Quetiapine is an atypical antipsychotic agent that has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia, bipolar disorder (including bipolar depression, bipolar mania, and adjunctive maintenance), and adjunctive use in the treatment of major depressive disorder. The use of antipsychotic agents has historically incurred the risk of extrapyramidal side effects (EPS), tardive dyskinesia, and metabolic side effects (e.g., weight gain, hyperglycemia, hyperlipidemia). Atypical, or second generation, antipsychotic agents have a unique pharmacological profile that combines rapid dissociation from dopamine-2 (D2) receptors with serotonergic antagonism that presumably accounts for its lower incidence of EPS and treatment of the negative symptoms of schizophrenia (Altamura et al., 2012). Stahl (2008) noted that quetiapine has a particularly rapid dissociation from D2 receptors (more so than other atypical agents), which can theoretically achieve the balance of occupying dopamine receptors long enough to abate psychosis while making dopamine available to improve mood and cognitive function. Additionally, Stahl (2008) cited the serotonergic activity and the increased availability of norepinephrine (via blockade of the norepinephrine transporter) as mechanisms by which quetiapine alleviates depression, anxiety, and potentially some of the other conditions for which quetiapine is being used in an off-label capacity. Histaminergic and alpha-adrenergic antagonism account for quetiapine’s sedating effect, explaining the off-label use of the drug as a sleep agent (Pinta & Taylor, 2007).
As an atypical antipsychotic agent, quetiapine has a more favorable side effect profile than first-generation agents, but recent research and clinical outcomes indicate that atypical antipsychotic agents pose a considerable risk of metabolic and, to a lesser extent, EPS consequences (Brauser, 2011). Furthermore, quetiapine prolongation and cardiac arrhythmias are rare but potentially deadly adverse reactions of all atypical antipsychotic agents (Stahl, 2008). Postmarketing data also indicate that quetiapine has a considerable potential for abuse (Compton, Thomas, Stinson, & Grant, 2007; Reeves & Brister, 2007). Despite its potency and potential for serious side effects, the off-label use of quetiapine is common practice. Quetiapine has been identified as the most commonly prescribed drug for non-FDA–approved uses (“Study for Off-Label Drug Use Urgently Needed,” 2008). The frequency with which quetiapine is prescribed off label indicates the need to establish the efficacy of quetiapine for various conditions and the need to clarify prescribing guidelines in cases where efficacy is established. AstraZeneca recently settled for $520 million as penalty for marketing quetiapine for non-FDA –approved uses such as anxiety, dementia, insomnia, impulsivity, and a variety of other conditions (U.S. Department of Justice, 2010). Marketing for off-label use is an FDA violation; however, it is unclear whether the claims that quetiapine can effectively treat these conditions with reasonable safety are evidence based. The AstraZeneca lawsuit underscores the importance of evaluating evidence for quetiapine’s many off-label uses. A synthesis of current data will serve to evaluate the evidence for quetiapine as an off-label pharmacological intervention for several psychiatric conditions in addition to evaluating any available practice guidelines for quetiapine use in each condition. The current article seeks to individually evaluate the efficacy of quetiapine treatment of generalized anxiety disorder (GAD), dementia, delirium, cluster B personality disorders, substance abuse disorders, and insomnia. An extensive search of electronic databases (e.g., CINAHL, PsycINFO, PubMed, MEDSCAPE, Cochrane Library, MEDLINE) was completed using the search terms quetiapine or Seroquel, off-label and anxiety, substance abuse, dementia, delirium, personality disorder, insomnia, and sleep.
Off-Label Use of Quetiapine for Generalized Anxiety Disorder
Anxiety disorders are a set of heterogeneous conditions characterized by fear, panic, and excessive worry (American Psychiatric Association [APA], 2000). The majority of the quetiapine studies identified involved the treatment of GAD, either as an adjunct to other pharmacological agents or as monotherapy. The APA currently has well established guidelines for the treatment of GAD. First-line interventions include cognitive-behavioral therapy, selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs); adjunctive agents include benzodiazepine agents, serotonin agonist agents, and some anti-epileptic mood stabilizers (non-FDA approved) (Hollander & Simeon, 2010). GAD is highly prevalent and highly treatable (Hollander & Simeon, 2010). Although safe and effective treatments for GAD are available, not all patients respond to established therapies, and quetiapine has emerged as an intervention for treating GAD (Comer, Mojtabai, & Olfson, 2011).
