Chapter 30 Quetiapine

Print: Chapter 30. Quetiapine

http://www.psychiatryonline.com/popup.aspx?aID=430077&print=yes…

1 of 16

10/05/2009 16:12

Print Close Window

Peter F. Buckley, Adriana E. Foster: Chapter 30. Quetiapine, in The American Psychiatric Publishing Textbook of

Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American

Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.430073. Printed 5/10/2009 from

www.psychiatryonline.com

Textbook of Psychopharmacology >

Chapter 30. Quetiapine

HISTORY AND DISCOVERY

Quetiapine is a second-generation antipsychotic (SGA) developed and subsequently marketed by

AstraZeneca. In preclinical trials, quetiapine showed both the features associated with

antipsychotic efficacy and a low rate of motor effects (Goldstein 1999; Nemeroff et al. 2002). The

Phase III placebo-controlled clinical trials necessary for product registration confirmed this

preclinical impression and demonstrated that quetiapine was efficacious in treating the

manifestations of psychosis (Arvanitis and Miller 1997; Small et al. 1997). Of note, these studies

also reported a low rate of treatment-emergent extrapyramidal side effects (EPS) with quetiapine

use across a wide range of dosages that was comparable to the rate among placebo recipients.

Quetiapine was approved in 1997 by the U.S. Food and Drug Administration (FDA) for the treatment

of schizophrenia. Approval for use in Europe and in other countries worldwide has followed. Further

clinical trials in patients with mania (McIntyre et al. 2005; Vieta et al. 2005) and patients with

bipolar depression (Calabrese et al. 2005; Thase et al. 2006) led the FDA to approve additional

indications for quetiapine’s use in the acute and maintenance treatment of bipolar disorder. Most

recently, the FDA has also approved a slow-release formulation of quetiapine for the treatment of

schizophrenia (Kahn et al. 2007; Möller et al. 2007; Peuskens et al. 2007). Quetiapine is an

established antipsychotic with broad efficacy and good tolerability, particularly with respect to EPS

(Miodownik and Lerner 2006).

STRUCTURE–ACTIVITY RELATIONS

Quetiapine is an SGA of the dibenzothiazepine class. It has a complex neuropharmacology, with

binding at brain receptors of several classes (Goldstein 1999). Its binding profile, in comparison

with that of several other antipsychotics, is shown in Table 30–1. Of considerable interest is the

fact that quetiapine has a relatively low binding profile for dopamine type 2 (D2) receptors (Kapur

et al. 2000a, 2000b; Kufferle et al. 1997; Seeman and Tallerico 1998; Stephenson 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. 2000b), quetiapine’s low D2 binding—typically

approximately 30%—is noteworthy.

TABLE 30–1. Comparative receptor binding profile of quetiapinea

Quetiapinea Ziprasidonea Risperidonea Olanzapinea Clozapinea Aripiprazoleb

D2

+ +++ +++ ++ +

+++b

5-HT2A

+ ++++ ++++ +++ +++ +++

5-HT2C

– ++++ +++ +++ ++ ++

5-HT1A

+

+++b

+ – +

+++b

5-HT1D c

– +++ + + – –

1-adrenergic ++ ++ +++ ++ +++ ++

M1

++ – – +++ +++ –

H1

+++ ++ ++ +++ +++ ++

5-HT/NE reuptakedPrint: Chapter 30. Quetiapine

http://www.psychiatryonline.com/popup.aspx?aID=430077&print=yes…

2 of 16

10/05/2009 16:12

Quetiapinea Ziprasidonea Risperidonea Olanzapinea Clozapinea Aripiprazoleb

5-HT

– ++ – – – ++

NE

+ ++ – – + —

Note. ++++ = Very high affinity; +++ = high affinity; ++ = moderate affinity; + = low affinity; – =

negligible affinity; D2 = dopamine type 2 receptors; H1 = histaminergic type 1 receptors; 5-HT =

5-hydroxytryptamine (serotonin); 5-HT2A = serotonin type 2A receptors; M1 = muscarinic type 1 receptors;

NE = norepinephrine.

aAll information from human studies unless noted otherwise.

b Partial agonist.

cBovine binding affinity.

d In rat synaptosomes.

Source. Schmidt AW, Lebel LA, Howard HR Jr, et al: “Ziprasidone: A Novel Antipsychotic Agent With a Unique

Human Receptor Binding Profile.” European Journal of Pharmacology 425:197–201, 2001. Otsuka

Pharmaceutical Co: Abilify (aripiprazole) full prescribing information. August 2008.

In attempting to reconcile this apparently subtherapeutic D2 receptor antagonism with the

well-recorded efficacy of quetiapine as an antipsychotic, Kapur and colleagues proposed an elegant

kiss and run hypothesis for quetiapine’s mechanisms of action (Kapur et al. 2000a). In a series of

studies, they found that when D2 receptor occupancy with quetiapine was measured with positron

emission tomography (PET) 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. They found that

in contrast to other antipsychotics, quetiapine had a more rapid “run-off” from D2 receptors; that is,

there was rapid dissociation of the D2 receptors (Kapur et al. 2000a). This was proposed to account

for the discrepancy between observations of clinical potency and pharmacodynamic subthreshold

receptor binding. This kiss-and-run theory is also put forward to explain the consistent observation

of low rates of EPS and lack of increased prolactin levels during treatment with quetiapine

(Nemeroff et al. 2002).

Quetiapine also, like clozapine, has strong binding at 5-hydroxytryptamine (serotonin) type 2

receptors (5-HT2 receptors). This profile contrasts with its relatively weak affinity for other

subclasses of the serotonin receptor family (Goldstein 1999). Quetiapine also has strong affinity for

1-noradrenergic receptors. This antagonism may relate to its propensity to induce postural

hypotension—especially during rapid dose titration. Additionally, quetiapine has strong antagonism

at histamine type 1 (H1) receptors. This most likely relates to its sedative effect. Weight gain

during quetiapine therapy may also emanate from H1 receptor antagonism. However, this

structure–activity relationship is less clear than the association between H1 antagonism and

sedation.

Relatively less is known about quetiapine’s effects on other aspects of neurochemistry that are

thought to be of relevance (but not central) to antipsychotic activity. Some studies have shown that

SGAs can induce brain cell proliferation (neurogenesis) in experimental animals (Lieberman et al.

2006). The evidence for quetiapine in this regard is sparse. Also, little is known about the effect of

quetiapine on brain neurotrophins. One study (Xu et al. 2002) reported that quetiapine could

reverse reductions in levels of brain-derived neurotrophic factor in an animal model. There is

accumulating evidence that other SGAs may also increase brain neurotrophins (Buckley et al.

2007).

