CHAPTER 27
Quetiapine
Peter F. Buckley, M.D.
Adriana E. Foster, M.D.
Matthew Byerly, M.D.
History and Discovery
Quetiapine is a second-generation antipsychotic (SGA) developed and subsequently marketed by AstraZeneca. In preclinical trials, quetiapine showed the features associated with antipsychotic efficacy, as well as a low rate of motor effects (Goldstein 1999; Nemeroff et al. 2002). Quetiapine was approved in 1997 by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia; it was subsequently approved in Europe and in other countries worldwide. Additional approvals and indications for quetiapine’s use in bipolar disorder, as well as approval of an extended-release formulation of quetiapine, have followed (Möller et al. 2007; Peuskens et al. 2007). The extended-release formulation has an additional indication as adjunctive treatment for major depression in patients who show inadequate response to antidepressants alone.
Structure–Activity Relations
Quetiapine is an SGA of the dibenzothiazepine class (Figure 27–1). Its complex neuropharmacology includes a relatively low binding profile for dopamine type 2 (D2) receptors (Kapur et al. 2000). Indeed, considering the idea that an antipsychotic needs to occupy 60% or more of D2 receptors in order to be clinically efficacious (Kapur et al. 2000), quetiapine’s low D2 binding—typically, approximately 30%—is noteworthy.
FIGURE 27–1. Chemical structure of quetiapine
Source. PubChem Compound Database, National Center for Biotechnology Information. Available at: http://www.ncbi.nlm.nih.gov/pccompound.
In attempting to reconcile this apparently subtherapeutic D2 receptor antagonism with the well-recorded efficacy of quetiapine as an antipsychotic, Kapur et al. (2000) proposed an elegant kiss and run hypothesis to explain quetiapine’s mechanisms of action. In a series of studies, they found that when D2 receptor occupancy with quetiapine was measured with positron emission tomography at shorter intervals (4 hours and 6 hours) than the conventional 12 hours after the last dose was taken, quetiapine did indeed show high D2 occupancy. In contrast to other antipsychotics, quetiapine demonstrated a more rapid “run-off” from D2 receptors; that is, there was rapid dissociation of the D2 receptors (Kapur et al. 2000).
Like clozapine, quetiapine has strong binding at 5-hydroxytryptamine (serotonin) type 2 (5-HT2) receptors. This profile contrasts with its relatively weak affinity for other subclasses of the serotonin receptor family (Nemeroff et al. 2002). Quetiapine also has strong affinity for α1-noradrenergic receptors. This antagonism may relate to its propensity to induce postural hypotension—especially during rapid dosage titration. Additionally, quetiapine has strong antagonism at histamine type 1 (H1) receptors. This most likely relates to its sedative effect. H1 receptor antagonism also appears to be a key contributor to weight gain during quetiapine therapy (Kim et al. 2007).
Pharmacokinetics and Disposition
Quetiapine’s absorption in the gastrointestinal tract is unaffected by food. With the tablet formulation, peak blood levels are achieved in about 2 hours, with effective plasma levels sustained for approximately 6 hours (DeVane and Nemeroff 2001). Although this provides the basis for the usual clinical regimen of twice-daily dosing, a short-term trial comparing once-daily dosing with twice-daily dosing demonstrated that the two regimens were equivalent in terms of efficacy and tolerability (Chengappa et al. 2003b). A positron emission tomography study (Mamo et al. 2008) found comparable plasma levels and D2 receptor occupancy between the immediate-release (IR) and the extended-release (XR) formulation.
Quetiapine is metabolized by cytochrome P450 (CYP) 3A4 to inactive metabolites. Coadministration with drugs that alter CYP3A4 activity is likely to result in clinically significant interactions. For example, the anticonvulsants carbamazepine and phenytoin are CYP3A4 inducers, and in their presence quetiapine dosages may need to be increased because of accelerated drug clearance (Potkin et al. 2002a, 2002b; Strakowski et al. 2002). Ritonavir, erythromycin, ketoconazole, and nefazodone are potent inhibitors of CYP3A4, and their concomitant use with quetiapine requires caution.
Clinical trials (Kahn et al. 2007; Lindenmayer et al. 2008) comparing the efficacy and tolerability of the XR formulation with the regular IR formulation indicated that quetiapine XR given once daily (at dosages of 400–800 mg/day) was effective for the treatment of schizophrenia and, on average, was similar in efficacy and tolerability to treatment with quetiapine IR. Quetiapine is excreted in the kidneys and is not affected by gender or smoking status. The metabolism of quetiapine is reduced by approximately 30% with advancing age (Goldstein 1999). Quetiapine is available only in tablet formulations; there are no liquid or intramuscular preparations.
