Quetiapine: efficacy, tolerability and safety in schizophrenia

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Drug Profile

Quetiapine: efficacy, tolerability and safety in schizophrenia Chanoch Miodownik and Vladimir Lerner†

CONTENTS Background Chemistry & pharmacodynamics Pharmacokinetics & metabolism Clinical efficacy & dosing Quetiapine & cognition Safety & tolerability Expert commentary Five-year view Key issues References Affiliations

†

Author for correspondence University of the Negev, Division of Psychiatry, Ministry of Health Be’er Sheva Mental Health Center, Faculty of Health Sciences BenGurion, Be’er Sheva, Israel Tel.: +972 864 01408 Fax: +972 864 01491 [email protected] KEYWORDS: doses, quetiapine, schizophrenia, side effects, treatment

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Quetiapine, a dibenzothiazepine derivative, is an atypical antipsychotic, multireceptor antagonist that has a preclinical profile similar to clozapine. Randomized studies have demonstrated the efficacy of quetiapine relative to placebo in the treatment of acute relapse and the long-term management of schizophrenia. Quetiapine is generally well tolerated relative to other antipsychotic medications, although side effects include sedation, orthostatic hypotension, anticholinergic and metabolic side effects. The purpose of this article is to critically review the current literature on quetiapine with an emphasis on emergent themes and key findings in the use of this agent for the treatment of schizophrenia. There are also continued efforts to understand, predict and manage the side-effect risk with quetiapine. Expert Rev. Neurotherapeutics 6(7), 983–992 (2006)

Schizophrenia is a severe, debilitating mental illness characterized by a progressive decline of the patient’s functioning and relationship with the outside world. Although some patients recover, the illness more usually follows a chronic-relapsing course. Conventional (typical) antipsychotics, such as haloperidol, perphenazine and others, that have been used for several decades, improve the positive symptoms of schizophrenia (e.g., delusions, hallucinations), but the adverse effects of these agents often interfere with long-term therapy. In addition, typical antipsychotics often have relatively little effect on the negative symptoms of schizophrenia (e.g., lack of motivation, social withdrawal) [1]. Over the past decade, atypical antipsychotics have entered psychiatry practice and become the treatment of choice for chronic schizophrenia. In numerous cases, treatment with these antipsychotics has replaced treatment with conventional antipsychotics, which is associated with a high incidence of adverse events, particularly acute and tardive extrapyramidal symptoms (EPS) [2]. Whereas conventional antipsychotics are only capable of suppressing positive symptoms, atypical

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antipsychotics are supposed to improve negative symptoms, affective symptoms and cognitive deficits [3,4]. The purpose of this article is to review some of the important clinical characteristics of quetiapine, such as efficacy, tolerability and safety, drawing primarily from the pivotal studies and case reports published during the last 5 years. Background

Quetiapine (Seroquel®, AstraZeneca) is the fourth atypical antipsychotic medication. It was discovered in 1984 and has been in clinical practice in the USA since 1997 for the treatment of schizophrenia. Currently, it is approved and available in more than 80 countries worldwide, including most European countries, Canada and Japan. Quetiapine is available as 25, 100, 200 and 300 mg film-coated tablets. Chemistry & pharmacodynamics

The pharmacodynamic properties of quetiapine have already been described in detail in many previous publications, without a significant discovery in this area. Therefore, this subject will be discussed from its basic information.

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Quetiapine, a dibenzothiazepine derivative, is a clozapinelike atypical antipsychotic. It demonstrates a low affinity for the dopamine-2 (D2) receptor and a higher affinity for the serotonin-2A (5-hydroxytriptamine [5-HT]2A) receptor and a very-high affinity for the histamine (H1) receptor. In addition to histaminic blockade, quetiapine blockades the α1-adrenergic (A1) receptor and muscarinic (M1) receptor [5–7]. Pharmacokinetics & metabolism

The absorption of quetiapine in the body is rapid. Its plasma concentration reaches a maximum in 1–2 h. The mean half-life of quetiapine is approximately 7 h. Its absorption is unaffected by food in the stomach and the drug is approximately 83% bound to serum proteins [8]. Quetiapine exhibits linear pharmacokinetics, so that blood levels change approximately in proportion to the dose taken [8]. Furthermore, its pharmacokinetics does not appear to be affected by ethnic background, gender, body weight or cigarette smoking. In pharmacokinetic studies, there were no apparent differences in adolescents compared with adults. In elderly patients, the mean plasma clearance of quetiapine is reduced by 30–50% compared with younger patients, so the initial target dosing may need to be lowered by an equivalent amount. No clinically significant differences were found for pharmacokinetic parameters for patients with renal or hepatic impairment compared with those for healthy control subjects [9]. The prescribing information states that the seroquel dose adjustment for patients with hepatic impairment is necessary [10]. The primary route of elimination of quetiapine in the body is through hepatic metabolism. Quetiapine is metabolized by the cytochrome P450 3A4 isoenzyme and the dose may need to be adjusted if quetiapine is coadministered with drugs that affect the activity of this isoenzyme [11]. After administration of [14C]quetiapine, approximately 73% of the radioactivity was excreted in the urine and 21% was excreted in feces. A total of 11 metabolites formed through hepatic oxidation and have been identified. A total of two of these metabolites were found to be pharmacologically active, but, because they circulate in the plasma at levels that are 2–12% that of quetiapine, they are unlikely to contribute substantially to the pharmacologic effects of the drug [6,8]. Clinical efficacy & dosing

Quetiapine is used for treatment of schizophrenia and other psychoses. It has a theoretically low propensity for movement disorder adverse effects. Most studies that evaluated the efficacy of quetiapine were short-term (6–12 weeks) [12]. Randomized, double-blind trials demonstrated that the drug is more effective than placebo, but is not better than typical antipsychotics [13]. According to a review by Srisurapanont and colleagues, quetiapine is effective for the treatment of schizophrenia, and has been found to have similar efficacy and treatment durations as risperidone and conventional antipsychotics [14]. Quetiapine has a lower risk of movement disorders but higher risks of dizziness, dry mouth and sleepiness. Moreover, in