PHARMACOKINETICS AND DISPOSITION

Quetiapine is absorbed in the gastrointestinal tract, and its absorption is unaffected by food. Peak

blood levels are achieved in about 2 hours, and effective plasma levels are sustained for

approximately 6 hours (DeVane and Nemeroff 2001). This provides the basis for the usual clinical

regimen of twice-daily dosing. However, Chengappa et al. (2003b) conducted a short-term trial

comparing once-daily dosing versus twice-daily dosing in patients with schizophrenia orPrint: Chapter 30. Quetiapine

http://www.psychiatryonline.com/popup.aspx?aID=430077&print=yes…

3 of 16

10/05/2009 16:12

schizoaffective disorder. The dosing profiles were equivalent in terms of efficacy and tolerability.

Using PET, Mamo et al. (2008) found comparable plasma levels and D2 receptor occupancy between

the immediate-release and the extended-release formulation.

Quetiapine is metabolized by cytochrome P450 (CYP) 3A4 to inactive metabolites. Although genetic

variations are not clearly described for the CYP3A4 enzyme, drug interactions with inhibitors and

inducers of CYP3A4 are likely to be clinically significant. The anticonvulsants carbamazepine and

phenytoin are common examples of CYP3A4 inducers, and in their presence quetiapine doses may

need to be increased due to accelerated drug clearance (Potkin et al. 2002a, 2002b; Strakowski et

1. 2002). Ritonavir, erythromycin, ketoconazole, and nefazodone are potent inhibitors of CYP3A4,

and their use requires caution when they are coadministered with quetiapine; while they are used,

doses of quetiapine should be lowered (de Leon et al. 2005; Wong et al. 2001).

In 2007, the FDA approved an extended-release (XR) formulation of quetiapine for the treatment of

schizophrenia on the basis of results from clinical trials (Kahn et al. 2007; Lindenmayer et al.

2008). These studies compared the efficacy and tolerability of XR and regular immediate-release

(IR) formulations. Overall, the results of these studies indicate that quetiapine XR given once daily

(at dosages of 400–800 mg/day) is effective for the treatment of schizophrenia. The XR

formulation appears to have efficacy comparable to that of the IR formulation. The XR formulation

was also similar in tolerability to the IR formulation in clinical trials, with perhaps some marginal

benefit in causing less sedation. Quetiapine is excreted in the kidneys and is not affected by gender

or smoking status (Thyrum et al. 2000). The metabolism of quetiapine is reduced by approximately

30% with advancing age (Goldstein 1999).

INDICATIONS AND EFFICACY

Quetiapine currently has the following FDA-approved indications:

Schizophrenia

Bipolar disorder

There are also reports of quetiapine’s efficacy in treating other conditions, such as mood disorders

in children and anxiety disorders, obsessive-compulsive disorder (OCD), and Parkinson’s disease in

adults. These uses have not been approved by the FDA. As a result of its use in the FDA indications

and also in several unapproved circumstances, quetiapine is the most frequently prescribed

antipsychotic in the United States at the time of writing. In this section of the chapter, we describe

results of pivotal and recent studies of quetiapine for its FDA-approved indications. For

completeness’s sake and in recognition of quetiapine’s use in nonapproved conditions, we also

provide an account of some studies of subjects with other conditions. The use of any medication (in

this case quetiapine) in situations that are not FDA-approved indications is not recommended for

clinical practice.

Schizophrenia

The pivotal product registration trials 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. In the United States, short-term (6-week) trials compared quetiapine and placebo

using quetiapine dosages of either 250 mg/day or 750 mg/day (Small et al. 1997) or daily dosages

of 75 mg, 150 mg, 300 mg, or 750 mg (Arvanitis and Miller 1997); the latter trial also compared

quetiapine and haloperidol. Similar to registration trials of other antipsychotics, these studies

established a range of effective dosages for quetiapine. However, they provided no clear evidence

of a dose-dependent increase in efficacy (although post hoc analyses have suggested that higher

doses of quetiapine are more efficacious). Additionally, because of the wide range of dosages used

in these studies, the initial dosing recommendations for quetiapine in schizophrenia patients were

unclear and were further complicated by a slow titration pattern. As a result, clinicians tended to

favor the lower end of the quetiapine dosing range.

Subsequent studies helped refine quetiapine dosing strategies. Clinicians are also now using higherPrint: Chapter 30. Quetiapine

http://www.psychiatryonline.com/popup.aspx?aID=430077&print=yes…

4 of 16

10/05/2009 16:12

doses of quetiapine that are, on average, more consistent with those used in recent studies. Emsley

et al. (2000) conducted a fixed-dose comparison trial of quetiapine at 600 mg/day versus

haloperidol at 20 mg/day. The drugs had similar efficacy in this 8-week trial of patients who were a

priori deemed “partial responders.” More recent studies have shown that the titration of quetiapine

can be quicker than heretofore considered. Pae et al. (2007) compared 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, up to 400 mg/day by day 5). The two groups fared equally well in

terms of tolerability during this 14-day study. The higher-dose, more rapid titration strategy had a

marginal advantage in overall efficacy. Information on the use of high dosages (>800 mg/day) of

quetiapine is very limited. Pierre et al. (2005) reported on quetiapine’s efficacy in a sample of

treatment-refractory schizophrenic patients at dosages of up to 1,200 mg/day. More fixed-dose

comparison studies with quetiapine are needed to assist clinicians in further refining their dosing

strategies with this agent.

Although two meta-analyses cast doubt on quetiapine’s efficacy with respect to first-generation

antipsychotics (FGAs; Davis et al. 2003; Geddes et al. 2000), most studies comparing quetiapine

with haloperidol or chlorpromazine report that the agents have similar efficacy in treating

schizophrenia (Emsley et al. 2000; Peuskens and Link 1997; Small et al. 1997). Given that today

most clinicians in the United States select one of the SGAs, comparisons between quetiapine and

other SGAs are perhaps more meaningful. Several studies have been published that inform this

consideration. A 4-month open-label trial of quetiapine and risperidone in a heterogeneous patient

population—although predominantly subjects with schizophrenia and related psychotic

disorders—showed overall comparability between the two agents (Mullen et al. 2001). Zhong et al.

(2006) reported on an 8-week comparative trial of quetiapine and risperidone in a chronic

schizophrenia patient population. The average quetiapine dosage was 525 mg/day and the average

risperidone dosage was 5.2 mg/day. The drugs proved similar in efficacy. Quetiapine-treated

patients had fewer EPS, lower prolactin levels, and fewer sexual side effects. Weight gain was

similar in both treatment groups. Quetiapine was more sedating and was more frequently

associated with dry mouth than was risperidone. Another study comparing quetiapine and

risperidone, a 6-month study, reported better efficacy with risperidone (Potkin et al. 2006).