Indications and Efficacy
Quetiapine in the XR and IR formulations is FDA approved for the following indications in adults: treatment of schizophrenia; acute treatment of manic or mixed episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium or divalproex; acute treatment of depressive episodes associated with bipolar I or II disorder; and maintenance treatment of bipolar I disorder as an adjunct to lithium or divalproex. The XR formulation is also approved for use as an adjunct to antidepressant therapy in the treatment of major depressive disorder in adults.
In addition, quetiapine is efficacious in the treatment of schizophrenia and bipolar disorder in pediatric populations (Barzman et al. 2006; DelBello et al. 2007; McConville et al. 2000). The IR formulation is FDA approved for the treatment of schizophrenia in adolescents (ages 13–17 years) and the acute treatment of manic or mixed episodes associated with bipolar I disorder in children and adolescents (ages 10–17 years).
There are also reports of quetiapine’s efficacy in treating anxiety disorders, obsessive-compulsive disorder (OCD), borderline personality disorder, and Parkinson’s disease. These uses have not been approved by the FDA. The use of any medication (in this case quetiapine) in situations that are not FDA-approved indications is not recommended in clinical practice.
Schizophrenia
Registration and early trials of quetiapine (Arvanitis and Miller 1997; Borison et al. 1996; Copolov et al. 2000; King et al. 1998; Peuskens and Link 1997; Small et al. 1997) demonstrated that quetiapine is an efficacious antipsychotic for the treatment of schizophrenia. Short-term (6-week) trials compared quetiapine, haloperidol, and placebo using quetiapine at flexible daily dosages of ≤250 mg or ≤750 mg (Small et al. 1997) or fixed daily dosages of 75 mg, 150 mg, 300 mg, 600 mg, or 750 mg (Arvanitis and Miller 1997); the latter trial found that 300 mg/day was superior (but not statistically significantly so) to the lower and higher dosages and was the only dosage demonstrating efficacy for negative symptoms (Arvanitis and Miller 1997). These studies established a range of effective dosages for quetiapine and also suggested that dosages of ≥250 mg/day were superior to lower dosages.
Subsequent studies helped refine quetiapine dosing strategies. An 8-week fixed-dosage comparison trial of quetiapine at 600 mg/day versus haloperidol at 20 mg/day showed similar efficacy for the two drugs in patients who were partial responders to first-generation antipsychotics (FGAs) (Emsley et al. 2000). A study comparing a rapid titration strategy (beginning at 200 mg/day, increasing to 800 mg/day by day 4) with a more conventional dosing strategy (50 mg/day on day 1, increasing up to 400 mg/day by day 5) showed similar efficacy and tolerability for the two strategies (Pae et al. 2007). Growing evidence from more recent studies (Honer et al. 2012; Lindenmayer et al. 2011) discourages the use of very-high-dosage quetiapine, and data are still lacking to indicate that dosages above 300–400 mg/day are more efficacious.
Most studies comparing quetiapine with either an FGA or another SGA have reported similar efficacy for the agents in treating schizophrenia (Emsley et al. 2000; Peuskens and Link 1997; Small et al. 1997). A 4-month open-label trial of quetiapine and risperidone showed overall comparability between the two agents (Mullen et al. 2001). An 8-week comparative trial of quetiapine (with an average dosage of 525 mg/day) and risperidone (with an average dosage of 5.2 mg/day) also found the drugs similar in efficacy (Zhong et al. 2006). Quetiapine-treated patients had fewer extrapyramidal side effects (EPS), lower prolactin levels, and fewer sexual side effects. Whereas weight gain was similar in both treatment groups, quetiapine was more sedating and was more frequently associated with dry mouth than was risperidone. A 6-month study comparing quetiapine and risperidone reported better efficacy for risperidone (Potkin et al. 2006), with quetiapine associated with more polypharmacy. A 6-month double-blind comparative trial of quetiapine and olanzapine (Kinon et al. 2006) reported that quetiapine-treated patients were less likely to complete the study, although relapse rates were comparable overall in the two treatment groups. More weight gain occurred in olanzapine recipients. As yet, no studies have directly compared quetiapine with aripiprazole, iloperidone, asenapine, or lurasidone in the treatment of schizophrenia.
