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Dosing of Quetiapine in Schizophrenia: How Clinical Practice Differs From Registration Studies
Abstract
A substantial number of patients with psychosis receive quetiapine in amounts that are greater than what is recommended in the product labeling approved by drug regulatory agencies. The purpose of this article is to review the past and present dosing patterns of quetiapine for the treatment of schizophrenia.
A PubMed search for the period January 1, 1990, to July 1, 2005, was conducted to identify English-language articles related to quetiapine dose in schizophrenia using the search terms quetiapine, dose, and schizophrenia. Trends in dosing of quetiapine in a large, state-operated psychiatric hospital system and the anecdotal evidence describing the use of quetiapine in excess of 800 mg/day were also reviewed.
The registration studies of quetiapine suggest a target dose range of 300 to 500 mg/day for schizophrenia. In contrast, among inpatients hospitalized in New York State in the period of April 1, 2004, to June 30, 2004, the mean dose of quetiapine prescribed was 620 mg/day, with 33.6% receiving doses in excess of 750 mg/day. Patients with nonwhite ethnicity, length of stay of at least 1 year, or history of prior state hospital admission were more likely to receive doses greater than 750 mg/day. Patients receiving quetiapine as antipsychotic monotherapy or in combination with other antipsychotics were equally likely to receive doses greater than 750 mg/day. Published anecdotal reports describe the use of quetiapine in excess of 800 mg/day and up to 2400 mg/day among patients not responding to lower doses, but currently there are no published reports from double-blind randomized clinical trials establishing the utility of this high-dose treatment strategy.
Dosing of quetiapine in clinical practice is higher than what has been established in the registration program for schizophrenia. Although there is anecdotal evidence describing the use of quetiapine in excess of 800 mg/day, double-blind randomized clinical trials are needed.
... As noted above striatal D2 occupancy does not correlate with plasma concentration and high dosage are not associated with EPS. Based on the above, it is not surprising that there have been anecdotal reports of dosage use up to 2400 mg when lower doses were felt not to be effective 83 . Although there is less likelihood of EPS, use of high dosage is limited by side-effects of sedation and other vegetative symptoms. ...
... Key reference was book by O'Dell and Schwartz on second generation antipsychotics 4 . Other key references were from articles by Citrome et al, Morrissette et al, Stahl et al and Moore et al1,32,66,82,83,99,100 . As it is still debated whether TDM should be routinely used in clinical situations AGNP came up with 4 levels of recommendations based on empirical evidence. ...
... More recent effectiveness studwhere prescribers are using dosages that exceed ies, such as CATIE (Clinical Antipsychotic Trials of product label recommendations. [2] This illustrates Intervention Effectiveness), have demonstrated the the gap between clinical practice and the state of the use of somewhat higher dosages of quetiapine, with evidence. ...
... [23] In similar design to the Canadian study but tests quethis double-blind, parallel group, multicentre study tiapine dosages of 600 mg/day versus 1200 mg/day conducted in Canada, in-or outpatients with schizo-among a planned enrolment of 60 inpatients with phrenia or schizoaffective disorder who were non-treatment-resistant schizophrenia or schizoaffective or partially responsive to 4 weeks of open-label disorder. [24] In contrast to the Canadian study, this treatment with quetiapine 800 mg/day were random-study is being conducted exclusively among inpa- anecdotal evidence [2] and the lack of seriously limit- ...
... Although high doses of atypical antipsychotics are commonly prescribed, quetiapine has received less attention in controlled studies relative to risperidone and olanzapine. [1][2][3][4][5] Switching to quetiapine in poorly responsive patients may be associated with some improvement. 6 Combinations of quetiapine and other antipsychotic drugs are commonly used, but rarely studied. ...
... 6 Combinations of quetiapine and other antipsychotic drugs are commonly used, but rarely studied. 5 Concerning quetiapine dose-response relationships, a lower threshold of 250 mg/d may be required for response, but few studies have evaluated doses higher than 450 mg/d. [7][8][9][10][11] No conclusions can be drawn regarding plasma quetiapine levels and clinical response. ...
Objective: Quetlap'me is often prescribed at higher than approved doses. We investigated the safety, tolerabiiity, and efficacy of quetiapine >800 mg/d. Method; A trial was carried out from October 2003-Septennber 2005 in 19 referral centers. Patients with DSM-IVschizophrenia or schizoaffective disorder were randomized on the basis of persistent symptoms of moderate severity (< 30% improvement in total Positive and Negative Syndrome Scale score after >4 weeks of quetiapine). The 8 week, double-blind study compared continuation of quetiapine 800 mg/d (n=43) versus 1,200 mg/d (n = 88).The primary outcome measure was emergent or worsening parkinsonism (Simpson-Angus Scale), Secondary outcomes were adverse events, metabolic side effects, and symptom severity. Results: Mean doses obtained were 799 mg/d and 1,144 mg/d in the 800-mg/d and >800-mg/d groups, respectively. Emergent or deteriorating parkinsonism in the high-dose group was 3.1% greater (95% Ci,-7.8% to 14.0%: P=.76) than in the 800-mg/d group, a value that was within the a priori limit of 16% defined as noninferiority. Both doses of quetiapine were safe and well tolerated. Weight gain was greater in the high-dose group (1.7 kg over 12 weeks; â 7% body weight, n = 11 [12.5%]) versus the 800-mg/d group (1.1 kg over 12 weeks; s 7% body weight, n =4 [9.3%]). The mean adjusted difference in weight gain (1.3 kg) was greater in the high-dose group (95% CI, 0.0-2.5; P=.044). Symptom severity declined, with no significant difference between groups.
... received less attention in controlled studies relative to risperidone and olanzapine. [1][2][3][4][5] Switching to quetiapine in poorly responsive patients may be associated with some improvement. 6 Combinations of quetiapine and other antipsychotic drugs are commonly used, but rarely studied. ...
... 6 Combinations of quetiapine and other antipsychotic drugs are commonly used, but rarely studied. 5 ...
Quetiapine is often prescribed at higher than approved doses. We investigated the safety, tolerability, and efficacy of quetiapine > 800 mg/d.
A trial was carried out from October 2003-September 2005 in 19 referral centers. Patients with DSM-IV schizophrenia or schizoaffective disorder were randomized on the basis of persistent symptoms of moderate severity (< 30% improvement in total Positive and Negative Syndrome Scale score after ≥ 4 weeks of quetiapine). The 8 week, double-blind study compared continuation of quetiapine 800 mg/d (n = 43) versus 1,200 mg/d (n = 88). The primary outcome measure was emergent or worsening parkinsonism (Simpson-Angus Scale). Secondary outcomes were adverse events, metabolic side effects, and symptom severity.
Mean doses obtained were 799 mg/d and 1,144 mg/d in the 800-mg/d and > 800-mg/d groups, respectively. Emergent or deteriorating parkinsonism in the high-dose group was 3.1% greater (95% CI, -7.8% to 14.0%; P = .76) than in the 800-mg/d group, a value that was within the a priori limit of 16% defined as noninferiority. Both doses of quetiapine were safe and well tolerated. Weight gain was greater in the high-dose group (1.7 kg over 12 weeks; ≥ 7% body weight, n = 11 [12.5%]) versus the 800-mg/d group (1.1 kg over 12 weeks; ≥ 7% body weight, n = 4 [9.3%]). The mean adjusted difference in weight gain (1.3 kg) was greater in the high-dose group (95% CI, 0.0-2.5; P = .044). Symptom severity declined, with no significant difference between groups.
The results did not demonstrate any advantage for use of quetiapine outside the approved dose range.
www.clinicaltrials.gov Identifier: NCT00328978.
... Dose-lowering strategies have also been discussed, but to date, there is a lack of evidence concerning the relationship between antipsychotic dose and weight gain [4,9,11]. In addition, it is essential to better characterize the dose-effect of AIWG outside the recommended dose range as well, since it is a common practice to either prescribe higher doses for patients who are not responding to treatment or lower doses to manage off-label conditions, such as anxiety, insomnia or obsessive-compulsive disorders [12,13]. This issue is of particular concern for quetiapine, for which off-label use in low doses is important, despite the absence of demonstrated efficacy and safety [14][15][16][17]. ...
Introduction The atypical antipsychotic quetiapine is known to induce weight gain and other metabolic complications. The underlying mechanisms are multifactorial and poorly understood with almost no information on the effect of dosage. Concerns were thus raised with the rise in low-dose quetiapine off-label prescription (i. e.,<150 mg/day).
Methods In this study, we evaluated the influence of quetiapine dose for 474 patients included in PsyMetab and PsyClin studies on weight and metabolic parameter evolution. Weight, blood pressure, lipid, and glucose profiles were evaluated during a follow-up period of 3 months after treatment initiation.
Results Significant dose-dependent metabolic alterations were observed. The daily dose was found to influence weight gain and increase the risk of undergoing clinically relevant weight gain (≥7% from baseline). It was also associated with a change in plasma levels of cholesterol (total cholesterol, LDL cholesterol, and HDL cholesterol) as well as with increased odds of developing hypertriglyceridemia, as well as total and LDL hypercholesterolemia. No impact of a dose increase on blood pressure and plasma glucose level was observed.