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4 years the same authors updated the review and concluded that quetiapine may produce a lower incidence of using medication for EP side effects, such as parkinsonism, akathisia and dystonia. In comparison to the low-dose quetiapine group the number of people leaving the three studies is significantly smaller in the high-dose group (49% dropout ≥ 250 mg/day vs 58% < 250 mg/day; n = 1066). The improvement on mental state was significantly higher in the high-dose group. Incidences of akathisia, dystonia, parkinsonism and need for antiEP side effect medication, were the same for both doses of quetiapine. In a large-scale, double-blind trial comparing multiple atypical antipsychotics against perphenazine (Clinical Antipsychotic Trials of Intervention Effectiveness [CATIE]), the authors came to the same conclusions [15]. Srisurapanont and colleagues in their updated version, add a statement that high dropout rates in short quetiapine studies are a major problem, and thus make interpreting any results problematic [7]. Quetiapine is effective for the treatment of schizophrenia, but it is not much different from first-generation antipsychotics and risperidone with respect to treatment withdrawal and efficacy. In comparison to first-generation antipsychotics and risperidone, quetiapine has a lower risk of movement disorders but higher risks of dizziness, dry mouth and sleepiness [7]. Overall, quetiapine (≤750 mg/day) was at least as effective as chlorpromazine (≤750 mg/day) and had similar efficacy to haloperidol (≤16 mg/day) in patients with acute schizophrenia in randomized, double-blind trials. At the dose of 600 mg/day, quetiapine was at least as effective as haloperidol 20 mg/day in patients with schizophrenia unresponsive or partially responsive to previous conventional antipsychotic treatment [16]. Quetiapine was found to be generally effective against both positive and negative symptoms [12]. In addition, quetiapine in the dose of up to 750 mg/day was also effective in the management of schizophrenia in patients who were switched from standard or atypical antipsychotic agents following inadequate response or intolerance [17]. Improvements in overall psychopathology and positive and negative symptoms with quetiapine (≤800 mg/day) in comparison with other atypical antipsychotic agents were similar to those with risperidone (≤8 mg/day) or olanzapine (15 mg/day) [12]. Data regarding efficacy of quetiapine in the treatment of first-episode schizophrenia, show that quetiapine is effective in patients with this disorder [18,19]. Data from several long-term treatments, both open-label and double-blind studies (over 52 weeks), suggest that quetiapine is an effective medication but relapse-prevention studies are required to confirm its efficacy in maintenance therapy [20,21]. In the CATIE trial published in the New England Journal of Medicine, the efficacy of atypical antipsychotics was determined by means of discontinuation of treatment. It demonstrated that the time of discontinuation of treatment for any cause was significantly shorter in the quetiapine group than the olanzapine group [15]. However, in this study olanzapine was dosed above the recommended upper limit.

Expert Rev. Neurotherapeutics 6(7), (2006)

Quetiapine

According to standard dosing recommendations for schizophrenia, titration to 400 mg/day is suggested using the following schedule, administered twice daily in divided doses: 50 mg on the first day of treatment, 100 mg day on the second day, 200 mg on the third day, 300 mg on the fourth day and 400 mg on the fifth day. In patients who respond to quetiapine, therapy should be continued at the optimal dose that maintains remission, within the range of 150–750 mg/day [22]. The dose adjustments to the optimal dose should be made on an individual basis. Some authors found that quetiapine has additional beneficial calming properties and successfully treats the symptoms of aggression, anxiety and hostility that can accompany acute exacerbations of schizophrenia [23,24]. This is supported by the CATIE study in which it is shown that quetiapine has a as high sedative effect as olanzapine [15]. In cases of irritability, hostility and aggressive behavior it is suggested to use quetiapine dose escalation more rapidly. A more rapid initiation schedule is proposed: 400 mg by day two, increasing to 600 mg/day by day three and often up to 800 mg/day by day four, or in severe cases 300 mg on day one, 600 mg on day two and 900 mg on day three [25,26]. Furthermore, while current prescribing information recommends that quetiapine should be administered at doses of up to 750 mg/day (800 mg/day in the USA and Canada), there is evidence that doses of quetiapine 1600–1800 mg/day have been well tolerated in some patients who did not adequately respond to a lower standard dose [25]. At the same time there are few reports concerning the danger of high doses (>1800 mg/day) of quetiapine, which patients ingested with the purpose of suicide [27–32]. According to Citrome and colleagues, the mean dose of quetiapine for schizophrenic patients is 620 mg/day, but approximately a third of patients received doses in excess of 750 mg/day [118]. Quetiapine & cognition

Cognitive impairment is a core feature of schizophrenia and a major impediment to social and vocational rehabilitation. A number of studies have claimed cognitive benefits from treatment with various atypical antipsychotics. Atypical antipsychotics produce a mild remediation of cognitive deficits in schizophrenia and specific atypicals have differential effects within certain cognitive domains. Effects of quetiapine on cognition were investigated in a group of patients with schizophrenia in several studies [33–35]. The patients improved in their attentional, motor and visuomotor skills, and in executive functions, as well as with respect to psychopathology, without an increase in motor side effects. According to Velligan and colleagues, quetiapine improved cognition in schizophrenic patients relative to conventional agents [36]. Safety & tolerability

Quetiapine is a well-tolerated medication. Since it has a low affinity and fast dissociation from postsynaptic D2 receptors, it was suggested that it has the least risk of producing acute EP side effects, tardive dyskinesia and neuroleptic malignant syndrome [37].


A review of the literature reveals a broad spectrum of reports on side effects. There are variations between reviewers. Nasrallah and Tandon reported that the most frequent adverse events (occurring with a frequency ≥10% in controlled trials with quetiapine vs placebo) were headache (19 vs 18%), somnolence (18 vs 11%) and dizziness (10 vs 4%), with most occurrences being mild or moderate in intensity and of limited duration [38]. According to the clinical studies supported by AstraZeneca, adverse events associated with quetiapine with incidence of 5% or more in patients receiving 75–750 mg/day, were dizziness, orthostatic hypotension, dry mouth and dyspepsia [10]. Most adverse events were mild-to-moderate in intensity. Orthostatic hypotension was observed in 7% of patients and usually during initial administration. In addition, these studies did not find significant differences between quetiapine and placebo groups (4 vs 3%, respectively) in an overall incidence of treatment discontinuation owing to adverse events [10]. An independent review of quetiapine side effects by Garver confirm the data that despite multireceptor affinity of quetiapine, its side effects remain mild [5]. There is almost a consensus regarding the beneficial effect profile of quetiapine and its safety. However, most reviews were written a short period of time after its introduction to clinical practice. To date many case reports have been published reporting some side effects that were previously unknown. In order for clinicians to become familiar with possible side effects and aware of unwanted events, we will describe the drug profile through its influence on different body systems. CNS

The most common side effects (≥10%) are somnolence and dizziness. The sedative effect can be used as an advantage in the therapeutic process in irritable patients [5]. Current data suggest that quetiapine is associated with placebo-level incidence of EPS across its entire dose range, appears to have a low risk for EPS in vulnerable patient groups (e.g., the elderly, adolescents or patients with organic brain disorders) and has a more favorable EPS profile than risperidone [12]. We found five case reports regarding quetiapine-induced improvement of tardive dyskinesia in eight schizophrenic patients [39–43]. However, in the last few years, a number of reports were published concerning acute and delayed-onset (tardive) movement disorders during quetiapine treatment [44–52]. The authors described different kinds of movement disorders including EP side effects [47,50], acute akathisia [51], acute dystonia [45,49], tic-like symptoms [48], myoclonus [52] and tardive dyskinesia (TD) [44,46]. Data regarding the drug’s long-term impact on TD are limited. According to the review by Margolese and colleagues, in two studies using the Abnormal Involuntary Movement Scale or EP Symptom Rating Scale a 1-year TD incidence treated rate with all types of antipsychotics was 2.7 and 0.74%, respectively [53]. Another single case report describes seizures associated with quetiapine treatment (500 mg/day) combined with carbamazepine (200 mg/day) in a patient with Alzheimer’s disease [54].

