therefore, a minimal effective dose of these FDA-approved antipsychotics in schizophrenia remains unknown. In contrast, lower doses of brexpiprazole, lurasidone, and ziprasidone in schizophrenia were not superior to placebo in reducing psychotic symptoms. However, there was no correlation between the doses of these drugs and the rates of somnolence (Table 1). These data suggest that, in addition to methodological issues that potentially affected the incidence of antipsychotic-induced somnolence, the pharmacological profiles of each individual antipsychotic might play a more important role. The following section explores potential mechanisms of antipsychotic-induced somnolence.

4 Mechanism of Antipsychotic-Induced Somnolence

4.1 Wakefulness and Sleep Systems

The wake–sleep cycle is a complicated physiological process, and its mechanism remains unclear although there are many hypotheses and theories [85, 86]. The basic mechanisms involved in this process include the transition from wakefulness to sleep, the initiation of sleep, and the subsequent generation of slow-wave sleep (SWS, the later part of non-rapid eye movement sleep [NREM]) and rapid eye movement sleep (REM). Any medication that decreases wakefulness and/or prolongs sleep can cause somnolence.

To maintain wakefulness, the ascending reticular activating system (ARAS) plays a very important role. This system includes norepinephrine-synthesizing neurons in the locus coeruleus, serotonin-synthesizing neurons in the raphe nuclei, acetylcholine-synthesizing neurons in the pedunculopontine tegmentum, glutamate-synthesizing neurons in the midbrain, and dopamine neurons in the substantia nigra compacta and ventral tegmental area [86]. In addition, at least four groups in the forebrain, including histaminergic cells in the posterior hypothalamus, hypocretinergic cells in the lateral hypothalamus, cholinergic cells in the basal forebrain, and cells in the suprachiasmatic nucleus, are also involved in promoting wakefulness independently or coordinating wake-promoting neurons in the brainstem [85,86 ] (Fig. 2).
Fig. 2

Neurochemicals involved in wakefulness and sleep

4.2 Neurochemicals for Wakefulness and Sleep

4.2.1 Wakefulness

Acetylcholine and histamine in the central nervous system (CNS) promote wakefulness (Fig. 2). The muscarinic antagonists, scopolamine and atropine, reduce motor and brain activities. Administering an H1 receptor agonist in the CNS increases brain activities and wakefulness while reducing sleep. In contrast, administering an H1 receptor antagonist, diphenhydramine, or a low dose of doxepin, increases sleep. Blocking autoinhibitory histamine H3 receptors with ciproxifan or tiprolisant increases wakefulness and improves excessive daytime sleepiness [86].

Generally, monoamines promote wakefulness (Fig. 2). Adrenergic neurons in the locus coeruleus play a very important role in the wake–sleep cycle and are normally inhibited by norepinephrine via α2 receptors. Serotonin in the CNS also promotes wakefulness. Serotonin selective reuptake inhibitors such as fluoxetine and citalopram increase wakefulness and reduce sleep. Serotonergic agonists of the 5-HT1A, 5-HT1B, 5-HT2, or 5-HT3 receptors also increase wakefulness. In contrast, 5-HT2 receptor antagonists such as ritanserin or agomelatine promote sleep and reduce wakefulness. Dopamine is a key neurotransmitter for wakefulness. Commonly used stimulants such as methylphenidate and amphetamine are good examples and can increase extracellular levels of dopamine and increase wakefulness [87].

4.2.2 Non-Rapid Eye Movement (NREM) and REM Sleep

Neurons in the preoptic area contain gamma-aminobutyric acid (GABA) and the inhibitory neuropeptide, galanin. These neurons promote sleep by coordinating the inhibition of arousal regions during NREM and REM sleep [86] (Fig. 2). Many commonly used medications for sleep are thought to be effective via activation of GABA receptors. These medications include benzodiazepines, barbiturates, and other newer non-benzodiazepine agents such as zolpidem.

Acetylcholine, serotonin, GABA, and melanin-concentrating hormones are involved in REM sleep. Somnogens such as adenosine, cyctokines, prostaglandins, and other neurochemicals are also involved in the initiation and maintenance of sleep [85, 86] (Fig. 2).