Discussion The dose-dependent effect highlighted for weight gain and lipid alterations emphasizes the importance of prescribing the minimal effective dose. However, as the effect size of a dose increase on metabolic worsening is low, the potential harm of low-dose quetiapine should not be dismissed. Prescriptions must be carefully evaluated and regularly questioned in light of side effect onset.
... 67 Quetiapine Available since 1997, quetiapine is a first-line treatment for persons with schizophrenia that is available in two oral daily formulations (immediate-release, extended-release). 26,[68][69][70][71] In addition to the quetiapine data from the CATIE and EUFEST analyses discussed above, a post hoc analysis 36 of 389 persons with schizophrenia drew its data from 3 pivotal clinical trials of quetiapine. [72][73][74] Summarized in Table 1, this study was not supportive of a specific anti-hostility effect. ...
Learning objective:
After participating in this activity, learners should be better able to:• Evaluate the anti-hostility effects of available atypical antipsychotic agents.
Abstract:
In addition to hallucinations and delusions, persons with schizophrenia may exhibit hostility. In clinical trials of antipsychotics, hostility is routinely measured as part of rating scales such as the Brief Psychiatric Rating Scale or Positive and Negative Syndrome Scale. The availability of the atypical antipsychotic clozapine in 1989 led to the observation that it is possible to have a treatment effect on hostility that is independent of the treatment effect on hallucinations or delusions, and independent of general sedative effects. The data supporting this notion of a specific anti-hostility effect are the most robust for clozapine as the data include specifically designed randomized, controlled clinical trials. A specific anti-hostility effect is also observable to various degrees with most of the other atypical antipsychotics, as evidenced in post hoc analyses of clinical trials originally conducted for regulatory purposes, supplemented by post hoc analyses of large effectiveness trials. The generalizability of these studies, however, may be limited. Participants in these trials were not selected for aggressive and hostile behavior. Some of the studies also excluded patients with substance use disorders. The latter is particularly important because alcohol and substance use are well known to increase risk for hostility and aggression. Nevertheless, the repeated demonstrations of the specificity of an anti-hostility effect (in terms of statistical independence of effects on other positive symptoms and of sedation) are of potential clinical importance.
... There is evidence describing the use of quetiapine in excess of 800 mg/day. 32 The side effects of quetiapine in the present patients were minimal and the increase in the BMI and drowsiness were the only changes noticed. Timadal et al. 30 found that quetiapine was well tolerated in schizophrenic patients and did not increase extrapyramidal systems. ...
Objectives: To find the effect of quetiapine on lipid peroxidation and serum total antioxidant status (TAS) in schizophrenic patients. Patients and methods: The subjects comprised 27 schizophrenic patients and 27 healthy volunteers. Clinical symptoms for the patients were assessed in Brief Individual Psychiatry Rating Scale (BPRS) items. The patients were treated with quetiapine (200-500 mg/day) orally for 8 weeks then reevaluated after the treatment. Blood samples from the patients were taken before and after quetiapine treatments. Other blood samples were taken from healthy subjects as a control group. Serum was obtained and analyzed for malondialdehyde (MDA) and TAS. Results: Base time and after 8 weeks of quetiapine treatment showed a significant decrease in BPRS score in the schizophrenic patients. Serum MDA was significantly higher in the schizophrenic patients (difference = 124.1% of control) than controls. The parameter decreased significantly after quetiapine treatment by 16.9% compared with before treatment values. Serum TAS, in the schizophrenic patients, was significantly lower (38.4%) than controls. Quetiapine increased serum TAS significantly by 21.1%. Quetiapine treatment significantly increased body mass index (BMI) by 2.9%. Conclusion: Quetiapine depressed lipid peroxidation, and raised serum TAS in schizophrenic patients. The change in these parameters by quetiapine may play a role in its therapeutic activit.
... The dosage ranges of antipsychotic drugs used for symptom remission in acute schizophrenia have been established in registration trials and in some post-marketing analyses. [194][195][196] The target doses of FGAs and SGAs for acute treatment are listed in Tables 2 and 3. ...
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... Pragmatic trials have consistently failed to support the view that newer antipsychotics have an inherently reduced liability to promote extrapyramidal side-effects (EPS) (Lieberman 2005;Jones 2006;Fischer-Barnicol 2008), leading to the inevitable conclusion that their advantage lies in licensed doses, pharmacokinetically derived, being lower than the empirically derived doses traditionally utilised with older drugs (Owens 2014). One might postulate that the comparability of tardive dyskinesia rates that has emerged with longer-term use of newer compounds relates to the fact that, in practice, doses of these tended to rise post-launch (Citrome 2005(Citrome , 2009. ...
The development of rational treatments for tardive dyskinesia has been held back by limitations to our understanding of its aetiology, which even now does not extend far beyond its association with centrally acting dopamine-blocking drugs. This article reviews briefly the major aetiological theories and addresses general management and specific treatment options. Primary prevention and early recognition remain the crucial management issues because, once the condition is established, there are no satisfactory treatments. The article considers two newly developed drugs, valbenazine and deutetrabenazine, in some detail as, although they are not yet licensed in Europe, they have largely been responsible for an upsurge in interest in tardive dyskinesia in the North American literature and are likely to be widely promoted in the future. Although possessed of undoubted benefits, the evidence suggests that these represent small steps rather than large leaps forward in treatment.
LEARNING OBJECTIVES
• Be able to discuss the major aetiological theories on the causation of a common, and sometimes serious, adverse action of antidopaminergic drugs
• Understand general management and specific treatment options
• Understand the pharmacology and efficacy of two drugs recently approved by the FDA for the treatment of tardive dyskinesia
DECLARATION OF INTEREST
D.C.O. is psychiatric commissioner on the Commission on Human Medicines, the UK drug regulator, and chair of its expert advisory group on CNS drugs. He is also a member of the psychiatry Scientific Advisory Group of the European Medicines Agency.
... For example, Citrome et al. reported that although the quetiapine registration studies suggested a target dose range of 300-500 mg/day for schizophrenia, the mean dose of quetiapine actually prescribed among inpatients hospitalized in New York State was 620 mg/day, with 33.6% receiving doses in excess of 750 mg/day. 3 Similarly, although the highest efficacious dose of ziprasidone recommended by the manufacturer's product label is 160 mg/day, the mean dose of ziprasidone prescribed among patients hospitalized in New York State was shown to be 179 mg/day, with 51.6% receiving doses in excess of 160 mg/day. 4 Thus, practical pharmacotherapy for acute schizophrenia patients should be evaluated based on data from real clinical practices and be independent of suggestions from the pharmaceutical companies. ...
Well-organized clinical guidelines of pharmacotherapy for schizophrenia are not necessarily applicable to emergency and acute-phase situations. Thus, practical pharmacotherapy for acute schizophrenia patients should be based on data from real clinical practice and be independent of pharmaceutical companies. This study investigated the current guidelines being used to determine the initially preferred antipsychotics, durations required before an antipsychotic is viewed as being ineffective, and the strategies utilized for early non-responders that include switching, high dose, and augmentation. In patients who develop side effects to the preferred antipsychotic drug, continued use may depend on the specific characteristics of the side effects. For acute-phase patients, antipsychotics with high efficacy and effectiveness may be chosen based on meta-analysis findings for not only double-blinded but also rater-blinded randomized controlled trials. Many previous studies have reported being able to make an early prediction at 2 weeks regarding the later response. These predictions were supported by the findings of a recent meta-analysis of 34 studies that examined 9,975 participants. In early non-responders to the initial antipsychotic, the effectiveness of the switching strategy appears to depend on the initial antipsychotic administered and the antipsychotic the patient is subsequently switched to. Furthermore, the effectiveness of the strategy between switching and augmentation might also depend on the initial antipsychotic administered. The current findings might serve as the basis for the use of dosing above the licensed range versus continuing the use of conventional dosing in non-responders, provided there is close monitoring of the side effects. Further research is required before any modifications of routine practices are undertaken regarding the direction of new potential treatments.
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... 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][28][29][30][31][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]. ...
... Treatment with second-generation (atypical) antipsychotics has been associated with weight gain and the development of diabetes mellitus (1). Although atypical antipsychotic drugs are of great benefit to a wide variety of individuals with psychiatric disorders, particularly patients with schizophrenia (2), clinical observations indicate that these drugs can cause adverse metabolic effects (3), including an increased risk of obesity, diabetes and metabolic syndrome (4). However, the mechanisms underlying this process remain unclear. ...