Three double-blind, placebo, randomized controlled trials (RCTs) demonstrated that quetiapine was effective in reducing symptoms of GAD as monotherapy in the acute or initial phases (Bandelow et al., 2010; Khan et al., 2011; Merideth, Cutler, She, & Eriksson, 2012). Two of the studies also contained active controls with first-line SSRIs (escitalopram [Lexapro®] and paroxetine [Paxil®]) (Bandelow et al., 2010; Merideth et al., 2012). Each of the three RCTs showed improved scores in the psychometric measures of the Hamilton Anxiety Scale (HAM-A) and Clinical Global Impression Scale (CGIS). The two studies that included active controls indicated that quetiapine has comparable anxiolytic effects to SSRIs with a quicker onset (Bandelow et al., 2010; Merideth et al., 2012). Bandelow et al. (2010) reported greater improvement at the 150-mg-per-day dose than the 50-mg-per-day dose. Adverse effects were typical of quetiapine including sedation, dizziness, and fatigue; only three patients experienced serious adverse reactions (i.e., syncope, suicidal ideation, and one patient experienced hyperglycemia and acute renal failure) (Stein et al., 2011). Each RCT lasted 10 weeks; therefore, findings should not be generalized to long-term therapy.
Evidence was scarce for maintenance therapy (long term) with quetiapine in the treatment of GAD. Katzman et al. (2011) completed a 52-week RCT to evaluate the effectiveness of quetiapine in the long-term treatment of GAD. The large-scale study began with 1,248 participants; 432 participants completed the study (an approximate 65% dropout rate). Two hundred thirty-five individuals (19%) dropped out due to adverse effects and 147 (12%) dropped out due to unwillingness to continue, with the remaining attrition being attributed to various other reasons (Katzman et al., 2011). CGIS and HAM-A scores improved with statistical significance in the majority of individuals who completed the study (p < 0.05) (Katzman et al., 2011). Statistically significant elevated levels of insulin, body weight, blood glucose, low-density lipoprotein cholesterol, and decreased levels of high-density lipoprotein cholesterol were reported in the quetiapine group (Katzman et al., 2011).
RCTs of quetiapine as an augmentation of anxiety partially responsive or nonresponsive to first-line agents were also available in the literature. One RCT demonstrated evidence of improved HAM-A and CGIS scores (McIntyre, Gendron, & McIntyre, 2007), whereas another RCT did not show improvement; however, results may have been confounded by insufficient quetiapine dosing and comorbidities (Simon et al., 2008). An open-label study showed some improvement of HAM-A scores with quetiapine augmentation over a 12-week period (Katzman et al., 2008). Two RCTs indicated that quetiapine augmentation expedited the improvement of anxiety symptoms, but ultimately the results were similar to monotherapy with an SSRI (Altamura et al., 2012; Simon et al., 2008). Weight gain and somnolence were the most prevalent adverse effects.
Current research points to the potential efficacy of quetiapine in the short-term management of GAD (Bandelow et al., 2010; Merideth et al., 2012). EPS, metabolic side effects, and cardiac abnormalities were minimized with a shorter duration of therapy (Katzman et al., 2011; Lorenz, Jackson, & Saitz, 2010). Adjunctive treatment with SSRIs raises the risk of serotonin syndrome (Lorenz et al., 2010). Daily dosing from 50 mg per day to 300 mg per day was common. Evidence for long-term quetiapine therapy for GAD was less compelling, with one RCT (Katzman et al., 2011) having a substantial dropout rate and a higher incidence and severity of metabolic consequences. Furthermore, long-term atypical antipsychotic agent therapy increases the risk of EPS, cardiac abnormalities, and tardive dyskinesia. The FDA rejected AstraZeneca’s bid to obtain approval for quetiapine in the treatment of GAD due to metabolic and cardiac risks (Lorenz et al., 2010). Nonetheless, quetiapine may have efficacy in short-term acute management of GAD, with the potential for benefiting patients who are awaiting therapeutic response from first-line agents or in cases where benzodiazepine agents may pose a risk factor (e.g., history of prior abuse) (Sattar, Bhatia, & Petty, 2004). With several other evidence-based treatment options, quetiapine management of GAD should most likely be reserved for circumstances in which more conventional interventions have failed. A synopsis of relevant research of quetiapine in GAD management is presented in Table A (available in the online version of this article).
Table A: Studies of Off-Label Use of Quetiapine for Generalized Anxiety Disorder
Off-Label Use of Quetiapine for Dementia
Dementia often entails troubling symptoms of agitation, aggression, and psychosis. Cholinesterase inhibitors Aricept® (donepezil) and Exelon® (rivastigmine) are FDA approved for the cognitive symptoms of dementia. Currently, there are no FDA-approved medications for the other psychiatric manifestations of dementia (e.g., agitation, aggression, delusions). Atypical antipsychotic agents carry a boxed warning regarding the use of these agents in patients with dementia due to an increased mortality risk and increased risk of injury. Yet, some data suggest that atypical antipsychotic agents can improve acute symptomology and reduce caregiver strain. Hence, prescribers are presented with a conundrum.