The most extensive comparative evaluation of quetiapine and other SGAs comes from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). In the Phase I study, more quetiapine-treated patients than olanzapine-treated patients had discontinued treatment by 18 months (78% vs. 64%), and a similar (not statistically significant) trend was seen in comparisons of quetiapine versus risperidone, ziprasidone, or perphenazine (Lieberman et al. 2005). In the Phase II study, discontinuation rates favored clozapine and olanzapine over risperidone and quetiapine (McEvoy et al. 2006). The results from the tolerability pathways were mixed and showed similar efficacy for quetiapine versus other agents (Stroup et al. 2007). The findings relating to quetiapine’s relative adverse-effects profile in this formative study are presented in the section “Side Effects and Toxicology.” Another interesting analysis from the CATIE schizophrenia studies (Stroup et al. 2007) examined how those patients originally assigned to the perphenazine arm of the Phase I study fared. In this analysis, switching to quetiapine was more efficacious than switching to any of the other agents. Many of the efficacy and tolerability differences among agents observed in the CATIE schizophrenia studies have been attributed to differential dosing profiles.
An analogous comparative trial of quetiapine, risperidone, and olanzapine was conducted with patients experiencing a first episode of psychosis—the Comparison of Atypicals in First Episode Psychosis (CAFE) study. Here, discontinuation rates were similar across drugs over the 1-year trial (McEvoy et al. 2007). Two recent studies inform the comparative efficacy and tolerability of quetiapine in adolescents with psychosis (and related conditions) (Arango et al. 2014; Pérez-Iglesias et al. 2014). Pérez-Iglesias et al. (2014) found that quetiapine increased weight and cholesterol levels over 3 months. Similarly, Arango et al. (2014) found that quetiapine increased weight (less so than olanzapine, more so than risperidone) over 6 months in children and adolescents, although in this study, there was no rise in cholesterol in quetiapine-treated patients.
The use of quetiapine in patients with prodromal features of schizophrenia has not yet been studied. A small study of quetiapine in schizophrenia patients with comorbid substance abuse was inconclusive (Brunette et al. 2009).
Mood Disorders
There is evidence that quetiapine is an effective and well-tolerated antipsychotic for treating patients with bipolar mania and bipolar depression. Bowden et al. (2005) demonstrated that quetiapine was superior to placebo in the treatment of mania. In this multicenter study, significantly more patients treated with quetiapine than with placebo met criteria for response (greater than 50% decrease from baseline score on the Young Mania Rating Scale) at 7, 21, and 84 days. Building on initial evidence for mood effects that was derived from observations on mood assessment items in the pivotal schizophrenia trials, the Quetiapine Experience with Safety and Tolerability (QUEST) study compared quetiapine with risperidone in a 4-month open-label, flexible-dose trial (Mullen et al. 2001). This study included patients with schizophrenia, schizoaffective disorder, bipolar disorder, and depression. At week 16, the mean dosage of quetiapine was 317 mg/day, and the mean dosage of risperidone was 4.5 mg/day. Mean improvement on the Hamilton Rating Scale for Depression was significantly greater in quetiapine recipients than in risperidone recipients.
Calabrese et al. (2005) and Thase et al. (2006) have studied quetiapine use in patients with bipolar depression. In an 8-week trial, Calabrese et al. (2005) compared two dosages of quetiapine (300 mg/day and 600 mg/day) with placebo. Both dosages were efficacious, with improvements observed across the full range of depressive and anxiety symptoms. Fifty-eight percent of patients met a priori criteria for treatment response. Additionally, this antidepressant effect was observed with a once-daily dosage regimen. In a subsequent similar study (Thase et al. 2006) of the same two dosages (300 mg/day and 600 mg/day), quetiapine was again compared with placebo in an 8-week trial in patients with bipolar depression. Again, both dosages of quetiapine showed efficacy across a broad range of depressive symptoms. These two studies led to FDA approval of quetiapine for treating bipolar depression.
Two large 8-week international multicenter studies—Efficacy of Monotherapy Seroquel in BipOLar DEpressioN (EMBOLDEN) I (Young et al. 2010) and II (McElroy et al. 2010)—compared quetiapine 300 mg/day and 600 mg/day with lithium 600–1,800 mg/day and placebo (EMBOLDEN I) and with paroxetine 20 mg/day and placebo (EMBOLDEN II) in bipolar patients with a major depressive episode. In the first study (Young et al. 2010), quetiapine at both dosages, but not lithium, led to significant improvement in symptoms of depression and anxiety. Compared with patients receiving placebo, patients treated with quetiapine 300 mg/day and 600 mg/day showed significant improvement on the Sheehan Disability Scale. In the second study (McElroy et al. 2010), quetiapine 300 mg/day and 600 mg/day, but not paroxetine 20 mg/day, led to significant improvement in depressive and anxiety symptoms. Neither lithium nor paroxetine led to significant functional improvement over placebo in these studies. In both studies, a small subgroup of patients with rapid-cycling bipolar disorder did not improve significantly from baseline with any of the drugs administered (quetiapine, lithium, or paroxetine).