Antipsychotic drugs are regularly used for the treatment of many types of psychiatric disorders. The administration of second-generation antipsychotics is often associated with weight gain and the development of diabetes mellitus; however, the molecular mechanisms underlying the effects of these drugs remain poorly understood. Leptin and insulin play key roles in the regulation of energy balance and glucose homeostasis, and resistance to the actions of these hormones can occur with obesity and inflammation, resulting in the pathogenesis of obesity and type 2 diabetes. In this study, the effects of risperidone on the insulin-induced protein kinase B (PKB) phosphorylation and leptin-stimulated signal transducer and activator of transcription 3 (STAT3) phosphorylation were investigated in the human SH-SY5Y neuroblastoma cell line. The treatment of these cells with risperidone induced the activation of extracellular signal-related kinase (ERK) by cellular cyclic adenosine 3-monophosphate (cAMP)-dependent protein kinase (also known as protein kinase A; PKA) and the mechanisms involved include the induction of suppressor of cytokine signaling 3 (SOCS3) and suppressor of cytokine signaling 6 (SOCS6) expression. The risperidone-induced ERK activation induced an upregulation of SOCS3 and SOCS6 mRNA expression levels. Taken together, these results suggest that risperidone modulates SOCS3 and SOCS6 expression through adenylate cyclase-mediated ERK activation, which, in turn, leads to an inhibition of insulin-induced PKB phosphorylation and leptin-stimulated STAT3 phosphorylation. Eventually, these effects result in excessive body weight gain due to the inhibition of both the leptin and insulin signaling pathways.
... However, since no clinical information was available it is not possible to draw any conclusions from this finding. It has been reported that the licensed dose of quetiapine is often exceeded [Citrome et al. 2005], and indeed prescribed quetiapine doses of up to 2700 and 2600 mg/day, respectively, have been recorded [Bakken et al. 2011;Castberg et al. 2007]. In the present study the prescribed dose ranged up to 1700 mg/day, and overall 6% of samples were from patients who were prescribed doses exceeding the British National Formulary recommended limit (800 mg/day) [BNF, 2012]. ...
Suggested predose plasma quetiapine target ranges for effective therapy in schizophrenia lie between 50 and 500 µg/l. We aimed to examine data from a quetiapine therapeutic drug monitoring (TDM) service to assess the plasma quetiapine concentrations attained at specified doses in clinical practice.
We studied TDM data from patients given immediate-release quetiapine in the period 2000-2011.
There were 946 samples from 487 patients (257 males, age at time of first sample, median [range] 34 [14-87] years, and 230 females, age at time of first sample, median [range] 38 [10-92] years). The plasma quetiapine concentration was <50 and <100 µg/l in 30% and 50% of samples, respectively (no quetiapine detected in 9% of samples). The relationship between dose and plasma quetiapine was poor. The mean (95% confidence interval [CI]) quetiapine dose was higher (t = 3.6, df = 446, p <0.01) in males versus females (641 [600-1240] and 548 [600-943] mg/day, respectively), although there was no difference in median dose (600 mg/day) or in the mean (95% CI) plasma quetiapine concentrations attained. Smoking habit had no discernible effect on plasma quetiapine concentration.
There was a poor relationship between dose and plasma quetiapine concentration in this study, as found by others. This is probably because of the short plasma half-life of the drug, at least in part. Nevertheless, quetiapine TDM can help assess adherence and measurement of quetiapine metabolites, notably N-desalkylquetiapine, as well as quetiapine itself may enhance the value of quetiapine TDM in future.
... The optimal dose for second-generation antipsychotics in general is difficult to determine from registration trials (Citrome and Volavka, 2002;Schwartz and Stahl, 2011), and iloperidone is no exception. Practice-based evidence (Citrome et al., 2005;Citrome et al., 2009) ...
The efficacy and tolerability characteristics of an antipsychotic are difficult to determine from a single registration study. We thus conducted an analysis that assessed key efficacy and tolerability outcomes post hoc from four pooled short-term (4-6 weeks) phase III studies that evaluated iloperidone versus placebo in patients with schizophrenia or schizoaffective disorder.
Patient-level data were pooled from four prospective, randomized, double-blind, placebo-controlled and active-controlled, multicenter trials of iloperidone in patients with schizophrenia or schizoaffective disorder aged 18-65 years. Iloperidone 4-8, 10-16, and 20-24 mg/day (all dosed twice daily) were compared with placebo. Active controls used for assay sensitivity included risperidone 4-8 mg/day, haloperidol 15 mg/day, and ziprasidone 160 mg/day. Outcomes of interest were change from baseline to endpoint in the Brief Psychiatric Rating Scale (derived) (BPRSd), Positive and Negative Syndrome Scale (PANSS)-total (PANSS-T) score, and PANSS-positive (PANSS-P) and PANSS-negative (PANSS-N) subscale scores. An analysis of covariance (with treatment and study as factors, baseline as a covariate) was performed to compare changes between the iloperidone treatment groups versus placebo, on the basis of a last-observation-carried-forward approach for the intent-to-treat (ITT) populations. Tolerability outcomes were obtained from spontaneously reported adverse events (AEs), and number needed to harm was calculated for each antipsychotic versus placebo for the total population.
The ITT population included both schizoaffective and schizophrenia patients (N = 2401): n = 370, n = 494, and n = 424 for iloperidone 4-8, 10-16, and 20-24 mg/day, respectively; n = 294 for risperidone; n = 114 for haloperidol; n = 144 for ziprasidone; and n = 561 for placebo. Treatment with iloperidone 10-16 mg/day or 20-24 mg/day was associated with significantly improved BPRSd, PANSS-T, PANSS-P, and PANSS-N scores versus treatment with placebo. When only patients with schizophrenia were included (n = 1941), the pattern of results was essentially unchanged. The active controls confirmed assay sensitivity. Across all iloperidone dose groups, the incidences of extrapyramidal disorders and akathisia were similar to those observed with placebo. AEs for which the frequency was greater for iloperidone than placebo and for which the 95% confidence interval for number needed to harm did not contain infinity were dizziness, dry mouth, somnolence, nasal congestion, fatigue, sedation, and tachycardia; in general, for these AEs, frequency was higher with higher doses, resulting in a lower number needed to harm.
Consistent with product labeling, iloperidone 10-16 mg/day or 20-24 mg/day demonstrated significant improvement over placebo on BPRSd and PANSS-T scores, as well as on PANSS-P and PANSS-N subscale scores over 6 weeks of treatment in patients with schizophrenia and in the ITT population, which includes patients with schizoaffective disorder. Iloperidone did not differ from placebo in terms of extrapyramidal disorders and akathisia.
... Information about optimal dosing was described in a metaanalysis in which dose-response curves were constructed from all available studies [106]. How to dose atypical antipsychotics has been problematic for some agents for which the information available at time of initial approval required extensive revision in the face of actual clinical experience in the field [122,[125][126][127]. ...
Introduction:
Meta-analyses are a convenient way for clinicians and researchers to review data regarding different interventions. Meta-analyses can overcome many of the limitations of individual studies, namely the power to detect differences, and help resolve the results of inconsistent studies.
Areas covered:
This paper is a review of meta-analyses of oral atypical antipsychotics for the treatment of schizophrenia, located through PubMed and the Cochrane Database of Systematic Reviews. A total of 91 meta-analyses were identified that included efficacy outcome data for the 10 atypical antipsychotics available in the USA (11 focused on clozapine, 17 for risperidone, 8 for olanzapine, 5 for quetiapine, 3 for ziprasidone, 10 for aripiprazole, 5 for paliperidone, 1 for iloperidone, 0 for asenapine or lurasidone, and 31 others that were classified more broadly). These include Cochrane Reviews and other similarly executed reports, as well as pooled analyses meta-tagged in PubMed as a meta-analysis.
Expert opinion:
In general, there is heterogeneity among the atypical antipsychotics in terms of efficacy, with clozapine evidencing consistent superiority over typical antipsychotics, trailed behind by olanzapine and risperidone. Meta-analyses generally do not support efficacy differences between the other atypical antipsychotics compared with the older typical agents. Although this review is focused on efficacy, other considerations are also important, including the large tolerability differences among all the agents and the need to individualize medication choice based on past history of therapeutic response, past history of tolerability issues and the individual's personal values and preferences.
... This time period was chosen to allow adequate time for dose titration. Clinically recommended dose ranges for bipolar disorder, derived from product package inserts and published literature, were 10-30 mg per day for aripiprazole (11)(12)(13)(14), 10-20 mg per day for olanzapine (14)(15)(16)(17), 300-800 mg per day for quetiapine (14,(18)(19)(20), 2-8 mg per day for risperidone (14,(21)(22)(23), and 80-160 mg per day for ziprasidone (14,(24)(25)(26). ...
A retrospective study using Medicaid claims identified patients with bipolar disorder for whom oral second-generation antipsychotics were prescribed and compared rates of adherence, persistence of use, and costs across five groups of patients taking aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone.
Medicaid claims data for 2,446 bipolar patients were analyzed from eight states. The 18-month observation period included the six months before and the 12 months after the index prescription date. Adherence was defined as a medication possession ratio >80%. Persistence of use was measured by the number of days of medication therapy before a 30-day gap. Mental health-related prescription costs, total prescription costs, total mental health-related costs, and total costs were assessed. Ziprasidone was the comparator.