Quetiapine was associated with more polypharmacy in that study. Kinon et al. (2006) reported on a

6-month double-blind comparative trial of quetiapine and olanzapine. Quetiapine-treated patients

were less likely to complete the study. 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 either ziprasidone or aripiprazole 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) schizophrenia studies. In the phase 1

study, in which the effectiveness of several antipsychotics was examined over 18 months, 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 2 study of efficacy pathways for patients with persistent symptoms, discontinuation rates

favored clozapine and olanzapine over risperidone and quetiapine (McEvoy et al. 2006). The results

from the tolerability pathways were more mixed, with similar efficacy observed between quetiapine

and other agents (Stroup et al. 2007). The findings relating to quetiapine’s relative adverse-effects

profile in this formative study are presented later in this chapter (see “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 1

study fared. In this analysis, switching to quetiapine was more efficacious than switching to any of

the other agents. Much 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 their first episode of psychosis—the Comparison of Atypicals in First EpisodePrint: Chapter 30. Quetiapine

http://www.psychiatryonline.com/popup.aspx?aID=430077&print=yes…

5 of 16

10/05/2009 16:12

Psychosis (CAFÉ) study. Here, discontinuation rates were similar with all three drugs over the

course of the 1-year trial (McEvoy et al. 2007). The comparative dosing profiles for quetiapine,

risperidone, and olanzapine in the CAFÉ study and the CATIE schizophrenia study, referenced

against the FDA-approved dosages, are shown in Table 30–2.

TABLE 30–2. Antipsychotic dosages used in CATIE and CAFÉ studies versus FDA-approved dosages:

quetiapine, olanzapine, and risperidone

CATIE (chronic) mean

modal dosage (mg/day)

CAFÉ (first episode) mean

modal dosage (mg/day)

FDA-approved dosage

range (mg/day)

Olanzapine 20.1 11.7 5–20

Risperidone 3.9 2.4 1–16

Quetiapine 543.4 506.0 25–800

Higher dosages may be required to achieve efficacy in chronic versus first-episode schizophrenia.

Note. CAFÉ = Comparison of Atypicals in First Episode Psychosis; CATIE = Clinical Antipsychotic Trials of

Intervention Effectiveness; FDA = U.S. Food and Drug Administration.

Source. Data derived from McEvoy et al. 2007 (CAFÉ) and Lieberman et al. 2005 (CATIE).

The use of quetiapine in patients with prodromal features of schizophrenia has not yet been

studied. Little is known about quetiapine’s efficacy in treatment-refractory patients. In a

subanalysis of more severely ill patients in an 8-week comparative trial of quetiapine and

haloperidol, quetiapine showed a small benefit over haloperidol (Buckley et al. 2004). The

open-label observational study by Pierre et al. (2005) also showed some benefit for quetiapine at

high doses in treatment-refractory patients. Sacchetti et al. (2004) reported a 50% response rate

in a small sample of patients who had been refractory to prior treatment with FGAs.

Information on the long-term efficacy of quetiapine is limited. Open-label follow-up in extension

studies for up to 4 years has shown sustained efficacy, with the average dosage of quetiapine

recorded at 450 mg/day (Buckley et al. 2004). A recently conducted 6-month placebo-controlled

study of quetiapine (the new XR formulation) in schizophrenia patients showed a clinically

beneficial effect on relapse prevention (Peuskens et al. 2007). Several studies have demonstrated

improvements in cognitive performance during quetiapine therapy in patients with schizophrenia

(Sax et al. 1998; Velligan et al. 2002, 2003).

Mood Disorders

There is evidence that quetiapine is an effective and well-tolerated antipsychotic for treating

patients with bipolar mania and bipolar depression. Initial evidence for mood effects were derived

from observations on mood assessment items in the pivotal schizophrenia trials. In one of the

pivotal product registration trials evaluating quetiapine (Small et al. 1997), both high and low

doses of quetiapine were significantly better than placebo in improving Brief Psychiatric Rating

Scale (BPRS) measures of mood disturbance in patients with schizophrenia (Goldstein 1999). In an

analysis of another pivotal trial comparing five dosages of quetiapine in patients with schizophrenia

(Arvanitis and Miller 1997), patients receiving 150 mg/day showed significant improvement in

BPRS-derived measures of mood. In the Quetiapine Experience with Safety and Tolerability

(QUEST) study, quetiapine was compared 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.

More recent studies have confirmed that quetiapine is efficacious for the acute treatment of mania

and bipolar depression. In short-term placebo-controlled trials, quetiapine as a monotherapy

reduced symptoms of mania. Quetiapine has also been assessed as an add-on agent with either

lithium or valproic acid. Calabrese et al. (2005) and Thase et al. (2006) have studied quetiapine in Print: Chapter 30. Quetiapine

http://www.psychiatryonline.com/popup.aspx?aID=430077&print=yes…

6 of 16

10/05/2009 16:12

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) versus 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 of the same

two dosages (300 mg/day and 600 mg/day; Thase et al. 2006), 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. Furthermore, Dorée et al. (2007)

recently reported that in a pilot study (n = 20) quetiapine was an efficacious augmenting agent for

major depression. There is also emerging information that quetiapine’s metabolite may have

mood-regulating effects (Goldstein et al. 2007).

Other Conditions and Patient Populations

The two studies on bipolar depression cited above (Calabrese et al. 2005; Thase et al. 2006) also

showed improvements in anxiety symptoms with quetiapine. Additionally, the sedative/calming

effect of quetiapine is well described in a variety of product registration trials (Buckley et al. 2007;

Chengappa et al. 2003a). Thus, there is interest in whether quetiapine may be helpful in treating

anxiety states, and off-label use of quetiapine in patients with anxiety disorders has been reported.

This is a complicated issue. A clinical trial of quetiapine to treat anxiety disorders is ongoing

(www.clinicaltrials.gov). There is also published information from a small study showing that

quetiapine reduces symptoms of both anxiety and posttraumatic stress disorder (Hamner et al.

2003).

Information has also been published on the use of quetiapine as an augmenting agent with

selective serotonin reuptake inhibitors in treating OCD (Dell’Osso et al. 2006; Denys et al. 2007).

Dell’Osso et al. (2006) showed that quetiapine provided benefit in a small case series of patients

with OCD. Denys et al. (2007) analyzed published augmentation studies in OCD patients and found

that quetiapine augmentation was efficacious and, interestingly, was more efficacious in patients

who were receiving lower doses of a selective serotonin reuptake inhibitor (SSRI) than in those

receiving higher SSRI doses.

Quetiapine appears to be an effective treatment for children with schizophrenia or bipolar disorder

(Barzman et al. 2006; DelBello et al. 2007; McConville et al. 2000). DelBello et al. (2007) recently

reported therapeutic effects of quetiapine in a cohort of children who showed subsyndromal

symptoms and were at risk for bipolar disorder but who did not actually meet diagnostic threshold

criteria for a bipolar diagnosis. Quetiapine is also used more broadly for treating agitation in

children (Findling et al. 2007).