4.3 Neurotransmitters and Receptors Involved in Antipsychotic-Induced Somnolence

Based on the neurochemicals for wakefulness and sleep, it is reasonable to speculate that antipsychotic-induced somnolence can be due to the blockade of dopamine, serotonin, norepinephrine, histamine, acetylcholine, and/or the activation of GABA and other inhibitory neurotransmitters (Fig. 2).

Among the antipsychotic-induced side effects, the mechanism for acute extrapyramidal side effects (EPS) has been studied the most, with a consensus that over 80 % D2 receptor blockade is necessary for acute EPS [88]. For somnolence, a positron emission tomography (PET) study found that the magnitude of H1 receptor occupancy with diphenhydramine was positively correlated to the severity of sleepiness [89], suggesting that antipsychotics can cause somnolence via the blockage of H1 receptors. Although neuroimaging studies can provide direct evidence between a receptor-binding potential of an antipsychotic and somnolence, it is impossible to use imaging technology to study more than one antipsychotic at a time.

In contrast, in vitro receptor binding assays are convenient, relatively inexpensive, and have become a standard for drug development [90]. Indeed, the results of antipsychotic-induced EPS from neuroimaging studies have been consistent with the results of in vitro studies, i.e., that antipsychotics with a high D2 receptor affinity are more likely to induce EPS than those with a low D2 receptor affinity. Therefore, in vitro affinities of an antipsychotic to different receptors have been used to predict the possibility and magnitude of certain side effects such as weight gain [91, 92].

4.3.1 Receptor Affinities of Antipsychotics

The affinity of an antipsychotic(s) to a receptor can be presented as Ki, the equilibrium disassociation constant for a competitor (commonly a studied ligand antipsychotic) with a concentration that reduces the specific binding of a radiolabeled standard by 50 % [90]. A ligand with the smallest Ki (commonly presented in units of nM) to a receptor has the highest affinity. Some studies used pKi, a negative logarithm of Ki, to present the affinities of antipsychotics to different receptors, [93], which made it difficult to compare the results with other studies using Ki.

No study has included all antipsychotics for receptor-binding assays. The largest study to date included 17 typical and atypical antipsychotics and 12 receptors [92]. As shown in Table 5, among the antipsychotics related to this review, clozapine had the highest affinity to H1 receptors, followed by olanzapine. The difference in Ki to H1 receptors between olanzapine and risperidone was more than sevenfold.
Table 5

Receptor affinity (nM) of commonly used antipsychotics based on a study of H1-histamine receptor affinity and typical and atypical antipsychotic induced short-term weight gaina

Drug

H1

D2

M3

5-HT1A

5-HT2A

5-HT2C

5-HT6

5-HT7

α1A

α2A

α2B

α2C

Clozapine

1.2

256

25

104.8

5.4

17

17

17.9

1.64

142

26

34

Olanzapine

2

34

105

2063

2

6.8

6.28

105.4

115

314.1

81.6

28.8

Perphenazine

8

1.4

1848

421

5.6

132

17

23

10

810.5

10.9

85.2

Quetiapine

11

245

10,000

431.6

101

2502

1865

30.2

22

3630

746.6

28.7

Risperidone

15

6.5

10,000

427.5

0.17

35

1188

66

5

150.8

107.6

1.3

Aripiprazole

29.7

0.66

4677

5.57

8.7

22.4

783.2

9.6

26

74

102

37

Ziprasidone

43

9.7

10,000

76

0.3

13

60.9

6.62

18

160

48

59

Haloperidol

1800

4

10,000

1202

53

10,000

3666

377.2

12

1130

480

550

aAdapted from Kroeze et al. [92]

However, in a different study, the Ki of risperidone to H1 receptors was even smaller than that of olanzapine [94]. The inconsistency of the affinities of different antipsychotics to the same receptors in different studies was also reported previously [91]. These findings suggest that the results of the receptor-binding properties of an antipsychotic cannot be compared between studies because of different studies using different methods or the same methods used by different investigator(s). Since an in vitro receptor-binding profile of a new antipsychotic is commonly achieved through comparing its affinity to a receptor with that of an existing antipsychotic(s), it is important to understand that the differences in receptor affinities are only valid within the same study.