In a long-term naturalistic study (Ketter et al. 2010) of quetiapine administered to 96 patients with bipolar disorder in a clinical setting, 38.5% of patients continued taking quetiapine for 328 days without the addition of other psychotropics, whereas 22.9% of patients continued taking quetiapine for 613 days with the addition of another psychotropic, most often for depression. In a small double-blind, placebo-controlled pilot study (DelBello et al. 2009) of quetiapine 300–600 mg/day in depressed adolescents with bipolar disorder, quetiapine neither differentiated from placebo nor induced significant change in symptoms from baseline to endpoint on measures of depressive, anxiety, or manic symptoms or clinical global impressions of bipolar severity. Bourin et al. (2014) reported superior efficacy when lithium was added to quetiapine XR, and this combination was well tolerated.
Dorée et al. (2007) reported that in a pilot study (n=20), quetiapine was an efficacious augmenting agent for antidepressant treatment in major depression. Anderson et al. (2009) also reported on quetiapine’s efficacy as an adjunctive treatment for patients with refractory depression. Quetiapine XR monotherapy at a mean daily dosage of 162.2 mg was shown to decrease symptoms of major depression at 8 weeks versus placebo (Bortnick et al. 2011). Cutler et al. (2009) reported that quetiapine XR 300 mg/day led to significantly higher rates of response and remission versus placebo in major depression, whereas quetiapine XR 150 mg/day had a significant effect only on response versus placebo. Quetiapine at dosages of 150–300 mg/day is now approved by the FDA as an adjunct to antidepressant treatment for a major depressive episode. In one of the studies leading to FDA approval of quetiapine XR for this indication, El-Khalili et al. (2010) demonstrated that quetiapine XR at 300 mg/day led to significant improvement in symptoms of depression from the first week of treatment when compared with placebo. In a review of registration studies for the major depression indication, McIntyre et al. (2009) concluded that quetiapine XR provides rapid and sustained relief of major depressive symptoms. Weisler et al. (2012) also reported substantial improvement in depressive symptoms in two 6-week clinical trials of quetiapine XR. Remission at 6 weeks was achieved by 23.5% of patients taking 150 mg/day and by 28.8% of patients taking 300 mg/day of quetiapine. Lin et al. (2014) used a national insurance database from Taiwan to compare in a mirror image design the effect of augmentation of antidepressant therapy over 1 year in patients with major depressive disorder. Quetiapine, olanzapine, and aripiprazole augmentations were each effective in reducing health care utilization. Masi et al. (2015) reported improvement from and tolerability of quetiapine in a small open-label study comparing quetiapine and risperidone in adolescents with bipolar disorder and comorbid conduct disorder.
Anxiety Disorders
The sedative/calming effect of quetiapine was well described in a variety of product registration trials (Chengappa et al. 2003a; Weiden et al. 2006), and studies in bipolar I disorder and bipolar depression (Calabrese et al. 2005; Hirschfeld et al. 2006; Thase et al. 2006) demonstrated improvements in anxiety symptoms with quetiapine.
In a small 8-week study (Vaishnavi et al. 2007) of social phobia treatment, there was no significant difference in Brief Social Phobia Scale scores between the quetiapine and placebo groups, although people who took quetiapine did show a robust response as measured by Clinical Global Impression—Improvement Scale (CGI-I) scores.
Two small studies of quetiapine augmentation in patients with generalized anxiety disorder (GAD) who had not responded to antidepressant therapy (Katzman et al. 2008; Simon et al. 2008) yielded contradictory results. A large double-blind, randomized, placebo-controlled study of monotherapy for GAD (Bandelow et al. 2010) compared quetiapine XR 50 mg/day or 150 mg/day, paroxetine 20 mg/day, and placebo. Significant separation from placebo on the primary outcome variable (mean reduction in Hamilton Anxiety Scale (Ham-A) total score) was seen for quetiapine XR 50 mg/day and 150 mg/day as early as 4 days into treatment, but not for paroxetine. After 8 weeks of treatment, both quetiapine 150 mg/day and paroxetine 20 mg/day had higher anxiety remission rates (Ham-A score ≤7) compared with placebo. Weight gain greater than or equal to 7% of body weight was noted in a higher percentage of patients treated with quetiapine than of those taking placebo. In a parallel-group, double-blind, placebo-controlled study by Katzman et al. (2011), 432 patients with GAD were randomly assigned to continue treatment long term with quetiapine XR (50 mg/day, 150 mg/day, or 300 mg/day) or to switch to placebo after an open-label run-in and stabilization period. During the randomized treatment period (from the point of random assignment to the end of the study), quetiapine XR significantly increased the time to occurrence of an anxiety event and decreased anxiety symptoms compared with placebo.