Studies evaluating the efficacy of quetiapine in the treatment of dementia are available in the research literature (Table B, available in the online version of this article). Data are mixed and subject to clinician interpretation. Two meta-analyses (Ballard & Howard, 2006; Schneider, Dagerman, & Insel, 2006) that included three RCTs (Ballard et al., 2005; Tariot et al., 2006; Zhong, Tariot, Mintzer, Minkwitz, & Devine, 2007) indicated that quetiapine did not significantly improve psychotic symptoms in patients with dementia, but symptoms of agitation and aggression showed some improvement at the 200-mg dose. Quetiapine had more discontinuations due to lack of response but fewer discontinuations due to adverse effects (Ballard & Howard, 2006; Schneider et al., 2006). Investigators were unable to combine efficacy outcomes of the three RCTs due to substantial variability in study design (Ballard & Howard, 2006; Schneider et al., 2006). The lack of antipsychotic agent effect may, however, be attributed to the relatively conservative quetiapine dosing (generally ⩽200 mg). Both studies identified quetiapine as the atypical agent with the lowest mortality risk and lower risk of injury (Ballard & Howard, 2006; Schneider et al., 2006), although Ballard et al. (2005) observed an increased risk for cognitive decline (p = 0.01).
Table B: Studies of Off-Label Use of Quetiapine for Dementia
Sultzer et al. (2008) completed a multicenter, National Institute of Mental Health (NIMH)-sponsored RCT of atypical antipsychotic agents used to treat Alzheimer’s dementia (Clinical Antipsychotic Trials of Intervention Effectiveness—Alzheimer’s Disease [CATIE-AD]) that included quetiapine (N = 105). Several outcome measures were used including the CGIS, Brief Psychotic Rating Scale, Cornell Scale for Alzheimer’s Depression, Mini Mental State Examination, and Caregiver Activity Survey. Overall, benefits for quetiapine on these scales were modest with numerical improvement, but only the CGIS outcome measure showed statistical significance (p = 0.04) (Sultzer et al., 2008). Quetiapine showed a smaller effect size than risperidone (Risperdal®) and olanzapine (Zyprexa®); however, adverse effects (e.g., worsened psychosis, unsteady gait, cardiovascular events) were less frequent in the quetiapine group. Again, smaller effect sizes for quetiapine may be attributed to smaller quetiapine doses (average 57 mg per day). The CATIE-AD study provides limited support for the use of quetiapine in the management of Alzheimer’s dementia. Quetiapine may be safer than other atypical agents when given in small doses (Sultzer et al., 2008)
Other studies (Rainer, Haushofer, Pfolz, Struhal, & Wick, 2007; Tariot et al., 2006; Zhong et al., 2007) had stronger indications for the efficacy of quetiapine in the treatment of dementia and accompanying psychosis, agitation, and aggression. The benefits of atypical antipsychotic agents in managing dementia-related psychiatric symptoms are limited but generally well accepted (Sultzer et al., 2008). However, the risks are also well documented, and the possibility of litigation and patient injury are factors that may influence prescriptive practices. Dementia patients receiving quetiapine should be closely monitored; the patient and the patient’s family should be given documented informed consent of the risk versus anticipated benefits.
Off-Label Use of Quetiapine for Delirium
Delirium is a precipitous state of confusion, agitation, and disorientation with a variety of medical and psychiatric etiologies (APA, 2000). Although the root causes of any delirium state should be ascertained and treated, delirium itself can lead to injury, protracted hospital stays, and death. Symptoms of delirium should be treated until the root cause is resolved (APA, 2000). Atypical antipsychotic agents have documented efficacy in the treatment of delirium (Turkel, Jacobson, Munzig, & Tavaré, 2012). Two RCTs indicated that treatment with quetiapine expedited recovery from delirium and ameliorated psychotic and cognitive symptoms (Devlin et al., 2010; Tahir et al., 2010). Both studies used flexible dosing schedules, and Tahir et al. (2010) indicated that higher dosing schedules may have yielded greater reduction of delirium. Turkel et al. (2012) completed a retrospective chart review that provides initial support for the use of quetiapine (and other atypical antipsychotic agents) in the management of pediatric and adolescent delirium. Significant adverse effects were not reported (Turkel et al., 2012). A 17-patient case series demonstrated that quetiapine hastened resolution of delirium and reduced the need for other pharmacological interventions (Wan, Kasliwal, McKenzie, & Barrett, 2011). Other published case studies also showed positive outcomes with quetiapine therapy (Marcantonio, 2012; Omura & Amano, 2003; Shinno et al., 2007). Psychiatric treatment for delirium is generally limited to an acute, short-term episode (⩽1 week) (Ely et al., 2001), and the abbreviated course of treatment minimizes the risk of EPS and metabolic adverse effects. Extant literature indicates that quetiapine is a fairly safe and effective treatment for delirium (Table C, available in the online version of this article).