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Metabolic & endocrine side effects

Sexual dysfunction

Weight gain is also one of the major unwanted adverse effects of treatment with many antipsychotic drugs. Quetiapine appears to have minimal short-term effects on body weight and a favorable long-term body weight profile [55]. However, some case reports demonstrated that quetiapine may also cause weight gain [56,57]. In an anecdotal case report there is a possibility that quetiapine can lead to even weight loss and anorexia [58]. In the Elicitor Responsive Element study, Bobes and colleagues compared weight gain induced by risperidone, olanzapine, quetiapine or haloperidol in schizophrenic patients [59]. No patient showed a clinically relevant weight gain on quetiapine, in contrast to olanzapine and risperidone. However, these data were not conclusive due to the short duration of treatment with quetiapine. In the CATIE study, Lieberman and colleagues found that weight gain in patients treated with quetiapine was similar to risperidone (mean weight change was 1.1 ± 0.9 and 0.8 ± 0.9 lb, respectively) [15]. Drug-induced hypothyroidism is known to occur with several medications. The manufacturer of quetiapine reports that elevated thyroid secreting hormone concentrations and subsequent treatment with thyroid hormone supplementation have occurred only rarely [10]. Kelly and Conley examined thyroid function in 38 adult schizophrenic patients after 6 weeks of prospective, double-blind, randomized treatment with quetiapine (400 mg/day), risperidone (4 mg/day) or fluphenazine (12.5 mg/day). The authors did not find influence of quetiapine on thyroid function and suggest that routine monitoring in quetiapine-treated patients without a history of thyroid disease is not recommended [60]. During the last few years, several case reports and studies have been published on the potential diabetes mellitus-inducing effect of some atypical antipsychotics [61]. There is a paucity of data regarding the association between quetiapine and hyperglycemia or new-onset diabetes mellitus, aside from a small number of case reports and retrospective case series [62–65] and one large database study by Sernyak and colleagues suggesting that quetiapine may also have a tendency towards induction of glucose intolerance [66]. According to their data, quetiapine may possess similar metabolic risks as clozapine and olanzapine. The potential serious event of the drug is described in a case report of an elderly patient who developed a rapid onset of diabetic ketoacidosis during quetiapine treatment [67].

Sexual dysfunction can be an important source of distress to patients and adversely affects compliance. It is one of the factors that must be taken into account when choosing a treatment. Sexual dysfunction is common in schizophrenic men treated with antipsychotics and is associated with diminished quality of life, decreased occurrence of romantic relationships and reduced intimacy when relationships are established. Most researchers agree that quetiapine has a positive influence by means of sexual side effects. According to data from AstraZeneca, impotence, abnormal ejaculation and amenorrhea were reported in pivotal trials to occur in less than 0.1% of patients [10]. A randomized, double-blind, 12-week trial compared the influence of risperidone (4 mg/day), quetiapine (400 mg/day) and fluphenazine (12.5 mg/day) on sexual functioning in people with schizophrenia [72]. They found that orgasm quality/ability improved significantly for quetiapine as compared with fluphenazine and risperidone. Montejo Gonzalez and colleagues [73] and Knegtering and colleagues [74] came to the conclusion that quetiapine demonstrated a low frequency of sexual dysfunction during shortand long-term treatment of patients with schizophrenia or schizophreniform disorder. In addition, in a recent comparative study, Bobes and colleagues found that quetiapine appears to improve this profile during short-term treatment; however, long-term data, with larger samples, are required with this latter drug [75]. Despite these previous findings, recent publications (two case reports and one open-label study) showed that quetiapine may also induce sexual dysfunctions, such as priapism [76,77] and diminished libido in both male and female subjects in almost a third of patients [78]. Quetiapine treatment has been associated with a significant reduction in serum prolactin levels, and has normalized raised prolactin levels after discontinuation of other previous antipsychotic treatment [55]. However, in 2002 the first report regarding prolactin serum elevation emerged [79]. Until now two more reports have appeared describing the same phenomenon with usual doses of quetiapine [78,80]. Irrespective of dose, quetiapine, unlike risperidone and amisulpride, does not elevate plasma prolactin levels compared with placebo, and previously elevated levels may even be normalized. In a case reported by Orlandi and colleagues, increased prolactin level decreased when the patient was switched to quetiapine and elevated back after mirtazapine was added [80]. Stevens and colleagues performed a cross-sectional retrospective medical chart review of 50 males treated with risperidone or quetiapine. Prolactin was above the upper limit of normal for 68% of the patients on risperidone and 20% of the patients on quetiapine. Both risperidone and quetiapine produced dose-related increases in serum prolactin levels. No correlation was found between duration of treatment and prolactin levels [81].

Cholesterol & triglycerides

Once cardiovascular diseases have an important role in the morbidity rate in the general population, there is an emphasis on serum cholesterol and lipids levels and its connection to neuroleptic drugs. There is a discrepancy between researchers who found quetiapine as having a beneficial or positive effect on both cholesterol, triglyceride and high-density lipoprotein [64] in contrast to those who suggest that quetiapine shares the propensity with other benzodiazepine-derived atypical antipsychotics, to primarily elevate serum triglyceride levels [62,68–71].