An analysis of the tolerability of quetiapine in patients with various disorders showed that patients with GAD, bipolar depression, or refractory major depression had significantly higher rates of discontinuation due to adverse effects versus placebo than did patients with schizophrenia or mania when treated with quetiapine XR dosages of ≥300 mg/day (Wang et al. 2011). In a systematic review and meta-analysis of all available trials of SGA medications, quetiapine was observed to have the most robust effect on anxiety symptoms (LaLonde and Van Lieshout 2011). The antianxiety effects of quetiapine were observed at lower dosages (typically 150 mg/day) than those used in schizophrenia studies, and the effects included overall improvement as well as remission. However, quetiapine was also associated with weight gain and high rates of medication discontinuation in these studies of anxiety disorder (LaLonde and Van Lieshout 2011). In three 8-week studies of quetiapine XR, Stein et al. (2011) reported rates of study discontinuation due to side effects of 13%, 16%, and 24% for quetiapine dosages of 50 mg/day, 150 mg/day, and 300 mg/day, respectively. In an 8-week placebo-controlled comparative trial of quetiapine XR and escitalopram, comparable improvements in anxiety symptoms, occurring early in the study, were observed with quetiapine and escitalopram (Merideth et al. 2012). In a more “real-world” population of patients with bipolar depression with substantial comorbidities (especially GAD), quetiapine XR showed no advantages over placebo in an 8-week trial (Gao et al. 2014).
At present, the FDA has not approved quetiapine for use in any anxiety disorders.
Other Disorders
Several small studies of quetiapine augmentation (at dosages up to 400 mg/day) of SSRI pharmacotherapy in refractory OCD yielded contradictory results (Atmaca et al. 2002; Carey et al. 2005; Fineberg et al. 2005); although improvement in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores was noted in patients treated with quetiapine, the response to quetiapine did not differentiate from placebo. Quetiapine’s efficacy as an augmenting agent with antidepressants in treatment-resistant OCD was recently reviewed in a meta-analysis of five double-blind randomized controlled trials (RCTs) (Komossa et al. 2010). Adjunctive quetiapine was not superior to placebo in reducing Y-BOCS scores by 25% (the criterion for response in these studies), but it did reduce the Y-BOCS score significantly by the endpoint compared with placebo. A small case series also showed that adjunctive quetiapine response may be enduring (Dell’Osso et al. 2006). Veale et al. (2014) conducted a meta-analysis of SGAs in OCD. In contrast to benefits seen with risperidone or aripiprazole, there was no effect seen with augmentation with either quetiapine or olanzapine.
Quetiapine has been studied in the treatment of posttraumatic stress disorder (Ahearn et al. 2006; Byers et al. 2010; Hamner et al. 2003; Kozaric-Kovacic and Pivac 2007; Sokolski et al. 2003; Stathis et al. 2005). All but one of the studies (Stathis et al. 2005) involved quetiapine being administered to veterans as an adjunctive agent added to selective serotonin reuptake inhibitors (SSRIs), other antidepressants, sedative–anxiolytics, or anticonvulsants. All were open-label studies, and with the exception of a retrospective chart review comparing quetiapine with the α1 receptor antagonist prazosin (Byers et al. 2010), none had a comparison group. The average quetiapine dosage used in these studies was 100–335 mg/day administered for 6–8 weeks. Quetiapine decreased symptoms of avoidance, hyperarousal, and recollection in the populations studied.
Other Conditions and Patient Populations
Quetiapine has also been used in elderly populations. In a 1-year open-label trial of quetiapine treatment in 151 elderly patients (mean age 76.8 years) with psychotic disorders (McManus et al. 1999), 52% of patients showed symptom improvement (as measured by a 20% or greater decline in Brief Psychiatric Rating Scale total score). Seventy percent of patients had some organic condition, predominantly Alzheimer’s disease, with the remaining patients having a diagnosis of schizophrenia, schizoaffective disorder, or delusional disorder. Quetiapine was well tolerated at a mean dosage of 100 mg/day. A 10-week study comparing two dosages of quetiapine (100 mg/day and 200 mg/day) with placebo in nursing home residents with dementia and agitation (Zhong et al. 2007) reported that only the 200 mg/day quetiapine dosage was efficacious in treating agitation. Quetiapine (100 mg/day) was also compared with risperidone (1.0 mg/day), olanzapine (5.5 mg/day), and placebo over 36 weeks in the CATIE Alzheimer’s disease study (Schneider et al. 2006). Overall, no effect on the Alzheimer’s Disease Cooperative Study–Clinical Global Impression of Change Scale was seen with any of the agents, and there were no differences between agents in time to discontinuation.