4.3.2 Histamine 1 Receptors

Antihistamines have been used for insomnia, and are believed to work via the blockage of histamine 1 receptors [91, 95]. Typical and atypical antipsychotics have different affinities to H1 receptors, with some binding affinities (Ki) of <10 nM [92]. All antipsychotics with a high H1 receptor affinity caused higher rates of somnolence, but the correlation between the H1 receptor affinity and the severity of somnolence is difficult to establish because varying doses of antipsychotics were used in different studies. Olanzapine 5–20 mg/day had an ARI of 9.2 % for somnolence relative to placebo in acute mania (Table 3), but quetiapine-IR 400–800 mg/day had an ARI of 12.2 % for somnolence relative to placebo. As shown in Table 5, olanzapine had a higher affinity to H1 receptors than did quetiapine. Therefore, theoretically, olanzapine should have a higher risk for somnolence relative to placebo than quetiapine. Similarly, ziprasidone had a lower H1 receptor affinity than aripiprazole (Table 5), but ziprasidone caused more robust somnolence in schizophrenia and bipolar disorder than aripiprazole (Fig. 1). These “opposing” findings could be due to the doses of these antipsychotics used in these studies. Although an overall positive correlation between H1 receptor affinities of antipsychotics and the rates of somnolence was seen [91], it will be impossible to compare the magnitude of the risk for somnolence due to H1 receptor blockade among antipsychotics.

4.3.3 Dopamine Receptors

Dopamine plays a very important role in wakefulness. However, in an early study in healthy volunteers, oral administration with pimozide, a strong D2 receptor antagonist, had little effect on sleep structure [96]. Similarly, aripiprazole, a D2 receptor partial agonist with high D2 receptor blockade, did not cause significant somnolence in bipolar depression (Table 4) or schizophrenia (Table 1). In contrast, haloperidol, a strong D2 receptor antagonist, did increase the risk for somnolence in schizophrenia (ARI 8.3 %, NNH 12) (Table 1), suggesting that the D2 receptor blockade may also play a role in antipsychotic-induced somnolence.

4.3.4 Serotonin Receptors

The role of serotonin receptors in wakefulness and sleep depends not only on serotonin receptors but also on the route of drug administration [97]. Ritanserin, a 5-HT(2A/2C) receptor antagonist, caused a significant increase in SWS in patients with insomnia. Like lorazepam, ritanserin impaired driving performance and increased SWS and daytime sleepiness [98]. Since all antipsychotics have relatively high affinities to one or more 5-HT receptors (Table 5), each antipsychotic may have an increased or decreased severity of somnolence through 5-HT receptors and their interactions with other receptors on the same or different neurons.

4.3.5 Adrenergic Receptors

Most antipsychotics also have a high affinity to α-receptors. The activation of noradrenergic β- and α1 receptors on adrenergic neurons in the locus coeruleus and other areas of the brainstem promotes wakefulness. Blocking these receptors with prazosin and timolol, or reducing norepinephrine release, produces sedation or increases sleepiness [99, 100]. Activation of α2 receptors with an α2 agonist in the locus coeruleus also increases NREM sleep [100]. In humans, significant correlations between antipsychotic affinities to α1 receptors and the incidence of drowsiness has been reported [91].

4.3.6 Cholinergic Receptors

Acetylcholine is an important neurotransmitter for wakefulness, and muscarinic 2 (M2) and 3 (M3) receptors in the brain are associated with arousal [101]. Blockage of these cholinergic receptors should promote sleep and/or cause somnolence. However, overall, antipsychotics have a low affinity to muscarinic receptors (Table 5), suggesting that the anticholinergic effect of antipsychotics may play a limited role in antipsychotic-induced somnolence.

4.3.7 Interactions among Receptors

Wakefulness and sleep-promoting systems are highly connected with different neurotransmitters, which execute their functions through different receptors. It is very unlikely that activation or inhibition of one group of receptors or one class of receptors by an antipsychotic is responsible for antipsychotic-induced somnolence. Antipsychotic-induced somnolence can be due to a direct effect of blocking H1 and other receptors or by acting on other neurotransmitter systems. Clozapine has been reported to directly interact with GABA receptors [102]. Zotepine activated neuronal activities in different regions of the brain and increased the extracellular levels of noradrenaline, dopamine, GABA, and glutamate in the prefrontal cortex [103]. Interactions between orexin and dopamine systems modulated by an atypical antipsychotic, sulpiride, were observed in the nucleus accumbens in rats [104].