Table C: Studies of Off-Label Use of Quetiapine for Delirium
Off-Label Use of Quetiapine for Cluster B Personality Disorders
Pharmacotherapy for personality disorders has become more prevalent in recent years, although more research is needed to accurately inform treatment (Rinne & Ingenhoven, 2007). Some data support the use of pharmacotherapy for target symptoms of personality disorders; however, psychotherapy remains the mainstay of treatment (LeBloc’h, Baumann, Stigler, Eap, & Zullino, 2007). Quetiapine has tentatively shown some benefit in the treatment of cluster B personality disorder symptoms such as mood lability, aggression, and impulsivity (LeBloc’h et al., 2007).
Five open-label studies showed favorable results for quetiapine as a means of decreasing various target symptoms including mood lability, impulsivity, aggression, and decreased neurocognitive functioning in patients with borderline personality disorder (BPD) (Le Bloc’h et al., 2007; Romine, Brown, Thuras, Lee, & Shultz, 2008; Van den Eynde et al., 2008, 2009; Villeneuve & Lemelin, 2005). Continual weight gain (p = 0.046) was observed in one of the open-label trials, although this study did not report screening for hyperlipidemia and hyperglycemia (Le Bloc’h et al., 2007). The remaining four open-label studies did not report assessment for metabolic side effects. Sedation was the primary side effect reported in these studies ranging from 7 to 12 weeks. Two case studies of patients with BPD with suicidal and self-mutilation behaviors indicated that self-destructive behaviors improved. One open-label trial reported no improvement in impulsivity (Roepke et al., 2008).
One RCT pilot study (N = 19) indicated that quality of life and overall functioning were improved for adolescents with conduct disorder being treated with quetiapine, but the secondary measure of parental quality of life was not improved (Conner, McLaughlin, & Jeffers-Terry, 2008). Assessment of metabolic side effects was not reported in this 7-week study. Four case studies involving high doses of quetiapine in sociopathic prison inmates reflected improvements of impulsivity and aggression (Walker, Thomas, & Allen, 2008). Assessment of metabolic side effects was not reported in this 8-week study.
Clinicians evaluating the evidence for quetiapine treatment in target symptoms of personality disorders may want to consider the potential for metabolic side effects of long-term quetiapine therapy (as personality disorders are chronic conditions [APA, 2000]) and reserve quetiapine treatment for acute episodes. Table D (available in the online version of this article) presents a synopsis of available evidence.
Table D: Studies of Off-Label Use of Quetiapine for Cluster B Personality Disorders
Off-Label Use of Quetiapine for Substance Abuse Disorders
Quetiapine has been investigated as a potential means of alleviating substance abuse and dependence disorders. Data are mixed regarding the efficacy of quetiapine in the treatment of substance disorders, with some evidence pointing toward beneficial effects whereas other data indicate quetiapine may have an independent potential for abuse (Erdogan, 2010). Other studies have shown short-term gains for acute withdrawal (Pinkofsky et al., 2005) or no therapeutic benefit (Brown, Gabrielson, & Gu, 2010; Litten et al., 2012; Tapp, Wood, Kennedy, & Sylvers, 2011).
One RCT indicated that quetiapine decreased the frequency of alcohol craving and consumption over a 6-week period (Ray, Chin, Heydari, & Miotto, 2011); however, total abstinence was not an outcome measure, and patients were allowed to continue marijuana use during the study. Patients reached a target dose of 400 mg per day, and screening for metabolic abnormalities and EPS was not reported. An earlier RCT also reported fewer drinking days and less cravings (Kampman et al., 2007). The study reported statistical significance for total abstinence (p = 0.012); however, these data must be interpreted with consideration to the fact that they pertain to 11 participants (9 total abstainers in the quetiapine group and 2 abstainers in the placebo group) of 61 total participants. Hence, a p value of 0.012 for total abstinence cannot be generalized to the entire sample, as only 11 of the 61 total participants achieved abstinence, and the study did not have statistical significance for total abstinence. Kampman et al. (2007) reported that quetiapine improved cravings and total days of alcohol consumption in type B alcoholics (early onset and severe alcoholism with accompanying psychiatric symptoms). It is unclear if quetiapine’s psychotropic (antidepressant, anxiolytic, mood stabilization) effects ameliorated drinking behaviors in the type B subset as opposed to having a direct correlation to reduction in drinking (i.e., it is possible that treatment of co-occurring psychiatric symptoms ameliorated drinking). Sedation was the main side effect reported. Screening for metabolic abnormalities and EPS were not reported by the authors. Self-report measures were used to determine outcomes in both of these studies.