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Quetiapine

Overall, quetiapine was associated with a normalization of prolactin levels and had the greatest benefits among these drugs regarding sexual functioning [72]. In order to evaluate the neuroendocrine effects of quetiapine, de Borja Goncalves Guerra and colleagues examined healthy volunteers. The results demonstrated an increase of prolactin and decrease of cortisol after quetiapine (150 mg) administration. They also found a late increase in growth hormone secretion, significant in comparison with placebo [82]. Pregnancy & lactation

It is a well known fact that potential consequences of an untreated psychotic episode may be severe and lead to the mother attempting suicide and/or infanticide. For these reasons, clinicians need to help mothers to take into consideration both fetal and neonatal risks of exposure to drugs versus the potential risk without medical treatment. Atypical antipsychotics in pregnancy and breast-feeding do not show evident advantages in safety, when compared with typical neuroleptic agents. To date we found only three published case reports [83–86] and one study including 151 pregnancy outcomes that included exposure to olanzapine, risperidone, quetiapine and clozapine [87]. The obtained results suggest that atypical antipsychotics do not appear to be associated with an increased risk for major malformations. No literature data are available regarding the secretion of quetiapine in human milk [85]. Cardiovascular effects

Consideration of the risk of QTc interval prolongation associated with atypical antipsychotic administration is mounting, as this can lead to sudden cardiac death. The majority of researchers agree with the idea that quetiapine has negligible effects on the QTc interval [38]. There are some reports which should attract the attention of clinicians to the possibility of cardiovascular side effects, especially arrhythmias, associated with an overdose of quetiapine [27,28,31] or with a combination of quetiapine and antidepressive agents, such as selective serotonin reuptake inhibitors [88]. There is one report about induction of torsade de pointes (ventricular fibrillation) in a multisomatic problems patient treated with a low dose of quetiapine [89]. The authors write that clinicians should be more vigilant regarding these potential adverse reactions and electrocardiograpic control may be suggested during therapy, especially in patients with cardiovascular disorders [88]. Beside cardiac problems, the next risk factors listed, such as obesity, age, treatment with multiple medications, female gender and machine artifact, should be considered in addition to the antipsychotic as a possible etiology of a prolonged QTc interval [90]. Some case reports of quetiapine overdose demonstrated QTc prolongation up to 537–710 ms (normal range 350–450 ms) [91]. According to the CATIE trial the mean change in QTc interval from baseline to last observation was 5.9 ± 1.9 ms in quetiapine-treated patients in comparison to


other atypicals (risperidone 0.2 ± 1.8 ms; olanzapine 1.2 ± 1.8 ms; ziprasidone 1.3 ± 2.2 ms; and perphenazine 1.4 ± 2.0 ms) [15]. In addition to arrhythmias, there is one report regarding myocarditis which, according to the authors’ suggestion, may have been the result of a hypersensitive reaction to quetiapine [92]. Hematological side effects

Since quetiapine, olanzapine and clozapine are related in chemical structure and pharmacological profile, the same effect of bone-marrow depression could be hypothesized. The mechanism by which these drugs induce hematological abnormalities remains uncertain, but hypothetically they could be immunologically mediated or caused by direct bone-marrow toxicity [93]. Leucopenia can be developed in approximately 1% of the subjects treated with quetiapine, and it resolves upon discontinuation [94]. In addition to other blood dyscrasias, which were described in the previous publications, during the last 5 years some new reports emerged about agranulocytosis, pancytopenia, leucopenia and granulocytopenia [93–98]. Huynh and colleagues reported about a patient who suffered from thrombotic thrombocytopenic purpura associated with quetiapine [99]. Ophthalmological

Potential risk factors associated with cataract formation are certain conventional antipsychotic medications in addition to increased age, high blood pressure, diabetes, cigarette smoking, alcohol use dietary deficiencies and trauma [38]. Early research did reveal cataract occurrence in dogs who received quetiapine, which prompted concern despite there being no known causal link between quetiapine and lens opacities in humans. Nevertheless, quetiapine’s manufacturer issued formal recommendations for ophthalmological follow-up examinations with the use of this drug, related only to the USA [10]. Whithorn and colleagues carried out follow-up research on a group of patients who were treated with quetiapine and did not find any evidence for cataract induced by this drug [100]. Several cases of cataracts have been identified according to the National Registry of Drug-Induced Ocular Side Effects (Portland, Oregon) yet according to the WHO criteria and extent of worldwide use, the risk of cataracts is highly unlikely. Thus, biannual exams as listed in the initial product labeling are not necessary [101,102]. The CATIE trial also examined this issue and did not find differences between atypical antipsychotics and perphenazine [15]. Side effects associated with mental changes

Although atypical antipsychotics are used in the treatment of various psychiatric disorders, there are few reports about any mental changes associated with them, including with quetiapine. To date four reports were published describing patients who demonstrated hypomania, mania or manic-like state associated with quetiapine treatment and one of them was dose-related [103–106]. Besides manic states, there is also a report concerning quetiapine associated depression in a patient with schizophrenia [107].

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Overdose

Other side effects

Several reports in the literature have noted the favorable risk–benefit profile of quetiapine. Overdoses of quetiapine of up to 20 g have been reported; however, with appropriate management in an intensive care setting there have been no reported fatalities [11]. Recently, a clinical and pharmacokinetic analysis of 14 cases concluded that quetiapine intoxications appear to proceed mildly. Tachycardia and somnolence were the main clinical symptoms in this case series. No fatalities occurred. The severity of clinical symptoms was not associated with either a high serum concentration or the suggested amount ingested of quetiapine [108]. Although the atypical neuroleptics are considered to be safe drugs, several reports and data concerning overdose leading to serious and/or fatal results have been accumulated in the last 3 years. Balit and colleagues reported 45 patients with quetiapine overdose (the median ingested dose was 3.5 g) and they found that seizures occurred in two patients, delirium occurred in three patients and mechanical ventilation was required in four patients. No arrhythmias or deaths occurred [109]. We found only three reports regarding death associated with quetiapine overdose [29,30,110], and in one of them the patient received a combination of overdose quetiapine and other medications but within therapeutic range dosages [29]. The cause of death was cardiac pulmonary arrest resulting from α-adrenergic and histamine receptor blockade. The combination between alcohol and neuroleptic drugs is known to be potentially dangerous. Khazaal and colleagues report regarding quetiapine overdose (3000 mg) associated with alcohol intoxication (320 ml of gin) [111]. This combination led to somnolence, sinus tachycardia and prolongation of QTc (460 ms). Urinary retention was published as a single case report following repeated high-dose quetiapine [32].

There is an anecdotal report about intranasal quetiapine abuse among inmates in the Los Angeles County Jail. The authors describe calming-down effects, which seem to be driven by quetiapine’s sedative and anxiolytic effects rather than by its antipsychotic properties. Accordingly, the drug has a street value (it is sold to other inmates for money) and is sometimes simply referred to as ‘quell’ [120].