Antipsychotic-induced somnolence can also occur via the interactions of neurotransmitters at a receptor level. Risperidone has little affinity to 5-HT6 receptors (Table 5). The combination of risperidone and a 5-HT6 antagonist (SB742457) increased rates of somnolence from 50 % with risperidone alone to 83 % with risperidone and SB742457 combined [105], suggesting that antipsychotic-induced somnolence can be a combined effect of an antipsychotic on different receptors, although H1 receptor antagonism may play a major role.

Aforementioned data suggest many factors potentially affect the incidence of antipsychotic-induced somnolence. These factors at least include antipsychotics per se, psychiatric diagnoses, dose and dosing schedules, and treatment duration. In the next section, we discuss the management of antipsychotic-induced somnolence, focusing on these potential factors.

5 Management of Antipsychotic-Induced Somnolence

5.1 Sleep Hygiene and Behavioral Intervention

When an antipsychotic is indicated for a patient, its effect on the wake–sleep cycle will depend not only on the drug per se but also on the “natural” wake–sleep pattern of the patient. It is well known that the duration and quality of sleep can affect daytime wakefulness and sleepiness. A good nights’ sleep can minimize antipsychotic-induced somnolence. Clinicians should educate patients about good sleep hygiene, such as avoiding or reducing alcohol, nicotine, and caffeine consumption, especially past late afternoon; keeping a relaxing bedtime routine; maintaining a regular sleep schedule; and avoiding daytime naps. Patients should have a regular active daytime schedule with fresh air breaks and should exercise regularly, but avoid reading or watching TV in bed. To reduce the risk for accidents, driving and/or using heavy machinery should be avoided when a patient experiences drowsiness. Likewise, to minimize the potential impact on the care of children or the elderly, assistance should be sought if a patient experiences drowsiness.

5.2 Management of Somnolence Based on Medication

As shown in Fig. 1, different antipsychotics had different risks for somnolence. Choosing an FDA-approved medication with a low rate of somnolence with equal efficacy in reducing psychotic, manic, or bipolar depressive symptoms should be prioritized when somnolence is a concern. However, other side effects, including weight gain and EPS should also be considered.

5.3 Management of Somnolence Based on Psychiatric Diagnoses and Comorbid Medical Conditions

All antipsychotics have been developed through studies in patients with schizophrenia. Using placebo as a common comparator (Tables 1, 3, 4), this review and our previous analyses have shown that overall, patients with schizophrenia were less likely to report somnolence and discontinue the study than patients with bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder [1, 2, 3, 4]. Since no study has included patients with a different diagnosis, and it is impossible to conduct a study that includes all patients with different diagnoses, whether the difference in the incidence of antipsychotic-induced somnolence between patients with schizophrenia and those with other psychiatric conditions is a true finding or an artefact will remain uncertain. However, the fixed-dosing schedule and a lower risk for somnolence relative to placebo of the majority of antipsychotics in schizophrenia compared with bipolar disorder supports that patients with schizophrenia are less likely to experience somnolence than are those with bipolar disorder.

In addition, sleep duration and quality of sleep could also affect the incidence of somnolence in patients with schizophrenia or bipolar disorder, but the magnitude of interference could not be established. Regardless, starting at a lower dose with a lower titration in patients with bipolar depression is more likely to reduce the risk for premature discontinuation. In contrast, clinical observation supports that somnolence and sedation may be beneficial to patients with acute psychosis, mania, agitation, and/or insomnia. Therefore, starting doses and titration speed of antipsychotics in different psychiatric conditions should be personalized.

Clinicians should keep in mind that the data reviewed here were from patients with relatively “pure” schizophrenia or bipolar disorder. Patients with some comorbid psychiatric conditions such as a substance use disorder have been excluded in previous studies (Tables 1, 2, 3, 4). Other factors with the potential to affect daytime sleepiness, such as obstructive sleep apnea, obesity, tobacco smoking, and medication(s) for medical diseases, have never been studied. Psychiatric and medical comorbidities in patients with a psychotic disorder or a mood disorder are commonly high [106, 107, 108]. The severity of symptoms with depression and anxiety can also affect daytime sleepiness. Clinicians should take all these into consideration before starting an antipsychotic to avoid unanticipated consequences.

5.4 Management of Somnolence Based on Doses

It remains unclear whether antipsychotic-induced somnolence has a threshold. With the exception of quetiapine-XR in bipolar depression, major depressive disorder, and generalized anxiety disorder [2], few studies utilized different fixed doses in different psychiatric conditions (Tables 1, 3, 4). Therefore, the dose-dependent relationship between an antipsychotic drug and the rate of somnolence is very difficult to establish. Even within some studies with different fixed doses, the relationship is difficult to determine because the aim of the initial study design was focused on efficacy rather than on somnolence or other side effects.