A multicenter RCT, also using self-report measures to determine reduction in drinking behaviors in 224 alcohol-dependent participants, did not yield data supporting the efficacy of quetiapine over a 30-day period (Litten et al., 2012). Somnolence and sedation were the main side effects reported, and self-report measures were used to determine quetiapine’s effect on alcohol craving and consumption. The authors did not report screening for metabolic abnormalities and EPS. Martinotti et al. (2008) reported decreased alcohol consumption and craving in patients with dual diagnosis (alcoholism and a comorbid psychiatric diagnosis) in an open-label study. Again, it is difficult to ascertain whether improvement in alcohol consumption is directly correlated to quetiapine versus a by-product of improved psychiatric symptoms. The authors reported weight gain and elevated glucose in this 16-week study.
Tapp et al. (2011) conducted an RCT evaluating the role of quetiapine in reduction of cocaine abuse. Findings were inconclusive, with reduction of craving and use self-reported in both the quetiapine and placebo groups. A previous open-label study indicated that quetiapine effectively reduced cocaine use and cravings, although sedation and weight gain (p = 0.001) were prominent side effects during the 6-week study (Kennedy et al., 2008). A retrospective chart review of 107 patients indicated that short-term quetiapine therapy was effective in eliminating symptoms of acute opiate withdrawal (Pinkofsky et al., 2005).
Clinicians may want to consider the modest evidence in light of the well-established side effects when considering long-term quetiapine therapy for substance abuse and dependence. Preliminary evidence indicates that quetiapine may have benefits for managing acute opiate withdrawal, although more studies are indicated. A summary of pertinent evidence is provided in Table E (available in the online version of this article).
Table E: Studies of Off-Label Use of Quetiapine for Substance Abuse Disorders
Off-Label Use of Quetiapine for Insomnia
Quetiapine has been increasingly prescribed for the off-label indication of insomnia (Coe & Hong, 2012). The balance of evidence indicates that quetiapine improves sleep patterns; however, evidence also shows that quetiapine causes significant weight gain even when used in small to moderate doses for sleep (Cates, Jackson, Feldman, Stimmel, & Woolley, 2009; Williams, Alinejad, Williams, & Cruess, 2008).
One RCT using 100-mg per night quetiapine for primary insomnia indicated quetiapine increased both sleep quality and amount (Cohrs, Rodenbeck, et al., 2004). Another RCT showed decreased nocturnal secretions of the stress hormone cortisol in patients treated with quetiapine (Cohrs, Pohlmann, et al., 2004). Tassniyom, Paholpak, Tassniyom, & Kiewyoo (2010) reported that quetiapine did not improve sleep in a 2-week RCT. The lack of effect for sleep might be attributed to the conservative quetiapine dose (25 mg per night). None of the RCTs included screening for metabolic abnormalities or EPS.
Two other open-label studies (Juri, Chaná, Tapia, Kunstmann, & Parrao, 2005; Wiegand et al., 2008) showed improved sleep with quetiapine treatment. Juri et al.’s (2005) study noted quetiapine’s sleep-improving effects in patients with Parkinson’s disease. These studies did not report screening for metabolic abnormalities. Cates et al. (2009) and Williams et al. (2010) both completed retrospective chart reviews of patients treated with quetiapine for insomnia (the former study included 534 patients). These reviews did not assess the effects of quetiapine on sleep, but rather on weight. Both studies reported significant weight gain with low doses of quetiapine for sleep (<100 mg per night) over periods ranging from 6 to 30 months. Screening for other metabolic abnormalities was not reported.
Current evidence points to quetiapine as an effective sleep-promoting agent. Clinicians should be advised to consider individual patient heath profiles when considering long-term quetiapine therapy for insomnia in light of the potential for weight gain (and other potential adverse effects) with even moderately low quetiapine dosing (Cates et al., 2009; Williams et al., 2010). A review of studies is presented in Table F (available in the online version of this article).