In contrast to the encouraging findings from open-label studies of quetiapine for Parkinson’s-associated psychosis, four of five later double-blind RCTs (Kurlan et al. 2007; Ondo et al. 2005; Rabey et al. 2007; Shotbolt et al. 2009) found no benefit for quetiapine in this population. The single positive RCT (Fernandez et al. 2009) was small (N=16) and excluded patients with delusions, which appear to be more difficult to treat than hallucinations in Parkinson’s disease (Shotbolt et al. 2010).
Agitation is a core aspect of several conditions. Currier et al. (2006) reported an interesting study of quetiapine in agitated patients in the emergency department. Here, Currier and colleagues reported that quetiapine could be used as an acute antiagitation agent if the dosage titration is judicious. Postural hypotension was observed in this study. Other studies of quetiapine and agitation report benefits in treating hostility both in adults with schizophrenia (Chengappa et al. 2003a) or bipolar disorder (Buckley et al. 2007) and in children with hostile behaviors (Barzman et al. 2006; Findling et al. 2007).
Black et al. (2014) examined low-dosage quetiapine (150 mg/day) and moderate-dosage quetiapine (300 mg/day) versus placebo in an 8-week, double-blind trial of inpatients with borderline personality disorder. Both dosages of quetiapine were effective across a range of symptoms in these patients, although there were more side effects with moderate-dosage quetiapine.
Side Effects and Toxicology
To illustrate the profile of adverse effects typically seen with quetiapine, we have tabulated the results from an 8-week RCT (Zhong et al. 2006) (Table 27–1) in which quetiapine was compared with risperidone. Overall, quetiapine was well tolerated, with only 6% of patients discontinuing treatment because of adverse effects.
Quetiapine (n=338; median dosage=525 mg/day) |
Risperidone (n=334; median dosage=5.2 mg/day) |
|||
Adverse effect |
n (%) |
n (%) |
P valuea |
|
Somnolence |
89 (26.3) |
66 (19.7) |
0.044 |
|
Headache |
51 (15.1) |
56 (16.7) |
0.599 |
|
Weight gain |
48 (14.2) |
45 (13.4) |
0.824 |
|
Dizziness |
48 (14.2) |
32 (9.6) |
0.0737 |
|
Dry mouth |
41 (12.1) |
17 (5.1) |
<0.01 |
|
Dyspepsia |
22 (6.5) |
26 (7.8) |
0.552 |
|
Nausea |
21 (6.2) |
22 (6.6) |
0.876 |
|
Pain |
21 (6.2) |
24 (7.2) |
0.536 |
|
Asthenia |
17 (5.0) |
14 (4.2) |
0.714 |
|
Agitation |
17 (5.0) |
10 (3.0) |
0.238 |
|
Pharyngitis |
15 (4.4) |
24 (7.2) |
0.140 |
|
Akathisia |
13 (3.8) |
28 (8.4) |
0.016 |
|
Vomiting |
13 (3.8) |
18 (5.4) |
0.364 |
|
Dystonia |
1 (0.3) |
18 (5.4) |
<0.001 |
|
aFisher exact test, unadjusted. Source. Adapted from Zhong et al. 2006. |
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Overall, the adverse-effect profile of the XR formulation of quetiapine is similar to that of the IR formulation.
Somnolence, Sedation, and Dizziness
Somnolence is a common side effect of quetiapine that most likely relates to its antihistaminergic activity. Although somnolence occurs early in treatment and generally decreases over time, it may persist in some patients. It may also cause patients to stop taking their medication, because sedation is generally a poorly tolerated side effect. In the bipolar depression study by Calabrese et al. (2005), somnolence was observed in 24% of patients taking quetiapine at a dosage of 300 mg/day and in 27% of patients taking 600 mg/day. In the long-term study by Ketter et al. (2010), sedation was present in 19.8% of patients. Dizziness is another troublesome side effect, and it may be associated with postural hypotension, an effect that is of even greater concern. As with sedation, dizziness can sometimes cause discontinuation of quetiapine therapy.