Clinically recommended doses of second-generation antipsychotic medications were prescribed for 45% of the patients (N = 1,102). Of these, 58% (N = 642 of 1,102) were adherent with the prescribed medication, with no significant differences between medication groups. Median time to nonpersistence of use averaged 96 days. Patients taking olanzapine were about 35% more likely than patients taking ziprasidone to discontinue taking their medication (hazard ratio = 1.34, 95% confidence interval = 1.02-1.76, p = .04). Mental health-related prescription costs and total prescription costs were lower for risperidone than ziprasidone. No statistically significant differences were found between the groups for all mental health-related costs or total costs.
Among patients in a sizeable Medicaid cohort for whom a second-generation antipsychotic medication was prescribed, less than half had a clinically recommended dose, and less than two-thirds with a clinically recommended dose were adherent to the medication, confirming that many patients with bipolar disorder do not receive clinically recommended doses of second-generation antipsychotics.
... In regards to dosing quetiapine higher than the FDA norm, Citrome et al. (2007) reported that in a New York State hospital system 40% or more of persistently ill patients were receiving greater that 750 mg/d [47]. A review paper comments that the use of quetiapine at doses greater than 800 mg/d up to 2400 mg/d has been noted in anecdotal reports [48]. This drug also is now approved as a monotherapy for bipolar depression and also as an augmentation strategy that is, added to SSRI or SNRI antidepressants, in unipolar major depressive disorder. ...
The second generation antipsychotics now have clinical approvals for the treatment of schizophrenia, bipolar depression, bipolar mania, autism, major depressive disorder and are used furthermore off-label to treat other mental disorders. Each agent is unique in its pharmacodynamic profile and allows for unique dosing strategies to be employed when treating these different disorders. Aims: To review relevant data regarding the second generation antipsychotics and their empirical dosing strategies. To further review and comment theoretically in these areas where substantial, definitive data are lacking.
A MEDLINE and recent textbook review was conducted regarding each second generation antipsychotic and cross-referenced with searches for major mental disorders. The findings are compiled in the review below.
The second generation antipsychotics are clearly delineated in the treatment of psychosis and mania and share similar mechanisms of action to achieve these results: dopamine-2 receptor antagonism for efficacy and serotonin-2a receptor antagonism for EPS tolerability. From here, each agent has a unique pharmacodynamic and pharmacokinetic profile where some agents carry more, or less antidepressant, anxiolyic, or hypnotic profiles. Choosing an agent, and dosing it in low, middle, or high ranges may result in differential effectiveness and tolerability.
The second generation antipsychotics have many clinical applications in psychiatric practice. This article serves to review this and also suggests ways clinicians may optimize treatment based upon patient diagnosis and utilizing appropriate dosing of each individual second generation antipsychotic.
... Although not assessed in this review, the dose-response relationship of quetiapine IR has been the subject of much debate, with some reports suggesting that higher than licensed dosages may be necessary for full therapeutic effect, [34][35][36] although a review of all available data found little robust evidence for prescribing above the licensed dose range. 37 In fixed-dose studies, clinical response appears optimal at a dose of around 300 to 400 mg/d. ...
To assess the relationships among quetiapine blood concentration, daily dose, dopamine receptor occupancy, and clinical outcome in order, if possible, to define a target plasma level range in which therapeutic response is enhanced and adverse events are minimized.
A search of the database Embase from 1974 to March 2009 and the databases MEDLINE and PubMed from 1966 to March 2009 was conducted. The drug name quetiapine was searched with each of the terms plasma levels, plasma concentration, therapeutic drug monitoring, and dopamine occupancy.
The search uncovered 42 relevant articles. All published reports of quetiapine plasma or serum concentration were considered for inclusion if reported in relation to a dose, clinical outcome, or dopamine occupancy. After application of exclusion criteria, 20 articles remained.
Trials designed primarily to investigate an interaction between quetiapine and another medication were excluded, as were those designed to compare methods of blood sample analysis.
There was a weak correlation between quetiapine dose and measured plasma concentration (from trough samples). Quetiapine dose was correlated with central dopamine D(2) occupancy, although the relationship between plasma level and D(2) occupancy is less clear.
The dose-response relationship for (immediate-release) quetiapine is established. Data on plasma concentration-response relationships are not sufficiently robust to allow determination of a therapeutic plasma level range for quetiapine. Therapeutic drug monitoring procedures are thus probably not routinely useful in optimizing quetiapine dose. Further examination of the relationship between peak quetiapine plasma concentration and clinical response is necessary.
... For that reason, we cannot make definite conclusions with regard to a direct or an indirect association between serotonin2A receptor and psychopathology; i.e., whether the association is a direct result of blockade of serotonin2A receptors, or is caused by for example a decreased subcortical and/or increased prefrontal dopamine release induced by serotonin2A receptor blockade (Glenthoj and Hemmingsen 1999), or by the affinity of quetiapine for other receptor systems. To achieve a full therapeutic response, it has been suggested that some patients might require higher than licensed dosages (above 800 mg/day; Citrome et al. 2005; Khazaal et al. 2007; Pierre et al. 2005 ). The use of highdose quetiapine is common in clinical practice, although support for this practice builds on case reports (Sparshatt et. ...
We have previously reported decreased frontal cortical serotonin2A receptor binding in 30 antipsychotic naïve first-episode schizophrenic patients and a relationship between this binding and positive psychotic symptoms. Until now, no longitudinal studies of serotonin2A receptor in first-episode antipsychotic-naïve schizophrenia patients have reported on the relationship between serotonin2A receptor occupancy and treatment effect after sustained treatment with a specific atypical antipsychotic compound.
Here, we measured serotonin2A receptor occupancy with [(18)F]altanserin PET in 15 first-episode antipsychotic-naïve schizophrenia patients before and after 6 months of quetiapine treatment. Moreover, we investigated possible relationships between clinical efficacy, oral dose, and plasma levels of quetiapine
Significant nonlinear relationships were found between serotonin2A receptor occupancy, quetiapine dose, and plasma concentration. There was a modest effect on positive symptoms up until a serotonin2A receptor occupancy level of approximately 60%. A receptor occupancy level between 60% and 70% appeared to exert the optimal serotonin2A receptor related treatment effect on positive symptoms whereas no additional serotonin2A receptor associated treatment effect was obtained above a receptor occupancy of 70%.
Taken together, the data point to a therapeutic role of the serotonin2A receptor in the treatment of subgroups of patients with schizophrenia. Specifically, the study indicates a serotonin2A receptor associated therapeutic window on positive symptoms in responding patients in the range between 60% and 70% occupancy in antipsychotic-naïve first-episode schizophrenia. We speculate that non-responding patients need higher dopamine D(2) receptor blockade. Future studies with concurrent measurement of interactions with the dopamine system are, however, warranted to clarify this.
... Although some of the reluctance of clinicians to use quetiapine may relate to less frequent use and lack of familiarity, inconsistencies in the published literature potentially increase clinical uncertainty. Recommendations about titration and dosing in schizophrenia may not be optimal [18]. Appropriate quetiapine dosing in adolescent [19] and early psychosis [20] patients are not adequately established, though a dose-finding study in the latter group has recently been reported [28]. ...
Unlabelled:
Objective. To evaluate the use of quetiapine in first episode psychosis in adolescents and adults in a 26-week open-label trial. Methods. Consenting patients were recruited from consecutive acute psychiatric admissions. Quetiapine was increased stepwise to 750 mg. Baseline, 2, 4, 12, 16, 20 and 26 week measurement included: BPRS, PANSS, CGI, and indices of tolerability and safety. Change was assessed using repeated measures ANOVA. Results. Of 73 first admission patients with psychosis, 15 entered the study. Loss of otherwise eligible patients was mainly related to prospective consent, which appeared to cause selection bias. All 15 patients were retained for 4-week Intention-to-Treat Analysis; nine completed the 26-week protocol (Completers Analysis). Non-completers dropped out shortly after 4 weeks. In the ITT Analysis, there was significant improvement on BPRS Total (P<0.01), PANSS Positive (P<0.05), and CGI (P<0.01) scores. No change in the 2-week BPRS Total score predicted subsequent non-response to quetiapine. In the Completers Analysis, onset of significant PANSS Negative score reduction did not occur until week 12. By 26 weeks all efficacy measures had substantially improved; and substance abuse was markedly less prevalent (P=0.02). Adverse events included postural hypotension, drowsiness, and significant weight gain (P=0.001).
Conclusions:
This uncontrolled trial suggests quetiapine is an effective first-line treatment in young early psychosis patients. Prospective consent is a major barrier to evaluating acute care for psychotic disorder.
... Although some of the reluctance of clinicians to use quetiapine may relate to less frequent use and lack of familiarity, inconsistencies in the published literature potentially increase clinical uncertainty. Recommendations about titration and dosing in schizophrenia may not be optimal [18]. Appropriate quetiapine dosing in adolescent [19] and early psychosis [20] patients are not adequately established, though a dose-finding study in the latter group has recently been reported [28]. ...