Table F: Studies of Off-Label Use of Quetiapine for Insomnia
As stated, off-label prescribing of quetiapine is a relatively common practice (“Study for Off-Label Drug Use Urgently Needed,” 2008). Several published studies have evaluated the efficacy of the various off-label uses for quetiapine. Comprehensive cross-sections of these studies are detailed in the current article. Outcomes are mixed within and between the various uses. The strongest evidence exists for quetiapine as a short-term anxiolytic and pharmacological intervention for the psychiatric sequela of delirium; quetiapine as short-term adjunct to other anxiolytic agents also demonstrates potential for efficacy, although evidence for GAD maintenance therapy with quetiapine is less compelling. Initial evidence also points toward quetiapine as a means of alleviating the initial symptoms of substance withdrawal; however, evidence for the long-term management of substance abuse disorders is not strong. Quetiapine has documented benefits in the psychiatric symptoms of dementia, although the risk of death and patient injury is also prominent. Clinicians are well advised to exercise prudence when using quetiapine in patients with dementia. Aggression, lability, and impulsivity associated with Axis II personality disorders has been shown to respond to quetiapine, but the appropriate duration of quetiapine therapy should be clarified. Studies indicate that quetiapine is an effective sleep agent; however, even low doses have been shown to precipitate weight gain.
Clinicians evaluating available data for prescriptive guidance on off-label uses of quetiapine should bear in mind the well-documented adverse side effect profile of long-term quetiapine therapy (notably hyperglycemia, weight gain, hyperlipidemia, and EPS) (Brauser, 2011). Dosing regimens need to be operationalized for the various off-label uses. Available data suggest that the efficacy for off-label prescribing of quetiapine may be more pronounced for acute, short-term interventions when more conventional methods have been unsuccessful.
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Studies of Off-Label Use of Quetiapine for Generalized Anxiety Disorder
|Study||Study Design||N||Quetiapine Dose/Frequency||Duration||Results|
|Merideth, Cutler, She, & Eriksson (2012)||RCT: placebo and active control
Monotherapy||219 (Q 150 mg)
207 (Q 300 mg)
213 (AC)||150 mg/day or 300 mg/day||10 weeks||Quetiapine improved anxiety symptoms with mild adverse effects at both doses (p < 0.001 for 150-mg dose; p < 0.05 for 300-mg dose).|
|Khan et al. (2011)||RCT
Monotherapy||234 (Q 50 mg)
241 (Q 150 mg)
241 (Q 300 mg)
235 (P)||50, 150, or 300 mg/day||10 weeks||Quetiapine improved anxiety symptoms with mild adverse effects at 50-mg (p < 0.001) and 150-mg (p < 0.01) doses; no statistical significance for 300 mg dose.|
|Bandelow et al. (2010)||RCT: placebo and active control
Monotherapy||221 (Q 50 mg)
218 (Q 150 mg)
217 (AC)||50 or 150 mg/day||10 weeks||Quetiapine improved anxiety symptoms with mild adverse effects at 150-mg dose (p < 0.01). No statistical significance at 50-mg dose.|
|Katzman et al. (2011)||Long-term open-label converted to RCT
216 (P)||50 to 300 mg/day||52 weeks||Quetiapine improved anxiety symptoms in those who finished the study (p < 0.05). There was a considerable dropout rate due to adverse events/poor adherence.|
|Altamura et al. (2012)||RCT
Adjunctive therapy||10 (Q)
10 (P)||50 mg/day||8 weeks||Quetiapine was numerically but not statistically effective as an adjunct to first-line agent (p = 0.37).|
|Simon et al. (2008)||RCT
Adjunctive therapy||22 (Q)
38 (P)||50 to 300 mg/day||10 weeks||Quetiapine did not significantly improve anxiety as an adjunct to first-line agent. No statistical significance.|
|Gabriel (2011)||Open-label trial
Adjunctive therapy||24||50 to 150 mg/day||12 weeks||Quetiapine was helpful as an adjunct to first-line agent. No p value given.|
Studies of Off-Label Use of Quetiapine for Dementia
|Study||Study Design||N||Quetiapine Dose/Frequency||Duration||Results|