Metabolic Effects
There is major concern about antipsychotic-induced weight gain and metabolic disturbances (Allison et al. 1999; Newcomer 2005; Newcomer et al. 2002). Quetiapine is clearly associated with weight gain, although the weight gain effect is not as great as that seen with clozapine or olanzapine. On the other hand, the weight-effects profile of quetiapine is not as favorable as that of ziprasidone or aripiprazole (Newcomer 2005) or that of the newer agents asenapine and lurasidone (Allergan 2015; Sunovion 2013)
In the 8-week comparative study by Zhong et al. (2006), weight gain that was clinically significant (a 7% increase above baseline weight) was observed in 10.4% of patients taking quetiapine and in 10.5% of patients taking risperidone. In the Phase I CATIE study, quetiapine had a moderate effect on weight (and other aspects of the metabolic profile) compared with other agents (Lieberman et al. 2005). Those data are shown in Table 27–2. In the first-episode CAFE study, quetiapine had a less favorable weight-effects profile compared with olanzapine or risperidone. Eighty percent of patients taking quetiapine gained weight, compared with 50% of those taking olanzapine and 2% of those taking risperidone. Interestingly, females taking quetiapine were less likely than males to gain weight in this 1-year study of patients treated for their first episode of psychosis (Patel et al. 2009). It is also important to consider quetiapine’s propensity to induce weight gain among bipolar patients (especially because these patients may also be taking lithium or valproic acid). In the 8-week EMBOLDEN I (Young et al. 2010) and EMBOLDEN II (McElroy et al. 2010) trials, weight gain of more than 7% body weight was present in 4.6% and 9%, respectively, of patients taking quetiapine 300 mg/day versus 8.3% and 11.3%, respectively, of those taking quetiapine 600 mg/day. In EMBOLDEN I and EMBOLDEN II, the average weight gains in quetiapine-treated patients were 0.6 kg and 1.1 kg, respectively, for the 300-mg/day groups and 0.8 kg and 1.7 kg, respectively, for the 600-mg/day groups.
Olanzapine |
Quetiapine |
Perphenazine |
Risperidone |
Ziprasidone |
P value |
|
Weight gain >7%, n/total N (%) |
92/307 (30) |
49/305 (16) |
29/243 (12) |
42/300 (14) |
12/161 (7) |
<0.001 |
Weight change (lb), mean±SE |
9.4±0.9 |
1.1±0.9 |
−2.0±1.10 |
0.8±0.9 |
−1.6±1.10 |
<0.001 |
Blood glucose change (mg/dL), exposure-adjusted mean±SE |
13.7±2.50 |
7.5±2.5 |
5.4±2.8 |
6.6±2.5 |
2.9±3.4 |
0.59 |
Glycosylated Hb (%), exposure-adjusted mean±SE |
0.40±0.07 |
0.04±0.08 |
0.09±0.09 |
0.07±0.08 |
0.11±0.09 |
0.01 |
Cholesterol (mg/dL), exposure-adjusted mean±SE |
9.4±2.4 |
6.6±2.4 |
1.5±2.7 |
−1.3±2.40 |
−8.2±3.20 |
<0.001 |
Triglycerides (mg/dL), exposure-adjusted mean±SE |
40.5±8.90 |
21.2±9.20 |
9.2±10.1 |
−2.4±9.10 |
−16.5±12.20 |
<0.001 |
Note. Hb=hemoglobin; SE=standard error. P values for laboratory values and for the change in weight are based on ranked analysis of covariance with adjustment for whether patient had an exacerbation in the preceding 3 months and the duration of exposure to the study drug in Phase I. Mean values for metabolic factors (other than weight change) were also adjusted for duration of exposure to study drug. Source. Adapted from Lieberman et al. 2005. |
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In the bipolar depression study by Calabrese et al. (2005), the mean changes in glucose levels were 6 mg/dL and 3 mg/dL with quetiapine dosages of 600 mg/day and 300 mg/day, respectively. In the comparative study of quetiapine and risperidone in the treatment of schizophrenia (Zhong et al. 2006), the mean changes from baseline in fasting glucose levels were 1.8 mg/dL with quetiapine and 5.6 mg/dL with risperidone. The metabolic profile of quetiapine appeared moderate in the Phase I CATIE schizophrenia study (see Table 27–2). Newcomer et al. (2009) conducted a euglycemic clamp study of quetiapine and found little evidence of insulin insensitivity. A recent meta-analysis by the Cochrane group involving head-to-head comparisons of SGAs (Komossa et al. 2010) found that quetiapine was associated with significantly greater cholesterol elevations than risperidone (mean difference 8.61 mg/dL) and ziprasidone (mean difference 16.01 mg/dL). In the CATIE Phase I trial (Lieberman et al. 2005), which included patients with chronic schizophrenia, quetiapine led to a mean change from baseline fasting triglyceride levels of +19.2 mg/dL, whereas a mean change of +42.9 mg/dL was observed for olanzapine, +8.3 mg/dL for perphenazine, −2.6 mg/dL for risperidone, and −18.1 mg/dL for ziprasidone. In a population of young patients with early psychosis treated with quetiapine, olanzapine, or risperidone, the CAFE study (Patel et al. 2009) found that elevations in fasting triglyceride levels at 52 weeks were significantly greater in quetiapine-treated patients than in risperidone-treated patients (44.3 vs. 8.2 ng/mL, respectively). Correll et al. (2014) reported baseline results from the pragmatic study Recovery After an Initial Schizophrenia