... Clinical efficacy of quetiapine 455 mg/day is comparable to haloperidol 8 mg/day [8] . The optimal dose of quetiapine is unclear, with dosing in excess of the recommended range often encountered [43,44] . Norquetiapine is an active metabolite of quetiapine and may explain quetiapine's efficacy in depression [45] . ...
Antipsychotic medications are conventionally divided into two groups: First-generation and second-generation antipsychotics (FGAs and SGAs). There is a disagreement about the role of these two groups in the treatment of schizophrenia.
To analyze the reasons for the disagreement and to propose a resolution that would improve the treatment of schizophrenia.
An overview of individual SGAs and several FGAs involved in the current disagreement is presented. Effectiveness studies that contributed to the SGAs versus FGAs disagreement are assessed, and meta-analyses of SGAs and FGAs are reviewed.
Efficacy variations within SGAs and FGAs result in overlaps between the two groups. Regarding safety, FGAs elicit more extrapyramidal side effects and tardive dyskinesia as well as prolactin elevations than SGAs, whereas some SGAs tend to be associated with more weight gain and disturbances in lipid and glucose regulation than FGAs. However, there are again considerable differences between individual agents and overlaps between the two groups in terms of side effects. The classification of antipsychotics into the two groups is no longer useful. The treatment selection for an individual patient should focus on the suitability of an individual antipsychotic for that patient rather than on the group membership of the drug.
... Because these recommendations are the result of registration studies that were used in evaluating aripiprazole for commercialization, these recommendations may not always apply in actual clinical practice. The patients enrolled in such trials may not be representative of the general clinical population in need of treatment – patients in registration trials need to provide informed consent, be free of alcohol or substance abuse, be in good physical health, be able to tolerate a washout off medication, be able to be treated with a monotherapy, and not be treatment resistant ( Citrome et al 2005b Citrome et al , 2005c). Dosing of antipsychotics in more challenging clinical populations may be quite different than the dosing used in registration trials. ...
Aripiprazole has been approved by regulatory agencies for the treatment of schizophrenia and bipolar I disorder. Although it is a dopamine partial agonist, it also has substantial binding affinity for the serotonin 5HT2A receptor. Several double-blind randomized clinical trials have established the efficacy and tolerability of aripiprazole within the dose range of 10-30 mg/day for schizophrenia, and 15-30 mg/day for manic or mixed states associated with bipolar I disorder. Relatively few comparative trials with other second-generation antipsychotics have been published for schizophrenia, with none available for bipolar disorder. The evidence so far suggests that in terms of efficacy for schizophrenia, aripiprazole is superior to placebo and haloperidol (long term), similar to perphenazine and risperidone, and inferior to olanzapine. Its tolerability profile in patients with schizophrenia appears superior to haloperidol, perphenazine, risperidone, and olanzapine. Efficacy in treating manic or mixed states was established in placebo-controlled trials. Among some patients with bipolar disorder, akathisia and gastrointestinal (GI) complaints can emerge at the start of treatment; however, the GI symptoms were time-limited in many instances. Appropriate dosing may also be important in individualizing therapy to improve tolerability, with lower starting doses becoming more important when adding to, or switching from, another antipsychotic. Aripiprazole appears to have a low propensity for weight gain, a favorable metabolic profile, and no association with hyperprolactinemia.
... For quetiapine, initiation at 50 mg, with doubling of the dose on days 2-4 to 400 mg/day and then an increase on day 5 to 600 mg/day, reflected a higher, more rapid increase than recommended. However, the highest dose of quetiapine used and recommended by the labeling may have been lower than that commonly employed in clinical practice for this patient population (31,32). After initiation of this study, an extended-release formulation of quetiapine requiring a shorter, 2-day titration schedule became available. ...
The authors compared paliperidone extended-release and quetiapine in patients with recently exacerbated schizophrenia requiring hospitalization.
In a 6-week double-blind study, inpatients with a recent exacerbation of schizophrenia were randomly assigned to treatment with paliperidone extended-release, quetiapine, or placebo. A 2-week monotherapy phase was followed by a 4-week additive-therapy phase. Target doses were at the upper end of recommended ranges: paliperidone extended-release, 9 or 12 mg/day, and quetiapine, 600 or 800 mg/day. The primary endpoint was the difference in mean total change score on the Positive and Negative Syndrome Scale (PANSS) between paliperidone extended-release and quetiapine at the 2-week monotherapy phase endpoint.
Six-week completion rates were 77.5% (124/160) with paliperidone extended-release, 66.7% (106/159) quetiapine, and 63.8% (51/80) placebo. Improvement in mean PANSS total change score was greater with paliperidone extended-release than with quetiapine from day 5 (-11.4 versus -8.2) through the monotherapy phase endpoint (-23.4 versus -17.1). Only paliperidone extended-release showed significantly greater PANSS improvement compared with placebo at 2 weeks. At the 6-week study endpoint, there was a significantly greater improvement with paliperidone extended-release compared with quetiapine despite similar use of additive therapy (predominantly other antipsychotics). Common adverse events with paliperidone extended-release, quetiapine, and placebo, respectively, were tremor (13.9%, 5.0%, 7.5%), somnolence (8.9%, 11.9%, 1.3%), insomnia (10.1%, 9.4%, 11.3%), and headache (12.0%, 7.5%, 13.8%). Six-week adverse event-related discontinuation rates were 6.3%, 10.1%, and 6.3%, respectively, in the paliperidone extended-release, quetiapine, and placebo groups.
Compared with quetiapine, paliperidone extended-release improved symptoms earlier and to a greater degree in patients with recently exacerbated schizophrenia requiring hospitalization, with no unexpected tolerability findings.
... The mis-match between product labeling and the prescriber-based evidence presented here is not unique to ziprasidone. For example, product labeling for quetiapine recommends a target dose range of 300 to 500 mg/d, which among inpatients is often exceeded (Citrome et al., 2005b). ...
Antipsychotic dosing used in clinical practice can differ from dosing originally recommended in product labeling. This has been reported for olanzapine and quetiapine, where higher doses are commonly used. This may be the case for ziprasidone as well.
To characterize changes over time in dosing for the initial and subsequent prescriptions of first-line second-generation antipsychotics used during treatment episodes for outpatients with schizophrenia and bipolar disorder, the 2001-2005 Thomson MarketScan Medicaid Database (Medicaid) and the 2001-2006 MarketScan Commercial Claims and Encounters Database (Commercial) were analyzed. Dose trends were evaluated using autoregressive time-series models.
Data were available for 49180 treatment episodes of schizophrenia (4683 Commercial and 44497 Medicaid) and 83289 treatment episodes of bipolar disorder (57961 Commercial and 25328 Medicaid). The initial prescription mean daily and overall mean daily doses of ziprasidone in schizophrenia episodes significantly increased across the Medicaid and Commercial populations, with similar trends observed for bipolar episodes. The first (May 2001) and last (December 2005) observed 3-month mean daily doses for ziprasidone were 112 mg/d and 138 mg/d for patients with schizophrenia and 93 mg/d and 113 mg/d for those with bipolar disorder in the Medicaid cohort, with similar findings for the Commercial cohort. Consistently significant trends in dose changes were not observed for the other medications, although quetiapine and olanzapine doses generally increased while aripiprazole and risperidone doses generally decreased.
There remains a need for controlled randomized clinical trials that test fixed doses of antipsychotics to ascertain the dose-response relationship within the dose range used in contemporary clinical practice.
... Co-prescription of inhibitors may not be very clinically relevant for quetiapine ADRs, because quetiapine is probably a drug with a very wide therapeutic window. Good tolerance of high doses twice as high as recommended (1600 mg/day) has been described ( Bobes et al., 2002), and in a study in state hospitals in New York ( Citrome, Jaffe, Levine, & Lindenmayer, 2005), the proportion of individuals receiving dosages >750 mg/day was 34% (and >1200 mg/day was 3%). As risperidone has a relatively narrow window, adding an inhibitor may have much more clinical relevance relative to causing ADRs. ...
New generation antipsychotic (NGA) drugs introduced to the US market after clozapine (aripiprazole, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone) are frequently used in individuals with intellectual disabilities (ID). However, there is very limited research to fully establish evidence-based or personalized medicine approaches for their use in this population. These guidelines take a pragmatic approach to establishing frameworks for their use by utilizing the prescribing information and reviewing the available literature on other relevant neuropsychiatric disorders. In the absence of expert consensus guidance and well-controlled comparison trials, we present a set of guidelines to inform initiation, dosing and monitoring of use in adults. Further, in these guidelines we provide practical information on drug-drug interactions and adverse drug reactions, and a brief review of discontinuation syndromes, potential for abuse, use during pregnancy and cost considerations. We also provide drug utilization review forms for each NGA to facilitate implementation of these guidelines, these guidelines provide a practical and necessary resource for practitioners treating psychiatric disorders and challenging behaviors in adult individuals with ID.
... 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][28][29][30][31][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, 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.
Resumen
Introducción
Este apartado presenta los resultados a largo plazo sobre el mantenimiento de la medicación antipsicótica y de los factores que influyen en este mantenimiento en una muestra representativa de pacientes con esquizofrenia seleccionados en el estudio SOHO en España.