The best data for the dose-dependent relationship between an antipsychotic and the rate of somnolence were from quetiapine-XR studies in major depressive disorder and generalized anxiety disorder [2], in which we found that antipsychotic-induced somnolence was dose-dependent, but the threshold for a significant difference of quetiapine relative to placebo appeared to be differ in different psychiatric conditions. The dose-dependence was non-linear. Instead, the quetiapine-induced somnolence had a ceiling effect, supported by similar ARIs for somnolence from quetiapine-XR 150 and 300 mg/d in generalized anxiety disorder and similar ARIs for somnolence from quetiapine-IR 300 and 600 mg/d in bipolar depression [1, 2, 3]. It is likely that, before an antipsychotic reaches its maximal severity of somnolence, smaller doses will cause less somnolence. Accordingly, adjusting doses in reaction to somnolence may reduce the severity of somnolence and the risk for discontinuation due to somnolence. In addition, a lower than FDA-approved dose may be acceptable because a minimal effective dose for the majority of antipsychotics in schizophrenia or bipolar disorder remains unknown (see Sect. 3.5.3).

5.5 Minimizing Concurrent Medication

Co-occurrence of other psychiatric disorders such as anxiety disorder in patients with psychotic disorders or mood disorders is the rule rather than the exception [106]. Insomnia can be a symptom of schizophrenia, mania, depression, anxiety, or a neurological condition. Most hypnotics target GABA receptors or histamine receptors, which may have an additive effect on antipsychotic-induced somnolence. Anxiolytics such as benzodiazepines, antihistamines, and antidepressants such as mirtazapine and trazodone also potentially cause somnolence. Therefore, avoiding or minimizing co-current medication(s) with somnolence properties will reduce the risk or severity of antipsychotic-induced somnolence (Fig. 2).

5.6 Waiting for Tolerance

In most cases, the severity of antipsychotic-induced somnolence was mild to moderate [78, 109]. Only a very small number of patients discontinued a medication due to intolerable somnolence [78, 109]. How long patients should wait before discontinuing a medication due to somnolence remains unknown, although clinical observations support the occurrence of tolerance to antipsychotic-induced somnolence.

Previously, we found that in the acute treatment of schizophrenia, [109], the median time to the onset of somnolence was 2 days for asenapine and olanzapine, and 6, 3, and 7 days for risperidone, haloperidol, and placebo, respectively. The median duration of somnolence was 15 days for asenapine and olanzapine and 3, 22.5, and 4.5 days for risperidone, haloperidol, and placebo, respectively. In the long-term treatment of schizophrenia, the time to onset and duration of somnolence with asenapine and olanzapine was 9.0 versus 12 days and 22 versus 21 days, respectively. In patients with persistent negative symptoms, the median time to onset and duration of somnolence with asenapine and olanzapine were 9.0 versus 7.5 days and 25.0 versus 41.5 days, respectively.

In bipolar mania [109], the median time to onset and duration of somnolence with asenapine, olanzapine, and placebo were 1, 2, and 2 days and 7, 8.5, and 5 days, respectively. Taken together, the onset of somnolence in short-term studies was within a few days, and the duration was within a couple of weeks. In contrast, the onset in long-term studies was within a couple of weeks and the duration was 3–6 weeks. Therefore, after utilizing other strategies such as decreasing the dose of a drug and reducing or eliminating concurrent medications, it is reasonable to wait about 4 weeks before discontinuing the drug because of somnolence.

5.7 Using Stimulant and Stimulant-Like Agents

Stimulants can potentially cause or worsen psychosis in schizophrenia and mania/hypomania in bipolar disorder. For these reasons, this group of medications has not been systematically studied in these two disorders that essentially or commonly need antipsychotics. Most studies of stimulants in schizophrenia have used modafinil or armodafinil [110, 111, 112, 113, 114, 115]. The most recent meta-analysis of randomized trials (pooled N = 372; median duration 8 weeks) concluded that modafinil or armodanifil (200 mg/d) had a significant effect on improvement of negative symptoms with small effect sizes. The absolute advantage was also small, and the advantage disappeared when chronically ill patients or those with a high negative symptom burden were treated. Modafinil/armodafinil did not benefit or worsen other symptom dimensions of schizophrenia. Meanwhile, cognition, fatigue, daytime drowsiness, adverse events, and dropout rates did not differ significantly between modafinil or armodafinil and placebo groups [111].