Episode (RAISE). All patients were in their first episode of psychosis, with less than 6 months of exposure to antipsychotics. Use of quetiapine was associated with a high ratio of triglycerides to high-density lipoprotein (HDL) cholesterol. The extent to which patients traverse during treatment from a normative metabolic state to dysregulation is also informative. In the first-episode CAFE study, treatment-emergent metabolic syndrome was observed among 51 patients (13.4% of the population in a study where 4.3% met metabolic syndrome criteria at study onset), with a distribution of 22 patients taking olanzapine, 18 taking quetiapine, and 11 taking risperidone (Patel et al. 2009). Another recent study of antipsychotic use in adolescents found an elevated risk of type 2 diabetes mellitus, with longer duration of antipsychotic exposure and olanzapine use conferring greater risk (Correll et al. 2014). In another first-episode comparative study, Pérez-Iglesias et al. (2014) found that first-episode patients treated with quetiapine, aripiprazole, or ziprasidone gained weight over 12 weeks of treatment, with >7% weight increase noted for 32% of patients receiving quetiapine, 45% of those receiving aripiprazole, and 23% of those receiving ziprasidone. Quetiapine and aripiprazole were also associated with greater increases in total cholesterol and low-density lipoprotein (LDL) cholesterol. Overall, quetiapine appears to carry a risk of causing weight gain and other metabolic disturbances. The potential that quetiapine may preferentially raise triglycerides is noteworthy, given that this effect could be a harbinger for later insulin resistance. This observation merits further consideration and vigilance over time.
Quetiapine is associated with a low risk of raising prolactin levels (Hamner et al. 1996; Lieberman et al. 2005; Small et al. 1997; Zhong et al. 2006).
Extrapyramidal Side Effects
The low-EPS advantage of quetiapine is compelling and consistent across studies. In the Seroquel Patient Evaluation on Changing Treatment Relative to Usual Medication (SPECTRUM) switch study (Larmo et al. 2005), switching to quetiapine from haloperidol, olanzapine, or risperidone was associated with a robust reduction in EPS. This low propensity for EPS was also seen in the bipolar depression studies (Calabrese et al. 2005; Thase et al. 2006).
Cardiovascular Effects
Quetiapine’s prescribing information (AstraZeneca 2013a, 2013b) carries a warning similar to that required in the prescribing information of many other antipsychotics concerning cardiovascular risks. The CATIE trial found no evidence of a heightened QTc risk with quetiapine relative to other SGAs and perphenazine (Lieberman et al. 2005). A curious and unsubstantiated claim is that quetiapine might have abuse potential (Pierre et al. 2005; Pinta and Taylor 2007). This observation merits further consideration and vigilance.
Other Effects
The potential of quetiapine to induce cataracts was studied in a pragmatic follow-up trial of patients (N=37; mean age 23 years) with first-episode psychosis that included regular slit-lamp ophthalmological examinations (Whitehorn et al. 2004). After exposure to quetiapine 500–600 mg/day for a mean of 22.4 months, none of the patients developed any ocular changes. Most clinicians do not obtain specialist eye examinations when prescribing quetiapine.
Abnormalities in thyroid hormone levels were observed in the large premarketing trials of quetiapine (Arvanitis and Miller 1997). A small RCT did find lower total thyroid hormone levels with quetiapine use, but no significant changes in free thyroxine (T4) or thyroid-stimulating hormone (TSH) levels (Kelly and Conley 2005).
Use During Pregnancy
As is the case with all SGAs, there is little information about the effects of quetiapine during pregnancy. A prospective study by McKenna et al. (2005) examined a sample of pregnant women in Canada, Israel, and England treated with SGAs, which was matched to a comparison group of pregnant women who were not exposed to these agents. Among them were 36 women treated with quetiapine. The pregnancy outcomes in the exposed and comparison groups were not significantly different, with the exceptions of the rate of low birth weight, which was 10% in exposed babies versus 2% in the comparison group (P=0.05), and the rate of therapeutic abortions, which was 9.9% in exposed women versus 1.3% in the comparison group (P=0.003). These findings suggest that atypical antipsychotics as a group are not associated with an increased risk for major malformations.
Conclusion
Quetiapine is now a well-established and widely prescribed antipsychotic. As detailed earlier, there is strong evidence for its efficacy in all of the current FDA-approved indications. Quetiapine is also used extensively under circumstances not approved by the FDA (i.e., off-label use), and evidence for its efficacy in some of these uses has been reviewed in this chapter. Additional clinical trials of quetiapine are ongoing (https.clinicaltrials.gov).
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