Reaction to discontinuation

It is a well-known fact that the major reason for psychotic exacerbations is a sudden discontinuation of treatment, usually as an expression of noncompliance [112,113]. Therapeutic tolerance, rebound psychosis or supersensitivity psychosis were found to develop with clozapine, olanzapine and quetiapine [114–117]. Margolese and colleagues examined (in a 3-year open-label study), therapeutic tolerance and rebound psychosis during quetiapine maintenance monotherapy in 23 male outpatients with schizophrenia and schizoaffective disorder. The results suggest the conclusion that therapeutic tolerance, rebound psychosis or supersensitivity psychosis were found to develop with quetiapine [117]. The authors try to explain the phenomenon by the loose bonding of quetiapine to the D2 receptor. On the other hand, Thurstone and Alahi reported a possible development of quetiapine withdrawal syndrome [119]. The syndrome consists of diaphoresis, elevated blood pressure, emesis, lightheadedness, nausea, nervousness, orthostatic hypotension and tachycardia.

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Expert commentary

The clinical trials currently available suggest that quetiapine has been proved effective in the treatment of schizophrenia, and it has been approved in over 70 countries, including the USA and much of Europe. Its efficacy is clearly superior to that of placebo, is similar to that of haloperidol or chlorpromazine, and appears to have similar efficacy to risperidone and olanzapine. It has a benign side-effect profile, particularly regarding to EPS. Clinical trials support the use of quetiapine in treating elderly patients. Although there are some reports of serious side effects, generally quetiapine is considered a safe drug. Clinicians have to be aware of the possibility of a wide range of adverse events mentioned above, and to be alert to even rare entities like myocarditis, blood dyscrasias or seizures. According to the information that patients who are treated with antipsychotics (including quetiapine) have a higher risk of hyperlipidemia, a quarterly fasting lipid panel is necessary for the initial year, in order to pick up cases of severe hypertriglyceridemia. It is recommended by some authors that a lipid panel be obtained at baseline for all patients with schizophrenia and annually thereafter for patients taking relatively low-risk agents or quarterly thereafter for patients taking relatively highrisk agents. Moreover, careful monitoring of weight, body mass index and glucose levels is advised before and during treatment with atypical antipsychotic agents [61,121–123]. There are polar opinions regarding almost every adverse event, therefore there is no one way to judge the efficacy versus disadvantages and side effects of this drug. In order to clarify all these controversies more randomized controlled trials should be carried out to determine its position in everyday clinical practice. These recommended studies have to be independent without any support from the commercial company. (There are only few independent studies, such as the CATIE trial). Five-year view

Although quetiapine was introduced as an atypical antipsychotic drug with clinical efficacy in schizophrenic patients, there are some new reports and pioneer studies regarding its efficacy in treating mood disorder. As in many other atypical neuroleptics, it is expected that over the next few years we will witness new studies which will examine the efficacy and tolerability of quetiapine in treating a broad spectrum of mental disorders, such as manic states, bipolar depression, anxiety disorders, obsessive–compulsive disorder, aggression, hostility, posttraumatic stress disorder, borderline personality disorder, delirium and comorbid substance abuse.


Quetiapine

Key issues • Most authors agree that quetiapine is effective as other typical and atypical antipsychotics for treatment of schizophrenia. • The side-effect profile appears to be reasonably safe. • Quetiapine has a sedative effect and may be useful for treating agitative patients. • Weight gain and endocrine effects do occur with quetiapine, but to a lesser degree than risperidone and olanzapine. • There are a few reports of serious events but most of them are associated with an overdose of quetiapine. • The combination of high-dose quetiapine with selective serotonin reuptake inhibitor antidepressants requires caution because it may induce cardiac arrhythmias. References 1

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Tandon R. Improvement without impairment: a review of clinical data for quetiapine in the treatment of schizophrenia. J. Clin. Psychopharmacol. 23(3 Suppl. 1), S15–S20 (2003). Peuskens J. Clinical effectiveness in adults with chronic schizophrenia. Eur. Neuropsychopharmacol. 14(Suppl. 4), S453–S459 (2004). Kasper S, Muller-Spahn F. Review of quetiapine and its clinical applications in schizophrenia. Expert Opin. Pharmacother. 1(4), 783–801 (2000). Bridler R, Umbricht D. Atypical antipsychotics in the treatment of schizophrenia. Swiss Med. Wkly 133(5–6), 63–76 (2003).

5

Garver DL. Review of quetiapine side effects. J. Clin. Psychiatry 61(Suppl. 8), 31–33 (2000).

6

Nemeroff CB, Kinkead B, Goldstein J. Quetiapine: preclinical studies, pharmacokinetics, drug interactions, and dosing. J. Clin. Psychiatry 63(Suppl. 13), 5–11 (2002).

7

Srisurapanont M, Maneeton B, Maneeton N. Quetiapine for schizophrenia. Cochrane Database Syst. Rev. (2), CD000967 (2004).

8

DeVane CL, Nemeroff CB. Clinical pharmacokinetics of quetiapine: an atypical antipsychotic. Clin. Pharmacokinet. 40(7), 509–522 (2001).

9

10

11

Thyrum PT, Wong YW, Yeh C. Single-dose pharmacokinetics of quetiapine in subjects with renal or hepatic impairment. Prog. Neuropsychopharmacol. Biol. Psychiatry 24(4), 521–533 (2000). AstraZeneca. Seroquel (Quetiapine Fumarate) Tablets. Product monograph. Wilmington (DE), AstraZeneca, (2001). Dev V, Raniwalla J. Quetiapine: a review of its safety in the management of schizophrenia. Drug Saf. 23(4), 295–307 (2000).


12

Cheer SM, Wagstaff AJ. Quetiapine. A review of its use in the management of schizophrenia. CNS Drugs 18(3), 173–199 (2004).

13

Worrel JA, Marken PA, Beckman SE et al. Atypical antipsychotic agents: a critical review. Am. J. Health Syst. Pharm. 57(3), 238–255 (2000).

14

15

16

17

18

21

Kasper S, Brecher M, Fitton L et al. Maintenance of long-term efficacy and safety of quetiapine in the open-label treatment of schizophrenia. Int. Clin. Psychopharmacol. 19(5), 281–289 (2004).

22

Cutler AJ, Goldstein JM, Tumas JA. Dosing and switching strategies for quetiapine fumarate. Clin. Ther. 24(2), 209–222 (2002).

23

Arango C, Bernardo M. The effect of quetiapine on aggression and hostility in patients with schizophrenia. Hum. Psychopharmacol. 20(4), 237–241 (2005).

24

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(2), 530–541 (2003).

25

Arango C, Bobes J. Managing acute exacerbations of schizophrenia: focus on quetiapine. Curr. Med. Res. Opin. 20(5), 619–626 (2004).

26

Larmo I, Nayer AD, 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).