Métodos
El SOHO fue un estudio prospectivo, de 3 años de observación sobre los resultados del tratamiento de la esquizofrenia en pacientes ambulatorios que iniciaron la terapia o se cambiaron a un nuevo antipsicótico, que fue realizado en 10 países europeos, y se centró en olanzapina. Se usó el método de Kaplan-Meier para analizar el tiempo hasta la suspensión del tratamiento y el modelo de riesgo proporcional de Cox para investigar los factores relacionados con la suspensión.
Resultados y conclusiones
Se incluyeron 1.688 pacientes en los análisis. El mantenimiento de la medicación a los 3 años dependió del antipsicótico prescrito, siendo máximo con clozapina (57,6%, IC 95% 39,2-74,5), seguido de olanzapina (48,3%, IC 95% 45,1-51,5) y mínimo con quetiapina (19%, IC 95% 13-26,3). La suspensión del tratamiento fue significativamente menos frecuente con olanzapina que con risperidona (p=0,015), antipsicóticos típicos retardados (p=,001), antipsicóticos típicos orales (p < 0,001) o quetiapina (p < 0,001); pero no que con clozapina (p=0,309). El mantenimiento más largo también se asoció con más habilidades sociales y mejor estado cognitivo inicial; por el contrario, un periodo más corto hasta la suspensión se asoció con la necesidad de estabilizantes del ánimo durante el seguimiento. Este estudio destaca las diferencias en los antipsicóticos en la práctica cotidiana clínica, puesto que algunos de ellos se asociaron con períodos de mantenimiento de medicación más largos que otros. Este estudio tiene algunas limitaciones debido a los sesgos posibles de selección y de información derivados de la asignación a tratamientos no sistemáticos y no aleatorizados y a la existencia de covariables no observadas que pueden influir en el resultado.
One method of determining potentially useful antipsychotic dosing ranges is to examine what is being used in the field. Once a medication has become available for some time and clinicians are experienced in using it, a possible assumption is that the doses used in the “real world” may be the best ones to try. For patients with a suboptimal treatment response, a place to look for dosing information would be among inpatients with persistent symptoms.
Die Entscheidung zum Einsatz eines bestimmten Medikaments wird zunächst von seinen pharmakodynamischen Eigenschaften bestimmt, d. h. der qualitative Aspekt der erwünschten Wirkung steht initial im Vordergrund. Quantitative Fragen schließen sich an, denn die Substanz sollte in genau richtiger Konzentration an den Wirkort, im Falle der Psychopharmaka in das zentrale Nervensystem (ZNS), gebracht werden. Ist die Konzentration am Wirkort zu hoch, können unerwünschte Arzneimittelwirkungen dominieren, ist die Konzentration zu niedrig, wird die therapeutische Wirkung nicht ausreichend sein (Abb. 6.1.1). Die Pharmakokinetik be schreibt und erklärt diese Zusammenhänge, ins besondere den zeitlichen Konzentrationsverlauf der Medikamente und ihrer Metabolite in Flüs sig keiten und Geweben des Körpers. Sie versucht auch zu erklären, welche biologischen Mechanismen für diese Vorgänge verantwortlich sind.
Abbildung 6.1.1:
Schematische Darstellung eines Plasmaspiegelverlaufes nach oraler Applikation
A 33 year-old patient suffering from undifferentiated schizophrenia developed severe venlafaxine abuse with craving-like behaviour and discontinuation symptoms. In the course of the disease venlafaxine abuse resulted in the induction of a mania-like syndrome. Venlafaxine therapy was terminated. Nevertheless, after some weeks the patient discontinued the prescribed drug therapy and put himself again on venlafaxine - without letting us know. This case report shall call attention to the possible adverse drug reaction (ADR) of severe venlafaxine abuse. However, in this patient illness-related factors may have contributed considerably to the development of substance abuse behaviour.
The mandate of the Centers for Medicare & Medicaid Services to decrease the use of antipsychotics in long-term care facilities requires creative solutions. Low-dose quetiapine is used for a multitude of behavioral disorders and sleep problems in the nursing facility population.
Yet, at doses of 25 mg per day or less, it doesn't have strong affinity (if any) for the dopamine-2 (D2) receptor, but it does maintain affinity for the histamine-1 and alpha-1 receptors. This begs the question: If it's not antagonizing the D2 receptor, could the use of something with similar
receptor-affinity produce the same result, allowing discontinuation of the antipsychotic altogether? Using knowledge of receptor affinities and the pharmacologic action of low-dose quetiapine, consultant pharmacists may have one additional tool in their armamentarium of fighting inappropriate antipsychotic use.
Objectives: To find the effect of quetiapine on lipid peroxidation and serum total antioxidant status (TAS) in schizophrenic patients. Patients and methods: The subjects comprised 27 schizophrenic patients and 27 healthy volunteers. Clinical symptoms for the patients were assessed in Brief Individual Psychiatry Rating Scale (BPRS) items. The patients were treated with quetiapine (200-500 mg/day) orally for 8 weeks then reevaluated after the treatment. Blood samples from the patients were taken before and after quetiapine treatments. Other blood samples were taken from healthy subjects as a control group. Serum was obtained and analyzed for malondialdehyde (MDA) and TAS. Results: Base time and after 8 weeks of quetiapine treatment showed a significant decrease in BPRS score in the schizophrenic patients. Serum MDA was significantly higher in the schizophrenic patients (difference = 124.1% of control) than controls. The parameter decreased significantly after quetiapine treatment by 16.9% compared with before treatment values. Serum TAS, in the schizophrenic patients, was significantly lower (38.4%) than controls. Quetiapine increased serum TAS significantly by 21.1%. Quetiapine treatment significantly increased body mass index (BMI) by 2.9%. Conclusion: Quetiapine depressed lipid peroxidation, and raised serum TAS in schizophrenic patients. The change in these parameters by quetiapine may play a role in its therapeutic activit. © 2014 DAR Publishers/University of Jordan. All Rights Reserved.
Aims and method
To study the difference between high- and low-dose quetiapine in acute treatment of schizophrenia. Data available from published double-blind fixed-dose trials were combined and analysed.
Results
There was no statistically significant difference between high- (750–800 mg/day) and low-dose (300–400 mg/day) quetiapine in terms of the response rate, change in positive symptoms score and the discontinuation rates either as a result of lack of response or adverse effects.
Clinical implications
Combined evidence from fixed-dose trials does not support the prevalent practice of targeting the higher dose of quetiapine for optimal treatment response in schizophrenia.
Summary This paper examines two aspects of antipsychotic treatment that have undergone revision based on recent research findings.
The first concerns the relationship between the dose of antipsychotic medication and its efficacy. Evidence now exists that
not all antipsychotics behave the same in this regard. For haloperidol and risperidone the near maximal effective dose appears
to be much lower than originally thought, while for clozapine and olanzapine (and possibly quetiapine) increasing the dose
above that normally prescribed may provide improved efficacy. The second aspect to be dealt with concerns the time it takes
to the initial clinical response with antipsychotic treatment. There is compelling evidence that most patients respond rapidly,
and a strong correlation has been described between early symptom reduction and later outcome. This raises the possibility
of developing an accurate model to predict treatment outcome by combining early treatment response with other clinical and
demographic outcome predictors.
Objectives:
The aim of this naturalistic study was to assess course and predictors of symptomatic remission in outpatients with first-episode psychosis during quetiapine monotherapy.
Methods:
In 131 outpatients presenting with first-episode psychosis, socio-demographic and clinical variables including PANSS-8 and CGI-S scores were compared at baseline and follow-up between the subgroups with and without symptomatic remission during 12 weeks of flexible-dose treatment with quetiapine.
Results:
Logistic regression revealed a low degree of negative symptoms at baseline, younger age, shorter duration of psychotic episode, early treatment response, and the absence of concomitant diseases as predictors for symptomatic remission whereas general disease severity, PANSS-8 total score, gender, alcohol or substance abuse had no predictive value.
Conclusions:
Our study underlines the predictive value of early treatment response and a low degree of negative symptoms in outpatients with first-episode psychosis. It also confirms the usability of the symptomatic remission criterion as a cross-sectional threshold criterion in clinical practice.
Quetiapine is often prescribed at doses higher than those approved by regulatory authorities, with limited evidence from controlled trials. The objective of this study was to assess the safety, tolerability, and efficacy of high-dose quetiapine (1200 mg/d) compared with a standard dose of 600 mg/d among patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, schizophrenia or schizoaffective disorder hospitalized at 2 state-operated psychiatric facilities. In order to be eligible for randomization, subjects were required to prospectively fail to demonstrate an initial therapeutic response during a 4-week run-in phase with quetiapine at 600 mg/d (immediate release and dosed twice a day). Lack of an adequate initial response was defined a 15% or lower decrease in the Positive and Negative Syndrome Scale total score. Patients were then randomized to either continue quetiapine at 600 mg/d for an additional 8 weeks or to receive 1200 mg/d quetiapine instead. No significant differences were observed between the high dose (n = 29) and standard dose (n = 31) groups in change from baseline to endpoint on extrapyramidal symptoms, electrocardiographic changes, or most laboratory measures between groups. There was a significant difference between groups for triglycerides (P = 0.035), and post hoc tests revealed a decrease in triglycerides from baseline (mean [SD], 162.7 [59.3] mg/dL) to endpoint (mean [SD], 134.8 [62.7] mg/dL) for the 600 mg/d group (P = 0.019). The mean change in the Positive and Negative Syndrome Scale total score did not differ between groups. In conclusion, quetiapine at 1200 mg/d, although reasonably tolerated, did not confer any advantages over quetiapine at 600 mg/d among patients who had failed to demonstrate an adequate response to a prospective 4-week trial of 600 mg/d.