Quetiapine has also been used in the elderly. McManus et al. (1999) reported baseline and 12-week

data for 151 elderly patients (mean age, 76.8 years) who were treated in a 1-year open-label trial

of quetiapine. Seventy percent of patients had some organic condition, predominantly Alzheimer’s

disease, with the majority of remaining patients having a diagnosis of a functional psychosis such

as schizophrenia, schizoaffective disorder, or delusional disorder. Fifty-two percent of all patients

achieved a 20% or greater decline in BPRS total score. Quetiapine was well tolerated at a mean

dosage of 100 mg/day. Zhong et al. (2007) reported a 10-week study comparing two dosages of

quetiapine (100 mg/day and 200 mg/day) versus placebo in nursing home residents with dementia

and agitation. Quetiapine at 100 mg/day was not efficacious, whereas quetiapine at 200 mg/day

was efficacious for 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). This is the largest comparative study to date of

the relative efficacy and tolerability of antipsychotics in elderly patients with Alzheimer’s disease

and related dementias. Overall, no effect was seen with any of the agents, and no differences were

seen between the agents in terms of time to discontinuation of treatment for any reason.

Several neuropsychiatric conditions, the most notable being Parkinson’s disease, are associatedPrint: Chapter 30. Quetiapine

http://www.psychiatryonline.com/popup.aspx?aID=430077&print=yes…

7 of 16

10/05/2009 16:12

with the emergence of transient or sometimes persistent psychotic symptoms (Juncos 1999). The

management of Parkinson’s disease is further complicated by hallucinations associated with

levodopa therapy. Older antipsychotics were effective in relieving psychotic symptoms in these

patients, but their use also aggravated the disease. Quetiapine may be a preferred treatment in

patients with Parkinson’s disease (Friedman 2003; Friedman et al. 1998; Juncos 1999; Targum and

Abbott 2000). In a 24-week study of quetiapine in 29 patients with Parkinson’s disease (mean age,

73 years), Juncos (1999) observed that treatment with quetiapine at a mean dosage of 62.5

mg/day improved psychosis without causing deterioration in motor function. Menza et al. (1999)

reported similar results using quetiapine at dosages of 12.5–150 mg/day in three patients with

Parkinson’s disease whose medication was switched from clozapine to quetiapine. In another

study, 25 patients with Parkinson’s disease were switched from either clozapine or olanzapine to

quetiapine; 17 (68%) of the patients were switched to quetiapine without a worsening of psychosis

(Friedman et al. 1998). Targum and Abbott (2000) reported that quetiapine stopped visual

hallucinations in 6 of 10 patients with Parkinson’s disease, but delusions were less responsive to

treatment. In a study by Merims et al. (2006), both clozapine and quetiapine showed efficacy in

treating psychosis in Parkinson’s disease patients. Clozapine was marginally more efficacious but

was associated with a high adverse-effect burden.

Agitation is a core aspect of several conditions. There is, of course, no FDA-approved drug for

treating agitation, and use of antipsychotics for nonapproved clinical indications is strongly

discouraged. Nevertheless, antipsychotics have been used to manage agitation in a variety of

circumstances. Currier et al. (2006) reported an interesting study of quetiapine in agitated patients

in the emergency room. Here, Currier and colleagues reported that quetiapine could be used as an

acute antiagitation agent if the dose titration is judicious. Postural hypotension was observed in

this study. Other studies of quetiapine and agitation reflect post hoc analyses of clinical trials and

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 conditions associated with disruptive,

hostile behaviors (Barzman et al. 2006; Findling et al. 2007).

SIDE EFFECTS AND TOXICOLOGY

To illustrate the profile of adverse effects that are typically seen with quetiapine, we have

reproduced herein the results from a recent clinical trial of 8 weeks’ duration (Zhong et al. 2006) in

which schizophrenic patients received an average quetiapine dosage of 525 mg/day (Table 30–3).

Overall, quetiapine was well tolerated in this study, and only 6% of patients discontinued treatment

due to adverse effects. The most commonly recorded side effects of quetiapine treatment in this

study were somnolence (26% of patients), headache (15%), weight gain (14%), dizziness (14%),

and dry mouth (12%).

TABLE 30–3. Comparative side-effect profile of quetiapine versus risperidone: adverse effects

present in 5% of patients in an 8-week study

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)

0.876Print: Chapter 30. Quetiapine

http://www.psychiatryonline.com/popup.aspx?aID=430077&print=yes…

8 of 16

10/05/2009 16:12

Quetiapine (n = 338; median

dosage, 525 mg/day)

Risperidone (n = 334; median dosage,

= 5.2 mg/day)

Adverse

effect

n (%)

n (%)

P

valuea

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 01 (0.3)

18 (5.4)

<0.001

a Fisher exact test, unadjusted.

Source. Adapted from Zhong KX, Sweitzer DE, Hamer RM, et al: “Comparison of Quetiapine and Risperidone

in the Treatment of Schizophrenia: A Randomized, Double-Blind, Flexible-Dose, 8-Week Study.” Journal of

Clinical Psychiatry 67:1093–1103, 2006.

Somnolence is a common side effect of quetiapine that most likely relates to its antihistaminergic

effects. It occurs early in treatment and generally decreases over time. It may persist in some

patients, however. 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 receiving quetiapine at a dosage of 300 mg/day and

in 27% of patients receiving 600 mg/day. Dizziness is another troublesome side effect when it

occurs. It may be associated with postural hypotension—an effect that is of even greater concern.

Sometimes, like sedation, this can cause discontinuation of quetiapine therapy.

There is growing concern about antipsychotic-induced weight gain and metabolic disturbances

(Allison et al. 1999; Brooke et al. 2009; Newcomer et al. 2002). Quetiapine is associated with

weight gain, although current evidence indicates that neither the frequency nor the magnitude of

the weight gain effect is 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 either ziprasidone or aripiprazole

(Brooke et al. 2009). The lack of data on long-term maintenance treatment with quetiapine makes

it hard to quantify its weight-effects liability with robust objectivity over the course of illness

(Brooke et al. 2009).

In a report of open-label extension studies of patients with schizophrenia who continued taking

quetiapine for up to 18 months, patients experienced on average a 1.74-kg increase over their

baseline weight (Brecher et al. 2000). Weight gain was most pronounced—and, conversely, least

pronounced—in those who were underweight and markedly obese, respectively. This is consistent

with a lower body mass index being a predictor for weight gain in genetic studies of weight gain in

schizophrenic patients (Müller and Kennedy 2006). In the 8-week comparative study by Zhong et

7. (2006), weight gain that was clinically significant (a 7.7% increase above baseline weight) was

observed in 10.4% of patients receiving quetiapine and in 10.5% of patients receiving risperidone.

The average weight gain was 1.6 kg for quetiapine recipients and 2.12 kg for risperidone recipients.

In the phase 1 CATIE schizophrenia study, quetiapine had a moderate effect on weight (and other

aspects of the metabolic profile) compared with the other agents in that major study (Lieberman et

4. 2005). Those data are shown in Table 30–4. In the first-episode CAFÉ study, quetiapine had a

more favorable weight-effects profile than did olanzapine or risperidone. Fifty percent of patients

taking quetiapine gained weight, compared with 80% of those taking olanzapine and 58% 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 (J. K. Patel, P. F.