Smith MA, McCoy R, Hamer-Maansson J et al. Rapid dose escalation with quetiapine: a pilot study. J. Clin. Psychopharmacol. 25(4), 331–335 (2005).

27

Tauscher-Wisniewski S, Kapur S, Tauscher J et al. Quetiapine: an effective antipsychotic in first-episode schizophrenia despite only transiently high dopamine-2 receptor blockade. J. Clin. Psychiatry 63(11), 992–997 (2002).

Beelen AP, Yeo KT, Lewis LD. Asymptomatic QTc prolongation associated with quetiapine fumarate overdose in a patient being treated with risperidone. Hum. Exp. Toxicol. 20(4), 215–219 (2001).

28

Gajwani P, Pozuelo L, Tesar GE. QT interval prolongation associated with quetiapine (Seroquel) overdose. Psychosomatics 41(1), 63–65 (2000).

29

Fernandes PP, Marcil WA. Death associated with quetiapine overdose. Am. J. Psychiatry 159(12), 2114 (2002).

30

Langman LJ, Kaliciak HA, Carlyle S. Fatal overdoses associated with quetiapine. J. Anal. Toxicol. 28(6), 520–525 (2004).

31

Kurth J, Maguire G. Pediatric case report of quetiapine overdose and QTc prolongation. Ann. Clin. Psychiatry 16(4), 229–231 (2004).

Srisurapanont M, Disayavanish C, Taimkaew K. Quetiapine for schizophrenia. Cochrane Database Syst. Rev. (3), CD000967 (2000). Lieberman JA, Stroup TS, McEvoy JP et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N. Engl. J. Med. 353(12), 1209–1223 (2005). 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(3), 121–131 (2000).

19

Ohlsen RI, O’Toole MS, Purvis RG et al. Clinical effectiveness in first-episode patients. Eur. Neuropsychopharmacol. 14(Suppl. 4), S445–S451 (2004).

20

Csernansky JG, Schuchart EK. Relapse and rehospitalisation rates in patients with schizophrenia: effects of second generation antipsychotics. CNS Drugs 16(7), 473–484 (2002).

989

Miodownik & Lerner

32

Sokolski KN, Brown BJ, Melden M. Urinary retention following repeated high-dose quetiapine. Ann. Pharmacother. 38(5), 899–900 (2004).

33

Good KP, Kiss I, Buiteman C et al. Improvement in cognitive functioning in patients with first-episode psychosis during treatment with quetiapine: an interim analysis. Br. J. Psych. (Suppl. 43), S45–S49 (2002).

34

Woodward ND, Purdon SE, Meltzer HY et al. A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. Int. J. Neuropsychopharmacol. 8(3), 457–472 (2005).

35

Kivircik Akdede BB, Alptekin K, Kitis A et al. Effects of quetiapine on cognitive functions in schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 29(2), 233–238 (2005).

36

Velligan DI, Prihoda TJ, Sui D et al. The effectiveness of quetiapine versus conventional antipsychotics in improving cognitive and functional outcomes in standard treatment settings. J. Clin. Psychiatry 64(5), 524–531 (2003).

37

38

39

40

Adityanjee, Schulz SC. Clinical use of quetiapine in disease states other than schizophrenia. J. Clin. Psychiatry 63(Suppl. 13), 32–38 (2002).

44

Ghelber D, Belmaker RH. Tardive dyskinesia with quetiapine. Am. J. Psychiatry 156(5), 796–797 (1999).

45

Jonnalagada JR, Norton JW. Acute dystonia with quetiapine. Clin. Neuropharmacol. 23(4), 229–230 (2000).

46

Ghaemi SN, Ko JY. Quetiapine-related tardive dyskinesia. Am. J. Psychiatry 158(10), 1737 (2001).

47

Sommer BR. Quetiapine-Induced extrapyramidal side effects in patients with Parkinson’s disease: case report. J. Geriatr. Psychiatry Neurol. 14(2), 99–100 (2001).

48

Huang SC, Lai TJ, Tsai SJ. A case report of quetiapine-related tic-like symptoms. J. Clin. Psychiatry 63(12), 1184–1185 (2002).

49

Kropp S, Hauser U, Ziegenbein M. Quetiapine-associated acute dystonia. Ann. Pharmacother. 38(4), 719–720 (2004).

50

Shim SS. Extrapyramidal symptoms associated with quetiapine. Aust. NZJ Psych. 37(6), 773 (2003).

51

Catalano G, Grace JW, Catalano MC et al. Acute akathisia associated with quetiapine use. Psychosomatics 46(4), 291–301 (2005).

52

Velayudhan L, Kirchner V. Quetiapineinduced myoclonus. Int. Clin. Psychopharmacol. 20(2), 119–120 (2005).

53

Margolese HC, Chouinard G, Kolivakis TT et al. Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 2: incidence and management strategies in patients with schizophrenia. Can. J. Psych. 50(11), 703–714 (2005).

Nasrallah HA, Tandon R. Efficacy, safety, and tolerability of quetiapine in patients with schizophrenia. J. Clin. Psychiatry 63(Suppl. 13), 12–20 (2002). Alptekin K, Kivircik BB. Quetiapineinduced improvement of tardive dyskinesia in three patients with schizophrenia. Int. Clin. Psychopharmacol. 17(5), 263–264 (2002). Gourzis P, Polychronopoulos P, Papapetropoulos S et al. Quetiapine in the treatment of focal tardive dystonia induced by other atypical antipsychotics: a report of 2 cases. Clin. Neuropharmacol. 28(4), 195–196 (2005).

54

Dogu O, Sevim S, Kaleagasi HS. Seizures associated with quetiapine treatment. Ann. Pharmacother. 37(9), 1224–1227 (2003).

55

Sussman N. Choosing an atypical antipsychotic. Int. Clin. Psychopharmacol. 17(Suppl. 3), S29–S33 (2002).

56

Wirshing DA, Boyd JA, Pierre JM et al. Delusions associated with quetiapinerelated weight redistribution. J. Clin. Psychiatry 63(3), 247–248 (2002).

41

Bouckaert F, Herman G, Peuskens J. Rapid remission of severe tardive dyskinesia and tardive dystonia with quetiapine. Int. J. Geriatr. Psychiatry 20(3), 287–288 (2005).

57

Atmaca M, Kuloglu M, Tezcan E et al. Nizatidine for the treatment of patients with quetiapine-induced weight gain. Hum. Psychopharmacol. 19(1), 37–40 (2004).

42

Nelson MW, Reynolds RR, Kelly DL et al. Adjunctive quetiapine decreases symptoms of tardive dyskinesia in a patient taking risperidone. Clin. Neuropharmacol. 26(6), 297–298 (2003).