|Ballard & Howard (2006)||Meta-analysisa||N/A||Variable||1995 to 2006||Moderate short-term benefit with considerable risk. No p value given for quetiapine.|
|Schneider, Dagerman, & Insel (2006)||Meta-analysisa||N/A||Variable||Not stated||Moderate short-term benefit with considerable risk. No p value given for quetiapine.|
|Sultzer et al. (2008)||RCTa||105 (Q)||Variable, mean 57 mg/day||36 weeks||Minimal short-term benefit for 1 of 4 outcome measures with considerable risk; p = 0.04 for CGIS.|
|Zhong, Tariot, Mintzer, Minkwitz, & Devine (2007)||RCT||124 (Q 100 mg)
117 (Q 200 mg)
92 (P)||100 or 200 mg/day||10 weeks||Quetiapine was moderately effective and fairly well tolerated (p = 0.065).|
|Tariot et al. (2006)||RCT||284||Flexible||10 weeks||Quetiapine showed moderately improved psychosis but not agitation and was fairly well tolerated with fewer side effects than haloperidol (Haldol®). Numerical improvements; no p value given.|
|Dolder & McKinsey (2010)||Retrospective cross-sectional study||43 (Q)
58 (no Q)||50 to 100 mg/night||2007 to 2009||Quetiapine was commonly prescribed without first using more conventional agents. No p value given.|
|De Deyn, Eriksson, & Svensson (2012)||RCT||68 (QXR)
32 (QIR)||Flexible||6 weeks||Quetiapine improved agitation and psychosis and was fairly well tolerated. Numerical improvement; no p value given.|
|Rainer, Haushofer, Pfolz, Struhal, & Wick (2007)||Rater-blinded control trial||34 (Q)
31 (R)||Flexible||8 weeks||Low-dose quetiapine was effective and well tolerated in treating behavioral and psychological symptoms of dementia (p = 0.05).|
Studies of Off-Label Use of Quetiapine for Delirium
|Devlin et al. (2010)||RCT||18 (Q)
18 (P)||Flexible||>10 days||Quetiapine improved delirium symptoms and treatment outcomes (p = 0.006, duration of delirium; p = 0.06, likelihood of being discharged home or to rehabilitation versus hospital floor).|
|Tahir et al. (2010)||RCT||21 (Q)
21 (P)||Flexible||Variable||Quetiapine expedited the resolution of psychiatric symptoms of delirium and was well tolerated (p = 0.026).|
|Turkel, Jacobsen, Munzig, & Tavaré (2012)||Retrospective chart review||19||Flexible||24 months||Quetiapine was effective and well tolerated in children and adolescents experiencing delirium (p ⩽ 0.001).|
|Wan, Kasliwal, McKenzie, & Barrett (2011)||Retrospective chart review||17||25 to 50 mg||2 years||Quetiapine was generally well tolerated and associated with a more rapid resolution of refractory delirium. No p value given.|
|Shinno et al. (2007)||Case studies||6||12 to 50 mg/day||2 weeks||Quetiapine was well tolerated and improved delirium in terminally ill cancer patients. No p value given.|
|Omura & Amano (2003)||Case studies||24||25 to 125 mg/day||1 week||Quetiapine was well tolerated and improved delirium symptoms (p ⩽ 0.001).|
|Marcantonio (2012)||Case study||1||25 to 50 mg||10 days||Quetiapine may have been helpful in relieving delirium symptoms. No p value given.|
Studies of Off-Label Use of Quetiapine for Cluster B Personality Disorders
|Romine, Brown, Thuras, Lee, & Shultz (2008)||Open label||16||200 to 300 mg||8 weeks||BPD symptoms and overall functioning (Global Assessment of Functioning) improved, and quetiapine was well tolerated (p = 0.001).|
|Conner, McLaughlin, & Jeffers-Terry (2008)||Randomized controlled pilot||9 (Q)
10 (P)||200 to 600 mg||7 weeks||Quetiapine improved behavior in adolescents with conduct disorder and was fairly well tolerated (p ⩽ 0.05).|
|Van den Eynde et al. (2009)||Open label||41||100 to 800 mg||12 weeks||Improved cognitive functioning, affective lability, and impulsivity in BPD and quetiapine was well tolerated (p ⩽ 0.0001).|
|Le Bloc’h, Baumann, Stigler, Eap, & Zullino (2007)||Open label||12||50 to 400 mg||8 weeks||Approximately half of the BPD patients improved with both inward (p = 0.006) and outward aggression (p = 0.018) and weight gain was common.|
|Van den Eynde et al. (2008)||Open label||41||100 to 800 mg||12 weeks||Improved impulsivity and affective symptoms in BPD patients (p ⩽ 0.0001).|
|Villeneuve & Lemelin (2005)||Open label||23||175 to 400 mg||12 weeks||BPD symptoms and overall functioning improved, and quetiapine was well tolerated in BPD patients (p = 0.018).|