Buckley, S. Woolson, et al., “Metabolic Profiles of Second-Generation Antipsychotics in EarlyPrint: Chapter 30. Quetiapine

http://www.psychiatryonline.com/popup.aspx?aID=430077&print=yes…

9 of 16

10/05/2009 16:12

Psychosis: Findings From the CAFE Study” (submitted for publication), October 2008). 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 BOLDER

(BipOLar DEpRession) study of patients with bipolar depression (Calabrese et al. 2005), 9% of

patients receiving quetiapine at a dosage of 600 mg/day and 8.5% of patients receiving 300

mg/day had a 7% or greater increase in weight. The average weight gains for quetiapine-treated

patients in this study were 1.6 kg and 1.0 kg for the 600-mg/day and 300-mg/day groups,

respectively.

TABLE 30–4. Comparative metabolic profiles of antipsychotics in the phase 1 CATIE schizophrenia

trial: change from baseline

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 09.2 ± 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 1. Mean values for metabolic

factors (other than weight change) were also adjusted for duration of exposure to study drug.

Source. Adapted from Lieberman JA, Stroup TS, McEvoy JP, et al, Clinical Antipsychotic Trials of Intervention

Effectiveness (CATIE) Investigators: “Effectiveness of Antipsychotic Drugs in Patients With Chronic

Schizophrenia.” New England Journal of Medicine 353:1209–1223, 2005.

We have less information on other aspects of quetiapine’s metabolic effects, in part because only

recently conducted studies have included careful measurements of fasting glucose and lipid levels.

In the bipolar depression study by Calabrese et al. (2005), the mean increases in glucose levels at

study endpoint 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 increases in fasting glucose levels from baseline to

study endpoint were 1.8 mg/dL with quetiapine and 5.6 mg/dL with risperidone. The metabolic

profile of quetiapine appeared moderate in the phase 1 CATIE schizophrenia study (see Table

30–4). Meyer and Stahl (2009) examined the biology of and reviewed the available data concerning

distinct metabolic profiles in the context of antipsychotic therapy. Newcomer et al. (2009) have

presented data from a euglycemic clamp study of quetiapine. They found little evidence of insulin

insensitivity, although it was noteworthy that there was a small signal of raised triglyceride levels

in this study. This was also found in another recent naturalistic study (de Leon et al. 2007). Overall,

quetiapine appears to carry a risk of causing weight gain and other metabolic disturbances. ThisPrint: Chapter 30. Quetiapine

http://www.psychiatryonline.com/popup.aspx?aID=430077&print=yes…

10 of 16

10/05/2009 16:12

risk appears to be variable in patients, and it is not as pronounced as the risk with either clozapine

or olanzapine. The results of an intriguing study in which the addition of quetiapine to clozapine

resulted in lower rates of diabetes (Reinstein et al. 1999) have not been replicated.

Two side-effect characteristics that distinguish quetiapine from other SGAs and from FGAs are its

low rates of prolactin elevation and low rates of EPS. Consistently, 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). In the quetiapine versus risperidone schizophrenia study (Zhong et al. 2006),

mean prolactin levels were reduced by 11.5 mg/mL in quetiapine-treated patients, whereas they

were increased by 35.5 mg/mL in risperidone-treated patients. Similar effects on prolactin levels

were observed with quetiapine in both the CATIE and CAFÉ schizophrenia studies (Lieberman et al.

2005; McEvoy et al. 2007).

The low-EPS advantage of quetiapine is compelling and consistent across studies. Indeed, in the

SPECTRUM switch study (Larmo et al. 2005), switching to quetiapine from either an FGA or an SGA

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). Moreover, quetiapine’s EPS

advantage has propelled it to the status of being the agent of choice among neurologists who treat

psychosis in patients with Parkinson’s disease.

The potential of quetiapine to induce cataracts is still unknown. The relationship of antipsychotic

therapy in general to cataract formation is unclear (Isaac et al. 1991; Johnson 1998). A large

pragmatic trial that includes regular specialist ophthalmological examinations to investigate the

incidence of cataract formation during therapy with quetiapine is nearing completion

(www.clinicaltrials.gov). It is hoped that this study will shed new light on the issue. At present it

appears that most clinicians do not obtain specialist eye examinations when prescribing quetiapine.

Abnormalities in thyroid hormone levels were a concern that emanated from early trials of

quetiapine (Arvanitis and Miller 1997). This no longer appears to be a clinically meaningful risk, and

recent studies have not shown any consistent evidence of thyroid dysfunction with quetiapine use

(Kelly and Conley 2006).

Quetiapine’s prescribing information (AstraZeneca 2008a, 2008b) possesses a warning similar to

that required in the prescribing information of many other antipsychotics concerning cardiovascular

risks. These potential cardiac risks, especially prolongation of the QTc interval (the ventricular

depolarization and repolarization phase, or QT phase, of the electrocardiogram corrected for heart

rate), have been comprehensively reviewed by Glassman and Bigger (2001). However, there is no

evidence of any heightened QTc risk with quetiapine (Lieberman et al. 2005). It is also suggested

that quetiapine might have abuse potential (Pierre et al. 2005; Pinta and Taylor 2007). Given that it

is used more broadly than other SGAs, this observation merits further consideration and vigilance.

Overall, the adverse-effect profile of the XR formulation is similar to that of the IR formulation. 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) studied 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 birthweight, 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). Atypical antipsychotics

as a group did not appear to be associated with an increased risk for major malformations. Yaeger

et al. (2006) reported that among 39 prospectively identified cases of fetal exposure to quetiapine,

including the 36 in the study by McKenna et al. (2005), no congenital malformations were found.

CONCLUSION

Quetiapine is now a well-established and widely prescribed antipsychotic. There is strong evidence

for efficacy in all current FDA-approved indications: the treatment of schizophrenia and bipolarPrint: Chapter 30. Quetiapine

http://www.psychiatryonline.com/popup.aspx?aID=430077&print=yes…

11 of 16

10/05/2009 16:12

disorder. This agent is also used extensively under circumstances not approved by the FDA

(off-label use), and evidence for efficacy in some of these uses is reviewed (but not endorsed

clinically) in this chapter. Major clinical trials of quetiapine for several unapproved uses are ongoing

(www.clinicaltrials.com). Quetiapine possesses a particularly favorable profile with respect to D2

receptor antagonism–related side effects. Its low propensity to cause EPS is well established, and

studies have consistently shown that quetiapine does not appear to elevate prolactin levels. These

two differential tolerability advantages are important when considering whether a patient might

benefit from switching from his or her current medication to quetiapine (Weiden and Buckley

2007). On the other hand, the weight-gain effects and metabolic profile of quetiapine are of

concern. However, the weight and metabolic risks have yet to be clearly determined for quetiapine

relative to other SGAs. Based on current evidence, it appears to have an intermediate position

among the SGAs with respect to metabolic risk. Overall, quetiapine represents a useful addition to

the psychopharmocological armamentarium, with established efficacy and a broadly favorable

tolerability profile.