58

Khawaja IS, Azeem MW, Ebrahim A. Weight loss and anorexia with quetiapine. Psychiatr. Serv. 56(4), 490 (2005).

43

Sasaki Y, Kusumi I, Koyama T. A case of tardive dystonia successfully managed with quetiapine. J. Clin. Psychiatry 65(4), 583–584 (2004).

990

59

Bobes J, Rejas J, Garcia-Garcia M et al. Weight gain in patients with schizophrenia treated with risperidone, olanzapine, quetiapine or haloperidol: results of the EIRE study. Schizophr. Res. 62(1–2), 77–88 (2003).

60

Kelly DL, Conley RR. Thyroid function in treatment-resistant schizophrenia patients treated with quetiapine, risperidone, or fluphenazine. J. Clin. Psychiatry 66(1), 80–84 (2005).

61

Cohen D. Atypical antipsychotics and new onset diabetes mellitus. An overview of the literature. Pharmacopsychiatry 37(1), 1–11 (2004).

62

Domon SE, Cargile CS. Quetiapineassociated hyperglycemia and hypertriglyceridemia. J. Am. Acad. Child Adolesc. Psychiatry 41(5), 495–496 (2002).

63

Jin H, Meyer JM, Jeste DV. Phenomenology of and risk factors for new-onset diabetes mellitus and diabetic ketoacidosis associated with atypical antipsychotics: an analysis of 45 published cases. Ann. Clin. Psychiatry 14(1), 59–64 (2002).

64

Wirshing DA, Boyd JA, Meng LR et al. The effects of novel antipsychotics on glucose and lipid levels. J. Clin. Psychiatry 63(10), 856–865 (2002).

65

Sneed KB, Gonzalez EC. Type 2 diabetes mellitus induced by an atypical antipsychotic medication. J. Am. Board Fam. Pract. 16(3), 251–254 (2003).

66

Sernyak MJ, Leslie DL, Alarcon RD et al. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am. J. Psychiatry 159(4), 561–566 (2002).

67

Takahashi M, Ohishi S, Katsumi C et al. Rapid onset of quetiapine-induced diabetic ketoacidosis in an elderly patient: a case report. Pharmacopsychiatry 38(4), 183–184 (2005).

68

Meyer JM. Novel antipsychotics and severe hyperlipidemia. J. Clin. Psychopharmacol. 21(4), 369–374 (2001).

69

Shaw JA, Lewis JE, Pascal S et al. A study of quetiapine: efficacy and tolerability in psychotic adolescents. J. Child Adolesc. Psychopharmacol. 11(4), 415–424 (2001).

70

Atmaca M, Kuloglu M, Tezcan E et al. Weight gain, serum leptin and triglyceride levels in patients with schizophrenia on antipsychotic treatment with quetiapine, olanzapine and haloperidol. Schizophr. Res. 60(1), 99–100 (2003).

71

Atmaca M, Kuloglu M, Tezcan E et al. Serum leptin and triglyceride levels in patients on treatment with atypical antipsychotics. J. Clin. Psychiatry 64(5), 598–604 (2003).

72

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


Quetiapine

73

on sexual functioning in people with schizophrenia. Psychoneuroendocrinology 31(3), 340–346 (2005).

86

Lee A, Giesbrecht E, Dunn E et al. Excretion of quetiapine in breast milk. Am. J. Psychiatry 161(9), 1715–1716 (2004).

Montejo Gonzalez AL, RicoVillademoros F, Tafalla M et al. A 6-month prospective observational study on the effects of quetiapine on sexual functioning. J. Clin. Psychopharmacol. 25(6), 533–538 (2005).

87

McKenna K, Koren G, Tetelbaum M et al. Pregnancy outcome of women using atypical antipsychotic drugs: a prospective comparative study. J. Clin. Psychiatry 66(4), 444–449 (2005).

74

Knegtering R, Castelein S, Bous H et al. A randomized open-label study of the impact of quetiapine versus risperidone on sexual functioning. J. Clin. Psychopharmacol. 24(1), 56–61 (2004).

75

Bobes J, Garc A-Portilla MP, Rejas J et al. Frequency of sexual dysfunction and other reproductive side-effects in patients with schizophrenia treated with risperidone, olanzapine, quetiapine, or haloperidol: the results of the EIRE study. J. Sex Marital Ther. 29(2), 125–147 (2003).

76

77

78

79

80

81

82

83

84

85

du Toit RM, Millson RC, Heaton JP et al. Priapism. Can. J. Psych. 49(12), 868–869 (2004). Davol P, Rukstalis D. Priapism associated with routine use of quetiapine: case report and review of the literature. Urology 66(4), 880 (2005). Atmaca M, Kuloglu M, Tezcan E. A new atypical antipsychotic: quetiapine-induced sexual dysfunctions. Int. J. Impot. Res. 17(2), 201–203 (2005). Alexiadis M, Whitehorn D, Woodley H et al. Prolactin elevation with quetiapine. Am. J. Psychiatry 159(9), 1608–1609 (2002). Orlandi V, Speca A, Salviati M et al. Abnormal prolactin elevation in a schizophrenic patient in treatment with quetiapine and mirtazapine. The role of opioid system. J. Clin. Psychopharmacol. 23(6), 677–679 (2003). Stevens JR, Kymissis PI, Baker AJ. Elevated prolactin levels in male youths treated with risperidone and quetiapine. J. Child Adolesc. Psychopharmacol. 15(6), 893–900 (2005). de Borja GGA, Castel S, Benedito-Silva AA et al. Neuroendocrine effects of quetiapine in healthy volunteers. Int. J. Neuropsychopharmacol. 8(1), 49–57 (2005). Tenyi T, Trixler M, Keresztes Z. Quetiapine and pregnancy. Am. J. Psychiatry 159(4), 674 (2002). Taylor TM, O’Toole MS, Ohlsen RI et al. Safety of quetiapine during pregnancy. Am. J. Psychiatry 160(3), 588–589 (2003). Gentile S. Clinical utilization of atypical antipsychotics in pregnancy and lactation. Ann. Pharmacother. 38(7–8), 1265–1271 (2004).


101

Fraunfelder FW. Twice-yearly exams unnecessary for patients taking quetiapine. Am. J. Ophthalmol. 138(5), 870–871 (2004).

102

Shahzad S, Suleman MI, Shahab H et al. Cataract occurrence with antipsychotic drugs. Psychosomatics 43(5), 354–359 (2002).

88

Pacher P, Kecskemeti V. Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns? Curr. Pharm. Des. 10(20), 2463–2475 (2004).