Extended release quetiapine fumarate (quetiapine XR) was initiated at the recommended maximum dose 800 mg and maintained at the same dose in five patients with schizophrenia. Although the loadings of quetiapine XR were well tolerated in four patients in these five cases, one patient with a history of cerebral infarction developed serious side-effects, notably bladder distention and dizziness. This case series indicates that loading with maximum dose quetiapine XR may be tolerable and used safely in most schizophrenia patients with no other concurrent disease such as brain infarction.
This study aimed to characterize the inpatient utilization of depot antipsychotics.
The characteristics of adults with schizophrenia or schizoaffective disorder, hospitalized for at least 28 days, and who were prescribed depot antipsychotics were examined from 2004 to 2006 using a database from a large state-operated psychiatric hospital system. Demographic and clinical characteristics of patients receiving depot fluphenazine or haloperidol were compared to those prescribed depot risperidone.
We identified 2210 unique patients who initiated treatment with a depot antipsychotic (after receiving oral antipsychotics). Of these, 1484 (67.1%) received depot fluphenazine or haloperidol, and 726 (32.9%) received risperidone as their initial depot antipsychotic. Patients who received depot risperidone did not differ from those receiving depot fluphenazine or haloperidol with regard to demographics, diagnosis of schizoaffective disorder, number of comorbid psychiatric or medical diagnoses, or diagnosis of substance abuse. Patients started on depot risperidone during the observation period had a longer length of stay prior to initiation of depot than those started on depot fluphenazine or haloperidol (583 days vs. 237 days, t=5.489, p<.001). Patients who started on depot risperidone were less likely to be discharged on that medication than were patients who started on depot fluphenazine or haloperidol (odds ratio from Cox regression model=0.846 [95% CI 0.745-0.960]).
Patients initiated on depot risperidone had a longer length of stay prior to their first injection and were less likely to be discharged on that medication compared to patients initiated on depot fluphenazine or haloperidol, possibly indicating that patients initiating depot risperidone had a more severe or treatment-resistant course of illness and/or that there were reimbursement barriers for the outpatient utilization of depot risperidone, or that efficacy differences exist between the depot antipsychotics at the doses used in this population.
Negative symptoms in schizophrenia respond poorly to antipsychotics, but may improve when these are augmented with selective serotonin reuptake inhibitors (SSRIs). The molecular mechanisms underlying the augmentation are unclear. Nevertheless, significant progress has been made, pointing to some candidate systems which may be involved in SSRI-antipsychotic synergism. Thus, the enhanced dopamine release by SSRI-antipsychotic treatment is modulated by specific serotonergic receptors and by tyrosine hydroxylase. There are modifications in gamma-aminobutyric acid system via glutamate decarboxylase 67, protein kinase C beta and the receptor for activated C-kinase 1 (Rack1). Some studies indicate the input of transcription and neurotrophic factors as phospho-cyclic adenosine monophosphate response element-binding protein, Fos and fibroblast growth factor-2. Alterations in calcium signaling (neurogranin, regulator of G-protein signaling and Rack1) and in cytokine receptors for interleukin-8 and chemokine have also been reported. While as yet limited in scope, the evidence suggests definable molecular targets which may be implicated in drug development based on SSRI-antipsychotic synergistic actions.
Symptomatic remission was defined as a score of mild or less on each of eight key schizophrenia symptoms on the Positive and Negative Syndrome Scale (PANSS-8). To evaluate the symptomatic remission criterion in clinical practice and to determine predictors for achieving symptomatic remission, a 12-week non-interventional study (NIS) with quetiapine was conducted in Germany.
For the comparison of patients with and without symptomatic remission, sociodemographic and clinical variables of 693 patients were analyzed by logistic regression for their predictive value to achieve remission.
Four hundred and four patients (58.3%) achieved symptomatic remission after 12 weeks' treatment with quetiapine. Remission was significantly predicted by a low degree of PANSS-8 total score, PANSS single items blunted affect (N1), social withdrawal (N4), lack of spontaneity (N6), mannerism and posturing (G5), and low disease severity (CGI-S) at baseline. Predictors of non-remission were older age, diagnosis of schizophrenic residuum, multiple previous episodes, longer duration of current episode, presence of concomitant diseases, and alcohol abuse.
This study demonstrated that the majority of schizophrenia out-patients achieved symptomatic remission after 12 weeks treatment and confirms the importance of managing negative symptoms in order to achieve disease remission.
This study describes the use of "stat" medications for inpatients in a large state psychiatric hospital system, and examines the relationship between receipt of a "stat" for agitation and subsequent hospital discharge.
Use of "stat" medications in 2005 was retrospectively determined using a database that contains diagnosis and prescription information from 17 state-run adult civil facilities. A logistic regression model explored the relationship between receipt of a "stat" order for intramuscular preparations of either antipsychotics or lorazepam within the first 30 days of hospitalization and likelihood of hospital discharge by 6 months.
Among 7,202 patients who received antipsychotic medication in 2005, 3,240 (45%) also received a "stat" psychotropic medication during that year. Among 40,651 stat orders, 19,142 (47%) were for intramuscular antipsychotics or lorazepam presumably given for the treatment of agitation. Among 1,673 patients admitted in the first 6 months of 2005, 415 (25%) received at least one such "agitation stat." The percent discharged at six months among "agitation stat" receivers was 39%, compared to 69% among those who did not receive an "agitation stat" (chi-square = 115, df = 1, P < .001). Regression analysis showed that receiving an "agitation stat" in the first 30 days of hospitalization was associated with a 37% lower likelihood of being discharged by 6 months after admission (odds ratio .63, 95% CI: .46-.86).
"Stat" medications are commonly used. The use of "agitation stat" medications can be used as a proxy for clinical stability and may prove to be a useful outcome measure for future pharmacoepidemiologic studies of comparative medication effectiveness.
The aim of the current study was to evaluate quetiapine doses used across diagnosis categories in a sample of psychiatric inpatients.
Discharge letters of all adult inpatients who had received quetiapine between 1999 and 2005 were retrospectively reviewed. Logistic regressions were carried-out to assess links between quetiapine discharge dosage (> or =800 mg/day vs. <800 mg/day), diagnostic categories, substance abuse or dependence, benzodiazepine discharge doses, age and sex.
The data of 231 patients were included. Five hundred and for discharge documents were analyzed: 113 for psychotic disorders, 190 for personality disorders, 134 for bipolar and schizoaffective bipolar disorders, 29 for unipolar depression or anxiety disorders, and 35 for mental retardation. Considering psychotic disorders as a reference group, patients with personality disorders were statistically significantly less likely to be in the high quetiapine dosage group at discharge (P = 0.007, OR = 0.1 and CI [0.03; 0.6]).
Quetiapine seems to be used in a variety of clinical situations, with a wide range of doses and a lower dosage in patients treated for personality disorders.
The history of German legislation resulting in the developmental orientation of juvenile court law (JCL) led to setting the minimum age of criminal responsibility at the age of 14, which places Germany within the average range compared to other EU countries, even though most skills regarding the discernment of right- or wrong-doing are developed in earlier stages of life. The requirement put by section sign 3 JCL that legal discernment be emotionally grounded and the necessity to explore context factors (family or group, specific situation) make psychiatric evaluation of adolescents in court a delicate task. It is indispensable that new findings in neurobiology be considered upon making an assessment of the individual neuro-developmental status. In contrast, an assessment according to section sign 105 JCL considers the overall development irrespective of the crime(s). Developmental issues regarding legal prognosis are discussed for some types of offences (homicide, sexual offences, arson).
Rapid resolution of symptoms is a priority for clinicians treating acute psychosis, and rapid initiation of pharmacotherapy may prove beneficial. This study examined rapid dose initiation of quetiapine in acutely ill patients.
A 2-week, multicentre, randomised, parallel-group, open study. Inpatients (n = 269) diagnosed with schizophrenia or schizoaffective disorder received rapid (n = 139) or conventional (n = 130) initiation of quetiapine, followed by flexible dosing (maximum 800 mg/day). Primary outcome included proportion of patients experiencing > or =1 episode of selected AEs (somnolence, dizziness, orthostatic hypotension) during Week 1. Secondary outcomes included discontinuations due to AEs, and efficacy assessed by BPRS and CGI-S scores.