|Roepke et al. (2008)||Open label||15||400 mg||8 weeks||Quetiapine did not improve impulsivity in cluster B personality disorders; depressive symptoms were improved. No p value given.|
|Hilger, Barnas, & Kasper (2003)||Case studies||2||200 to 400 mg||4 weeks||Quetiapine improved impulsivity and overall functioning in BPD patients. No p value given.|
|Walker, Thomas, & Allen (2003)||Case studies||4||600 to 800 mg||8 weeks||Aggression, mood instability, and impulsivity were improved in patients with antisocial personality disorder. No p value given.|
Studies of Off-Label Use of Quetiapine for Substance Abuse Disorders
|Ray, Chin, Heydari, & Miotto (2011)||RCT||6 (Q)
9 (P)||400 mg/day||6 weeks||Quetiapine numerically lessened the frequency of alcohol consumption and alcohol craving; however, no statistical significance was found (p = 0.49, drinking in past 30 days self-report; p = 0.31, alcohol craving).|
|Litten et al. (2012)||RCT, multicenter||224||50 to 400 mg/day||30 days||Quetiapine was not shown to be effective. No differences between quetiapine and placebo group for alcohol consumption (no statistical significance).|
|Kampman et al. (2007)||RCT||29 (Q)
32 (P)||400 mg/day||12 weeks||Quetiapine reduced alcohol consumption in type B (early onset, severe with accompanying psychiatric symptoms) but not type A (late onset without accompanying psychopathology). Self-report measure, p = 0.04 (decreased craving for type B), p = 0.004 (fewer drinking days for type B). No statistical significance for total abstinence.|
|Brown, Gabrielson, & Gu (2010)||RCT||6 (Q)
6 (P)||400 to 800 mg/day||12 weeks||Quetiapine did not reduce the amount of cocaine ingested (no statistical significance).|
|Tapp, Wood, Kennedy, & Sylvers (2011)||RCT||29 (Q)
31 (P)||400 mg/day||12 weeks||No difference between placebo group and quetiapine group.|
|Kennedy et al. (2008)||Open label||11 (Q)
11 (P)||300 to 600 mg/day||6 weeks||Cocaine cravings decreased and weight increased (p ⩽ 0.001, self-report measure; p ⩽ 0.001, weight gain).|
|Martinotti et al. (2008)||Open label||28||300 to 800 mg/day||16 weeks||Alcohol use and craving was reduced from baseline in dual diagnosis patients, patients gained weight and blood glucose levels increased (p = 0.005, drinking days; p = 0.018, craving). Mean weight gain 0.6 kg (16 weeks). Mean glucose elevation 6 mg/dL (16 weeks).|
|Pinkofsky (2005)||Retrospective review||107||25 to 600 mg/day||5-day period for each patient (1 year of data)||Quetiapine alleviated some symptoms of opiate withdrawal; no p value given.|
|Sattar, Bhatia, & Petty (2004)||Retrospective chart review||9||153 mg/day (mean)||1 to 6 months||Quetiapine alleviated symptoms of substance withdrawal and postacute substance withdrawal and supported abstinence (p ⩽ 0.005).|
Studies of Off-Label Use of Quetiapine for Insomnia
|Tassniyom, Paholpak, Tassniyom, & Kiewyoo (2010)||RCT||8 (Q)
8 (P)||25 mg/night||2 weeks||Quetiapine did not aid in sleep. No p value given.|
|Cohrs, Rodenbeck, et al. (2004)||RCT||8 (Q)
8 (P)||100 mg/night||3 nights||Quetiapine increased sleep quality (p ⩽ 0.001).|
|Cohrs, Pohlman, et al. (2004)||RCT||7 (Q)
6 (P)||25 to 100 mg/night||9 nights||Quetiapine reduced nocturnal cortisol levels (p ⩽ 0.001).|
|Wiegand et al. (2008)||Open-label pilot||16||25 to 75 mg/night||6 weeks||Sleep improved from baseline (p = 0.02).|
|Juri, Chaná, Tapia, Kuntsmann, & Parrao (2005)||Open label||14||12.5 to 50 mg/night||12 weeks||Sleep improved from baseline in patients with Parkinson’s disease (p ⩽ 0.01).|
|Cates, Jackson, Feldman, Stimmel, & Woolley (2009)||Retrospective chart review||43||100 mg/night (average dose)||30 months||Effectiveness for sleep not evaluated. Patients gained weight when using low-dose quetiapine for sleep (p = 0.037; mean weight gain 2.2 kg)|
|Williams, Alinejad, Williams, & Cruess (2010)||Retrospective chart review||534||⩽100 mg/day||12 months||Effectiveness for sleep not evaluated. Low-dose quetiapine caused weight gain when used for sleep (p ⩽ 0.001, weight gain of 2 kg at 6 months; p ⩽ 0.001 weight gain 5 kg at 12 months).|