103

Atmaca M, Kuloglu M, Buyukbayram A et al. Quetiapine-associated and doserelated hypomania in a woman with schizophrenia. Eur. Psychiatry 17(5), 292–293 (2002).

89

Vieweg WV, Schneider RK, Wood MA. Torsade de pointes in a patient with complex medical and psychiatric conditions receiving low-dose quetiapine. Acta. Psychiatr. Scand. 112(4), 318–322 (2005).

104

Lykouras L, Oulis P, Hatzimanolis J. Manic symptoms associated with quetiapine treatment. Eur. Neuropsychopharmacol. 13(2), 135–136 (2003).

105

90

Gupta S, Nienhaus K, Shah SA. Quetiapine and QTc issues: a case report. J. Clin. Psychiatry 64(5), 612–613 (2003).

Pacchiarotti I, Manfredi G, Kotzalidis GD et al. Quetiapine-induced mania. Aust. NZJ Psych. 37(5), 626 (2003).

106

91

Vieweg WV. New generation antipsychotic drugs and QTc interval prolongation. Prim. Care Companion J. Clin. Psychiatry 5(5), 205–215 (2003).

Benazzi F. Quetiapine-associated hypomania in a woman with schizoaffective disorder. Can. J. Psych. 46(2), 182–183 (2001).

107

92

Roesch-Ely D, Van Einsiedel R, Kathofer S et al. Myocarditis with quetiapine. Am. J. Psychiatry 159(9), 1607–1608 (2002).

Mergui J, Jaworowski S, Lerner V. Quetiapine-associated depression in a patient with schizophrenia. Clin. Neuropharmacol. 28(3), 133–135 (2005).

108

93

Ruhe HG, Becker HE, Jessurun P et al. Agranulocytosis and granulocytopenia associated with quetiapine. Acta. Psychiatr. Scand. 104(4), 311–313 (2001).

Hunfeld NG, Westerman EM, Boswijk DJ et al. Quetiapine in overdosage: a clinical and pharmacokinetic analysis of 14 cases. Ther. Drug Monit. 28(2), 185–189 (2006).

109

94

Croarkin P, Rayner T. Acute neutropenia in a patient treated with quetiapine. Psychosomatics 42(4), 368 (2001).

Balit CR, Isbister GK, Hackett LP et al. Quetiapine poisoning: a case series. Ann. Emerg. Med. 42(6), 751–758 (2003).

110

95

Oluboka O, Haslam D, Lam T et al. Quetiapine-induced leucopenia: possible dosage-related phenomenon. Can. J. Psych. 48(1), 65–66 (2003).

Trenton A, Currier G, Zwemer F. Fatalities associated with therapeutic use and overdose of atypical antipsychotics. CNS Drugs 17(5), 307–324 (2003).

111

96

Nair P, Lippmann S. Is leukopenia associated with divalproex and/or quetiapine? Psychosomatics 46(2), 188–189 (2005).

Khazaal Y, Krenz S, Zullino DF. Quetiapine overdose associated with alcohol intoxication. German J. Psychiatry 7, 60–61 (2004).

112

97

Clark N, Weissberg E, Noel J. Quetiapine and leukopenia. Am. J. Psychiatry 158(5), 817–818 (2001).

98

Iraqi A. A case report of pancytopenia with quetiapine use. Am. J. Geriatr. Psychiatry 11(6), 694 (2003).

Lacro JP, Dunn LB, Dolder CR et al. Prevalence of and risk factors for medication nonadherence in patients with schizophrenia: a comprehensive review of recent literature. J. Clin. Psychiatry 63(10), 892–909 (2002).

113

99

Huynh M, Chee K, Lau DH. Thrombotic thrombocytopenic purpura associated with quetiapine. Ann. Pharmacother. 39(7–8), 1346–1348 (2005).

Ayuso-Gutierrez JL, del Rio Vega JM. Factors influencing relapse in the longterm course of schizophrenia. Schizophr. Res. 28(2–3), 199–206 (1997).

114

Llorca PM, Vaiva G, Lancon C. Supersensitivity psychosis in patients with schizophrenia after sudden olanzapine withdrawal. Can. J. Psych. 46(1), 87–88 (2001).

100

Whitehorn D, Gallant J, Woodley H et al. Quetiapine treatment in early psychosis: no evidence of cataracts. Schizophr. Res. 71(2–3), 511–512 (2004).

991

Miodownik & Lerner

115

Ekblom B, Eriksson K, Lindstrom LH. Supersensitivity psychosis in schizophrenic patients after sudden clozapine withdrawal. Psychopharmacology (Berl.) 83(3), 293–294 (1984).

118

Citrome L, Jaffe A, Levine J et al. Dosing of quetiapine in schizophrenia: how clinical practice differs from registration studies. J. Clin. Psychiatry 66(12), 1512–1516 (2005).

116

Stanilla JK, de Leon J, Simpson GM. Clozapine withdrawal resulting in delirium with psychosis: a report of three cases. J. Clin. Psychiatry 58(6), 252–255 (1997).

119

Thurstone CC, Alahi P. A possible case of quetiapine withdrawal syndrome. J. Clin. Psychiatry 61(8), 602–603 (2000).

117

Margolese HC, Chouinard G, Beauclair L et al. Therapeutic tolerance and rebound psychosis during quetiapine maintenance monotherapy in patients with schizophrenia and schizoaffective disorder. J. Clin. Psychopharmacol. 22(4), 347–352 (2002).

992

120

Pierre JM, Shnayder I, Wirshing DA et al. Intranasal quetiapine abuse. Am. J. Psychiatry 161(9), 1718 (2004).

121

Koro CE, Meyer JM. Atypical antipsychotic therapy and hyperlipidemia: a review. Essent. Psychopharmacol. 6(3), 148–157 (2005).

122

Tariot PN, Ismail MS. Use of quetiapine in elderly patients. J. Clin. Psychiatry 63(Suppl. 13), 21–26 (2002).

123

Kopala LC, Good KP, Milliken H et al. Treatment of a first episode of psychotic illness with quetiapine: an analysis of 2 year outcomes. Schizophr. Res. 81(1), 29–39 (2006).

Affiliations •

Vladimir Lerner, MD, PhD University of the Negev, Division of Psychiatry, Ministry of Health Be’er Sheva Mental Health Center, Faculty of Health Sciences Ben-Gurion, Be’er Sheva, Israel Tel.: +972 864 01408 Fax: +972 864 01491 [email protected]

•

Chanoch Miodownik University of the Negev, Division of Psychiatry, Faculty of Health Sciences Ben-Gurion, Be’er Sheva, Israel Tel.: +972 864 01404 Fax: +972 864 01491 [email protected]