REFERENCES

Allison DB, Mentore JL, Heo M, et al: Antipsychotic-induced weight gain: a comprehensive research

synthesis. Am J Psychiatry 156:1686–1696, 1999 [Full Text] [PubMed]

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 42:233–246, 1997 [PubMed]

AstraZeneca Pharmaceuticals: Seroquel (quetiapine fumarate) tablets, full prescribing information.

July 2008a

AstraZeneca Pharmaceuticals: Seroquel XR (quetiapine fumarate) extended-release tablets, full

prescribing information. July 2008b

Barzman DH, DelBello MP, Adler CM, et al: The efficacy and tolerability of quetiapine versus

divalproex for the treatment of impulsivity and reactive aggression in adolescents with co-occurring

bipolar disorder and disruptive behavior disorder(s). J Child Adolesc Psychopharmacol 16:665–670,

2006 [PubMed]

Borison RL, Arvanitis LA, Miller BG: ICI 204,636, an atypical antipsychotic: efficacy and safety in a

multicenter, placebo-controlled trial in patients with schizophrenia. US Seroquel Study Group. J Clin

Psychopharmacol 16:158–169, 1996 [PubMed]

Brecher M, Rak IW, Melvin K, et al: The long-term effect of quetiapine (“Seroquel”) monotherapy on

weight in patients with schizophrenia. International Journal of Psychiatry in Clinical Practice

4:287–291, 2000

Brooke JO III, Chang HS, Krasnykh O: Metabolic risks in older adults receiving second-generation

antipsychotic medication. Curr Psychiatry Rep 11:33–40, 2009

Buckley PF, Goldstein JM, Emsley RA: Efficacy and tolerability of quetiapine in poorly responsive,

chronic schizophrenia. Schizophr Res 66:143–150, 2004 [PubMed]

Buckley PF, Paulsson B, Brecher M: Treatment of agitation and aggression in bipolar mania: efficacy

of quetiapine. J Affect Disord 100 (suppl 1):S33–S43, 2007

Calabrese JR, Keck PE Jr, Macfadden W, et al: A randomized, double-blind, placebo-controlled trial

of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry 162:1351–1360, 2005

[Full Text] [PubMed]

Chengappa KN, Goldstein JM, Greenwood M, et al: A post hoc analysis of the impact on hostility and

agitation of quetiapine and haloperidol among patients with schizophrenia. Clin Ther 25:530–541,

2003a

Chengappa KN, Parepally H, Brar JS, et al: A random-assignment, double-blind, clinical trial of once-Print: Chapter 30. Quetiapine

http://www.psychiatryonline.com/popup.aspx?aID=430077&print=yes…

12 of 16

10/05/2009 16:12

vs twice-daily administration of quetiapine fumarate in patients with schizophrenia or

schizoaffective disorder: a pilot study. Can J Psychiatry 48:187–194, 2003b

Copolov DL, Link CG, Kowalcyk B: A multicenter, double-blind randomized comparison of quetiapine

(ICI 204,636, “Seroquel”) and haloperidol in schizophrenia. Psychol Med 30:95–105, 2000

[PubMed]

Currier GW, Trenton AJ, Walsh PG, et al: A pilot, open-label safety study of quetiapine for treatment

of moderate psychotic agitation in the emergency setting. J Psychiatr Pract 12:223–228, 2006

[PubMed]

Davis JM, Chen N, Glick ID: A meta-analysis of the efficacy of second-generation antipsychotics.

Arch Gen Psychiatry 60:553–564, 2003 [PubMed]

de Leon J, Armstrong SC, Cozza KL: The dosing of atypical antipsychotics. Psychosomatics

46:262–273, 2005

de Leon J, Susce MT, Johnson M, et al: A clinical study of the association of antipsychotics with

hyperlipidemia. Schizophr Res 92:95–102, 2007

DelBello MP, Adler CM, Whitsel RM, et al: A 12-week single-blind trial of quetiapine for the

treatment of mood symptoms in adolescents at high risk for developing bipolar I disorder. J Clin

Psychiatry 68:789–795, 2007 [PubMed]

Dell’Osso B, Mundo E, Altamura AC: Quetiapine augmentation of selective serotonin reuptake

inhibitors in treatment-resistant obsessive-compulsive disorder: a six-month follow-up case series.

CNS Spectr 11:879–883, 2006 [PubMed]

Denys D, Fineberg N, Carey PD, et al: Quetiapine addition in obsessive-compulsive disorder: is

treatment outcome affected by type and dose of serotonin reuptake inhibitors? Biol Psychiatry

61:412–414, 2007 [PubMed]

DeVane CL, Nemeroff CB: Clinical pharmacokinetics of quetiapine: an atypical antipsychotic. Clin

Pharmacokinet 40:509–522, 2001 [PubMed]

Dorée JP, Des Rosiers J, Lew V, et al: Quetiapine augmentation of treatment-resistant depression: a

comparison with lithium. Curr Med Res Opin 23:333–341, 2007 [PubMed]

Emsley RA, Raniwalla J, Bailey PJ, et al: A comparison of the effects of quetiapine (“Seroquel”) and

haloperidol in schizophrenic patients with a history of and a demonstrated, partial response to

conventional antipsychotic treatment. PRIZE Study Group. Int Clin Psychopharmacol 15:121–131,

2000 [PubMed]

Findling RL, Reed MD, O’Riordan MA, et al: A 26-week open-label study of quetiapine in children

with conduct disorder. J Child Adolesc Psychopharmacol 17:1–9, 2007 [PubMed]

Friedman JH: Atypical antipsychotics in the EPS-vulnerable patient. Psychoneuroendocrinology 28

(suppl 1):39–51, 2003

Friedman JH, Goldstein S, Jacques C: Substituting clozapine for olanzapine in psychiatrically stable

Parkinson’s disease patients: results of an open label pilot study. Clin Neuropharmacol 21:285–288,

1998 [PubMed]

Geddes J, Freemantle N, Harrison P, et al: Atypical antipsychotics in the treatment of schizophrenia:

systematic overview and meta-regression analysis. BMJ 321:1371–1376, 2000 [PubMed]

Glassman AH, Bigger JT Jr: Antipsychotic drugs: prolonged QTc interval, torsades de pointes, and

sudden death. Am J Psychiatry 158:1774–1782, 2001 [Full Text] [PubMed]

Goldstein JM: Quetiapine fumarate (Seroquel): a new atypical antipsychotic. Drugs Today (Barc)

35:193–210, 1999 [PubMed]

Goldstein JM, Christoph G, Grimm S, et al: Unique mechanism of action for the antidepressantPrint: Chapter 30. Quetiapine

http://www.psychiatryonline.com/popup.aspx?aID=430077&print=yes…

13 of 16

10/05/2009 16:12

properties of the atypical antipsychotic quetiapine. Presented at the annual meeting of the

American Psychiatric Association, San Diego, CA, May 19–24, 2007

Hamner MB, Arvanitis LA, Miller BG, et al: Plasma prolactin in schizophrenia subjects treated with

Seroquel (ICI 204, 636). Psychopharmacol Bull 32:107–110, 1996 [PubMed]