In addition to modafinil and armodafinil [116], methylphenidate has been studied in bipolar depression with open-label therapy adjunctive to a mood stabilizer and ongoing psychotropics [117]. The overall efficacy of armodafinil adjunctive to a mood stabilizer, including some atypical antipsychotics in bipolar depression, was inconsistent. Some but not all studies demonstrated that armodafinil improved energy/fatigability and leaden paralysis/physical energy [116]. Although modafinil/armodafinil adjunctive to a mood stabilizer and/or an antipsychotic(s) did not increase the risk for switching to mania/hypomania or worsen psychosis, the benefit and risk of using these agents for antipsychotic-induced somnolence needs further investigation.

6 Conclusions

According to randomized placebo-controlled and active-controlled studies of antipsychotics in schizophrenia, bipolar mania, and bipolar depression, and the incidence of self-reported somnolence, antipsychotics can be classified as high somnolence (clozapine), moderate somnolence (olanzapine, perphenazine, quetiapine-IR or XR, risperidone, and ziprasidone), and low somnolence (aripiprazole, asenapine, haloperidol, lurasidone, paliperidone, and cariprazine). Patients with schizophrenia are less likely to have antipsychotic-induced somnolence than are those with bipolar disorder. Using an antipsychotic with a higher risk for somnolence may be appropriate for patients, especially as inpatients, with acute psychosis, mania, agitation, and/or insomnia. In contrast, for patients with depression, stable schizophrenia, or bipolar disorder, especially as outpatients, an antipsychotic with a lower risk of somnolence is preferred. Educating patients about healthy sleep hygiene, starting a drug dose based on diagnoses, reducing the dose and slowing the titration of a drug, and minimizing concurrent somnolence-prone medications are important strategies for the management of somnolence. Although the H1 receptor blockade may play a major role in antipsychotic-induced somnolence, interactions between multiple neurotransmitters and receptors are inevitable in antipsychotic-induced somnolence. Future studies should use rating scales to monitor changes in antipsychotic-induced somnolence.

Notes

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.

Compliance with Ethical Standards

Funding

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.

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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.Google Scholar
  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.PubMedCrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.CrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.CrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.CrossRefPubMedGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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).Google Scholar
  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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011;34:845–58.PubMedPubMedCentralCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedPubMedCentralCrossRefGoogle 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.PubMedGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle Scholar
  95. 95.
    Church DS, Church MK. Pharmacology of antihistamines. World Allergy Organ J. 2011;4(3 Suppl):S22–7.PubMedPubMedCentralGoogle 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.PubMedCrossRefGoogle Scholar
  97. 97.
    Monti JM. Serotonin control of sleep-wake behavior. Sleep Med Rev. 2011;15:269–81.PubMedCrossRefGoogle 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.Google Scholar
  99. 99.
    Berridge CW, Schmeichel BE, España RA. Noradrenergic modulation of wakefulness/arousal. Sleep Med Rev. 2012;16:187–97.PubMedPubMedCentralCrossRefGoogle 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.PubMedCrossRefGoogle Scholar
  101. 101.
    Yeomans JS. Muscarinic receptors in brain stem and mesopontine cholinergic arousal functions. Handb Exp Pharmacol. 2012;208:243–59.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedPubMedCentralCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedPubMedCentralCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedPubMedCentralCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedPubMedCentralGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedPubMedCentralCrossRefGoogle 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.CrossRefGoogle Scholar
  117. 117.
    Dell’Osso B, Ketter TA. Use of adjunctive stimulants in adult bipolar depression. Int J Neuropsychopharmacol. 2013;16(1):55–68.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Division of Mood DisordersShanghai Hongkou District Mental Health CenterShanghaiChina
  2. 2.Department of PsychologyWeifang Medical UniversityShandongChina
  3. 3.Department of NeurologyWeifang Medical University Affiliated HospitalShandongChina
  4. 4.Mood and Anxiety Clinic in the Mood Disorders Program of University Hospitals Case Medical Center/Case Western University School of MedicineClevelandUSA

Personalised recommendations