Hamner MB, Deitsch SE, Brodrick PS, et al: Quetiapine treatment in patients with posttraumatic

stress disorder: an open trial of adjunctive therapy. J Clin Psychopharmacol 23:15–20, 2003

[PubMed]

Isaac NE, Walker AM, Jick H, et al: Exposure to phenothiazine drugs and risk of cataract. Arch

Ophthalmol 109:256–260, 1991 [PubMed]

Johnson GJ: Limitations of epidemiology in understanding pathogenesis of cataracts. Lancet

351:925–926, 1998 [PubMed]

Juncos JL: Management of psychotic aspects of Parkinson’s disease. J Clin Psychiatry 60 (suppl

8):42–53, 1999

Kahn RS, Schulz SC, Palazov VD, 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 68:832–842, 2007 [PubMed]

Kapur S, Zipursky R, Jones C, et al: A positron emission tomography study of quetiapine in

schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine

D2 receptor occupancy. Arch Gen Psychiatry 57:553–559, 2000a

Kapur S, Zipursky R, Jones C, et al: Relationship between dopamine D2 occupancy, clinical

response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry

157:514–520, 2000b

Kelly DL, Conley RR: A randomized double-blind 12-week study of quetiapine, risperidone or

fluphenazine on sexual functioning in people with schizophrenia. Psychoneuroendocrinology

31:340–346, 2006 [PubMed]

King DJ, Link CG, Kowalcyk B: A comparison of bid and tid dose regimens of quetiapine (Seroquel)

in the treatment of schizophrenia. Psychopharmacology (Berl) 137:139–146, 1998 [PubMed]

Kinon BJ, Noordsy DL, Liu-Seifert H, et al: Randomized, double-blind 6-month comparison of

olanzapine and quetiapine in patients with schizophrenia or schizoaffective disorder with prominent

negative symptoms and poor functioning. J Clin Psychopharmacol 26:453–461, 2006 [PubMed]

Kufferle B, Tauscher J, Asenbaum S, et al: IBZM SPECT imaging of striatal dopamine-2 receptors in

psychotic patients treated with the novel antipsychotic substance quetiapine in comparison to

clozapine and haloperidol. Psychopharmacology (Berl) 133:323–328, 1997 [PubMed]

Larmo I, de Nayer A, Windhager E, et al: Efficacy and tolerability of quetiapine in patients with

schizophrenia who switched from haloperidol, olanzapine or risperidone. Hum Psychopharmacol

20:573–581, 2005 [PubMed]

Lieberman JA, Stroup TS, McEvoy JP, et al: Effectiveness of antipsychotic drugs in patients with

chronic schizophrenia. N Engl J Med 353:1209–1223, 2005 [PubMed]

Lieberman JA, Malaspina D, Jarskog LF: Preventing clinical deterioration in the course of

schizophrenia: the potential for neuroprotection. CNS Spectr 11 (suppl):10–13, 2006

Lindenmayer JP, Brown D, Liu S, et al: 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 41:11–35, 2008 [PubMed]

Mamo DC, Uchida H, Vitcu I, et al. Quetiapine extended-release versus immediate-release

formulation: a positron emission tomography study. J Clin Psychiatry 69:81–86, 2008 [PubMed]Print: Chapter 30. Quetiapine

http://www.psychiatryonline.com/popup.aspx?aID=430077&print=yes…

14 of 16

10/05/2009 16:12

McConville BJ, Arvanitis LA, Thyrum PT, et al: Pharmacokinetics, tolerability, and clinical

effectiveness of quetiapine fumarate: an open-label trial in adolescents with psychotic disorders. J

Clin Psychiatry 61:252–260, 2000 [PubMed]

McEvoy JP, Lieberman JA, Stroup TS, et al: Effectiveness of clozapine versus olanzapine, quetiapine,

and risperidone in patients with chronic schizophrenia who did not respond to prior atypical

antipsychotic treatment. Am J Psychiatry 163:600–610, 2006 [Full Text] [PubMed]

McEvoy JP, Lieberman JA, Perkins DO, et al: Efficacy and tolerability of olanzapine, quetiapine, and

risperidone in the treatment of early psychosis: a randomized, double-blind 52-week comparison.

Am J Psychiatry 164:1050–1060, 2007 [Full Text] [PubMed]

McIntyre RS, Brecher M, Paulsson B, et al: Quetiapine or haloperidol as monotherapy for bipolar

mania—a 12-week, double-blind, randomized, parallel-group, placebo-controlled trial. Eur

Neuropsychopharmacol 15:573–585, 2005 [PubMed]

McKenna K, Koren G, Tetelbaum M, et al: Pregnancy outcome of women using atypical antipsychotic

drugs: a prospective comparative study. J Clin Psychiatry 66:444–449, 2005 [PubMed]

McManus DQ, Arvanitis LA, Kowalcyk BB: Quetiapine, a novel antipsychotic: experience in elderly

patients with psychotic disorders. Seroquel Trial 48 Study Group. J Clin Psychiatry 60:292–298,

1999 [PubMed]

Menza MM, Palermo B, Mark M: Quetiapine as an alternative to clozapine in the treatment of

dopamimetic psychosis in patients with Parkinson’s disease. Ann Clin Psychiatry 11:141–144, 1999

[PubMed]

Merims D, Balas M, Peretz C, et al: Rater-blinded, prospective comparison: quetiapine versus

clozapine for Parkinson’s disease psychosis. Clin Neuropharmacol 29:331–337, 2006 [PubMed]

Meyer JM, Stahl SM: The metabolic syndrome and schizophrenia. Acta Psychiatr Scand 119:4–14,

2009 [PubMed]

Miodownik C, Lerner V: Quetiapine: efficacy, tolerability and safety in schizophrenia. Expert Rev

Neurother 6:983–992, 2006 [PubMed]

Möller H, Johnson S, Meulien D, et al: Once-daily quetiapine sustained release (SR) is effective and

well tolerated in patients with schizophrenia switched from the same total daily dose of quetiapine

immediate release (IR). Schizophr Bull 33:449, 2007 [PubMed]

Mullen J, Jibson MD, Sweitzer D: A comparison of the relative safety, efficacy, and tolerability of

quetiapine and risperidone in outpatients with schizophrenia and other psychotic disorders: the

quetiapine experience with safety and tolerability (QUEST) study. Clin Ther 23:1839–1854, 2001

[PubMed]

Müller D, Kennedy JL: Genetics of antipsychotic weight gain in schizophrenia. Pharmacogenomics

7:863–887, 2006 [PubMed]

Nemeroff CB, Kinkead B, Goldstein J: Quetiapine: preclinical studies, pharmacokinetics, drug

interactions, and dosing. J Clin Psychiatry 63 (suppl 13):5–11, 2002

Newcomer JW, Haupt DW, Fucetola R, et al: Abnormalities in glucose regulation during

antipsychotic treatment of schizophrenia. Arch Gen Psychiatry 59:337–345, 2002 [PubMed]

Newcomer JW, Ratner RE, Eriksson JW, et al: A 24-week multicenter, open-label, randomized study

to compare changes in glucose metabolism in patients with schizophrenia receiving treatment with

olanzapine, quetiapine and risperidone. J Clin Psychiatry (in press; 2009)

Pae CU, Kim JJ, Lee Cu, et al: Rapid versus conventional initiation of quetiapine in the treatment of

schizophrenia: a randomized, parallel-group trial. J Clin Psychiatry 68:399–405, 2007 [PubMed]

Peuskens J, Link CG: A comparison of quetiapine and chlorpromazine in the treatment ofPrint: Chapter 30. Quetiapine

http://www.psychiatryonline.com/popup.aspx?aID=430077&print=yes…

15 of 16

10/05/2009 16:12

schizophrenia. Acta Psychiatr Scand 96:265–273, 1997 [PubMed]

Peuskens JC, Trivedi JK, Malyarov S, et al: A randomized, placebo-controlled relapse-prevention

study with once-daily quetiapine sustained release in patients with schizophrenia. Schizophr Bull

33:453, 2007

Pierre JM, Wirshing DA, Wirshing WC, et al: High-dose quetiapine in treatment refractory

schizophrenia. Schizophr Res 73:373–375, 2005 [PubMed]

Pinta ER, Taylor RE: Quetiapine addiction? Am J Psychiatry 164:174–175, 2007 [Full Text]

[PubMed]

Potkin SG, Thyrum PT, Alva G, et al: Effect of fluoxetine and imipramine on the pharmacokinetics

and tolerability of the antipsychotic quetiapine. J Clin Psychopharmacol 22:174–182, 2002a

Potkin SG, Thyrum PT, Alva G, et al: The safety and pharmacokinetics of quetiapine when

coadministered with haloperidol, risperidone, or thioridazine. J Clin Psychopharmacol 22:121–130,

2002b

Potkin SG, Gharabawi GM, Greenspan AJ, et al: A double-blind comparison of risperidone,

quetiapine and placebo in patients with schizophrenia experience an acute exacerbation requiring

hospitalization. Schizophr Res 85:254–265, 2006 [PubMed]

Reinstein M, Sirotovskaya L, Jones L, et al: Effect of clozapine-quetiapine combination therapy on

weight and glycaemic control. Clin Drug Investig 18:99–104, 1999

Sacchetti E, Panariello A, Regini C, et al: Quetiapine in hospitalized patients with schizophrenia

refractory to treatment with first-generation antipsychotics: a 4-week, flexible-dose, single-blind,

exploratory, pilot trial. Schizophr Res 29:325–331, 2004

Sax KW, Strakowski SM, Keck PE Jr: Attentional improvement following quetiapine fumarate

treatment in schizophrenia. Schizophr Res 33:151–155, 1998 [PubMed]

Schneider LS, Tariot PN, Dagerman KS, et al: Effectiveness of atypical antipsychotic drugs in

patients with Alzheimer’s disease. N Engl J Med 355:1525–1538, 2006 [PubMed]

Seeman P, Tallerico T: Antipsychotic drugs which elicit little or no parkinsonism bind more loosely

than dopamine to brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiatry

3:123–134, 1998 [PubMed]

Small JG, Hirsch SR, Arvanitis LA, et al: Quetiapine in patients with schizophrenia: a high- and

low-dose double-blind comparison with placebo. Arch Gen Psychiatry 54:549–557, 1997 [PubMed]

Stephenson CM, Bigliani V, Jones HM, et al: Striatal and extra-striatal D(2)/D(3) dopamine receptor

occupancy by quetiapine in vivo: [(123)I]-epidepride single photon emission tomography (SPET)

study. Br J Psychiatry 177:408–415, 2000 [PubMed]

Strakowski SM, Keck PE Jr, Wong YW, et al: The effect of multiple doses of cimetidine on the

steady-state pharmacokinetics of quetiapine in men with selected psychotic disorders. J Clin

Psychopharmacol 22:201–205, 2002 [PubMed]

Stroup TS, Lieberman JA, McEvoy JP, et al: Effectiveness of olanzapine, quetiapine, and risperidone

in patients with chronic schizophrenia after discontinuing perphenazine: a CATIE study. Am J

Psychiatry 164:415–427, 2007 [Full Text] [PubMed]

Targum SD, Abbott JL: Efficacy of quetiapine in Parkinson’s patients with psychosis. J Clin

Psychopharmacol 20:54–60, 2000 [PubMed]

Thase ME, Macfadden W, Weisler RH, 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 26:600–609, 2006 [PubMed]

Thyrum PT, Wong YW, Yeh C: Single-dose pharmacokinetics of quetiapine in subjects with renal orPrint: Chapter 30. Quetiapine

http://www.psychiatryonline.com/popup.aspx?aID=430077&print=yes…

16 of 16

10/05/2009 16:12

hepatic impairment. Prog Neuropsychopharmacol Biol Psychiatry 24:521–533, 2000 [PubMed]

Velligan DI, Newcomer J, Pultz J, et al: Does cognitive function improve with quetiapine in

comparison to haloperidol? Schizophr Res 53:239–248, 2002 [PubMed]

Velligan DI, Prihoda TJ, Sui D, et al: The effectiveness of quetiapine vs conventional antipsychotics

in improving cognitive and functional outcomes in standard treatment settings. J Clin Psychiatry

64:524–531, 2003 [PubMed]

Vieta LN, Mullen J, Brecher M, et al: Quetiapine monotherapy for mania associated with bipolar

disorder; combined analysis of two international, double-blind, randomized, placebo-controlled

studies. Curr Med Res Opin 21:923–934, 2005 [PubMed]

Weiden PJ, Buckley PF: Reducing the burden of side effects during long-term antipsychotic therapy:

the role of “switching” medications. J Clin Psychiatry 68:14–23, 2007 [PubMed]

Wong YW, Yeh C, Thyrum PT: The effects of concomitant phenytoin administration on the

steady-state pharmacokinetics of quetiapine. J Clin Psychopharmacol 21:89–93, 2001 [PubMed]

Xu H, Qing H, Lu W, et al: Quetiapine attenuates the immobilization stress-induced decrease of

brain-derived neurotrophic factor expression in rat hippocampus. Neurosci Lett 321(1–2):65–68,

2002 [PubMed]

Yaeger DD, Smith HG, Altshuler LL: Atypical antipsychotics in the treatment of schizophrenia during

pregnancy and the postpartum. Am J Psychiatry 163:2064–2070, 2006 [Full Text] [PubMed]

Zhong KX, Sweitzer DE, Hamer RM, et al: Comparison of quetiapine and risperidone in the treatment

of schizophrenia: a randomized, double-blind, flexible-dose, 8-week study. J Clin Psychiatry

67:1093–1103, 2006 [PubMed]

Zhong KX, Tariot PN, Mintzer J, et al: Quetiapine to treat agitation in dementia: a randomized,

double-blind, placebo-controlled study. Curr Alzheimer Res 4:81–93, 2007 [PubMed]

Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.