The proportion of patients with > or =1 selected AE during Week 1 was 5.4% and 10.1% in the conventional and rapid initiation groups, respectively. Most common AEs (>5% patients) were hypotension, tachycardia, somnolence and sedation. Overall, four (3.1%) and three (2.1%) patients from the conventional and rapid initiation group, respectively, withdrew due to AEs. BPRS and CGI-S scores decreased significantly (p < 0.001) from baseline in both groups.
A higher proportion of patients experienced AEs with rapid initiation of quetiapine (800 mg/day by Day 4), although withdrawals due to AEs were comparable. Rapid initiation of quetiapine was generally well tolerated and effective in this setting.
Quetiapine is a dopamine D2 and serotonin 5-HT2 antagonist with antipsychotic and mood-stabilizing properties. Recent studies suggest that higher doses of quetiapine combine superior therapeutic efficacy with good tolerability. We present five patients, in whom treatment with higher doses of quetiapine was associated with constipation. Our observations raise the question of dose-dependent constipation under treatment with quetiapine.
Drug utilization in the inpatient setting can provide a mechanism to assess drug prescribing trends, efficiency, and cost-effectiveness of hospital formularies and examine subpopulations for which prescribing habits may be different. Such data can be used to correlate trends with time-dependent or seasonal changes in clinical event rates or the introduction of new pharmaceuticals. It is now possible to provide a robust, dynamic analysis of drug utilization in a large pediatric inpatient setting through the creation of a Web-based hospital drug utilization system that retrieves source data from our accounting database. The production implementation provides a dynamic and historical account of drug utilization at the authors' institution. The existing application can easily be extended to accommodate a multi-institution environment. The creation of a national or even global drug utilization network would facilitate the examination of geographical and/or socioeconomic influences in drug utilization and prescribing practices in general.
Quetiapine fumarate (Seroquel [ICI 204,636]) is an atypical dibenzothiazepine antipsychotic with a greater affinity for 5-hydroxytryptamine2 (5-HT2) receptors than for D2 dopamine receptors; its efficacy in patients with schizophrenia was shown in early phase 2 trials (maximum dose, 750 mg/d).
In this multicenter, double-blind, placebo-controlled trial, 286 patients hospitalized with chronic or subchronic schizophrenia (DSM-III-R) were randomized to 6 weeks of treatment with high-dose quetiapine fumarate (< or = 750 mg/d), n = 96; low-dose quetiapine fumarate (< or = 250 mg/d), n = 94; or placebo, n = 96. The Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression Severity of Illness item scores were the primary efficacy variables. Secondary efficacy variables included the BPRS positive-symptom cluster score, the Modified Scale for the Assessment of Negative Symptoms summary score (United States only), and the total score from the negative scale of the Positive and Negative Syndrome Scale (Europe only). Scores were analyzed using an analysis of covariance for change from baseline at end point with last observations carried forward. The model included baseline score (covariate), center, and treatment. Extrapyramidal symptoms were assessed using the Simpson-Angus Scale and the Barnes Akathisia Scale; abnormal involuntary movements were assessed using the Abnormal Involuntary Movement Scale. Frequency distributions of grouped change-from-baseline scores were analyzed using chi 2 tests.
Of 280 patients in whom the efficacy of quetiapine was evaluated, 159 (42% of those receiving high-dose treatment; 57%, low-dose treatment; and 59%, placebo) withdrew before trial completion, primarily because of treatment failure. Significant (P < .001, BPRS; P = .003, Clinical Global Impression Severity of Illness item; and P = .003, BPRS positive-symptom cluster) differences were identified between patients receiving high-dose quetiapine and placebo for both primary efficacy variables, with end point differences in the BPRS positive-symptom cluster score showing quetiapine's consistency in reducing positive symptoms. The reduction of negative symptoms was less consistent; high-dose quetiapine was superior on the Modified Scale for the Assessment of Negative Symptoms but not on the negative scale of the Positive and Negative Syndrome Scale. Quetiapine was well tolerated and did not induce extrapyramidal symptoms, sustained elevations of prolactin, or clinically significant changes in hematologic parameters.
Quetiapine is an effective antipsychotic with a favorable safety profile. The optimum dose is probably greater than 250 mg/d.
Quetiapine is a new atypical antipsychotic medication. As such, relatively little has been published regarding its in vivo effects at the dopamine type 2 (D2) and serotonin type 2a (5-HT2a) receptor systems. The following study was undertaken to explore these effects across the clinical dose range and relate this information to its clinical profile.
Twelve patients with schizophrenia were randomly assigned to doses of 150 to 600 mg/d (n=3, at 150, 300, 450, and 600 mg/d) of quetiapine. After 3 weeks of treatment, D2 and 5-HT2a occupancy were measured using positron emission tomography (PET) imaging, 12 to 14 hours after the last dose. Clinical efficacy and adverse effect ratings were obtained at baseline, at the time of PET scanning, and at 12 weeks. Two additional patients were included to examine the effects of the drug 2 to 3 hours after last dose.
Quetiapine was an effective antipsychotic and improved the extrapyramidal symptoms and prolactin level elevation noted at baseline. It achieved these results with minimal (0%-27%) D2 occupancy 12 hours after the last dose. Study of the additional subjects revealed that quetiapine does give rise to transiently high (58%-64%) D2 occupancy 2 to 3 hours after a single dose that then decreases to minimal levels in 12 hours.
Quetiapine shows a transiently high D2 occupancy, which decreases to very low levels by the end of the dosing interval. Quetiapine's low D2 occupancy can explain its freedom from extrapyramidal symptoms and prolactin level elevation. The data suggest that transient D2 occupancy may be sufficient for its antipsychotic effect. Future studies controlling for nonpharmacological effects as well as activities on other receptors will be necessary to confirm this suggestion.
Although atypical antipsychotics are becoming the treatment of choice for schizophrenia, what makes an antipsychotic "atypical" is not clear. This article provides a new hypothesis about the mechanism of action of atypical antipsychotics.
Published data regarding the molecular, animal model, neuroimaging, and clinical aspects of typical and atypical antipsychotics were reviewed to develop this hypothesis. Particular attention was paid to data regarding the role of the serotonin 5-HT(2) and dopamine D(4) receptors in atypicality.
Neuroimaging data show that optimal dopamine D(2) occupancy is sufficient to produce the atypical antipsychotic effect. Freedom from motor side effects results from low D(2) occupancy, not from high 5-HT(2) occupancy. If D(2) occupancy is excessive, atypicality is lost even in the presence of high 5-HT(2) occupancy. Animal data show that a rapid dissociation from the D(2) receptor at a molecular level produces the atypical antipsychotic effect. In vitro data show that the single most powerful predictor of atypicality for the current generation of atypical antipsychotics is fast dissociation from the D(2) receptor, not its high affinity at 5-HT(2), D(4), or another receptor.
The authors propose that fast dissociation from the D(2) receptor makes an antipsychotic more accommodating of physiological dopamine transmission, permitting an antipsychotic effect without motor side effects, prolactin elevation, or secondary negative symptoms. In contrast to the multireceptor hypotheses, the authors predict that the atypical antipsychotic effect can be produced by appropriate modulation of the D(2) receptor alone; the blockade of other receptors is neither necessary nor sufficient.
Background: Quetiapine is a new atypical antipsychotic medication. As such, relatively little has been published regarding its in vivo effects at the dopamine type 2( D 2) and serotonin type 2a (5-HT2a) receptor systems. The following study was undertaken to explore these effects across the clinical dose range and relate this information to its clinical profile. Methods: Twelve patients with schizophrenia were randomly assigned to doses of 150 to 600 mg/d (n=3, at 150, 300, 450, and 600 mg/d) of quetiapine. After 3 weeks of treatment, D2 and 5-HT2a occupancy were measured using positron emission tomography (PET) imaging, 12 to 14 hours after the last dose. Clinical efficacy and adverse effect ratings were obtained at baseline, at the time of PET scanning, and at 12 weeks. Two additional patients were included to examine the effects of the drug 2 to 3 hours after last dose. Results: Quetiapine was an effective antipsychotic and improved the extrapyramidal symptoms and prolactin level elevation noted at baseline. It achieved these results with minimal (0%-27%) D2 occupancy 12 hours after the last dose. Study of the additional subjects revealed that quetiapine does give rise to transiently high (58%-64%) D2 occupancy 2 to 3 hours after a single dose that then decreases to minimal levels in 12 hours. Conclusions: Quetiapine shows a transiently high D2 occupancy, which decreases to very low levels by the end of the dosing interval. Quetiapine’s low D2 occupancy can explain its freedom from extrapyramidal symptoms and prolactin level elevation. The data suggest that transient D2 occupancy may be sufficient for its antipsychotic effect. Future studies controlling for nonpharmacological effects as well as activities on other receptors will be necessary to confirm this suggestion.
This review describes dosing strategies used to optimize the beneficial effects of atypical antipsychotic medications. Differences between manufacturers' recommended dosing and actual clinical practice are reconciled using evidence from pivotal double-blind randomized registration studies, other randomized clinical trials, case series, and case reports. With clozapine and perhaps olanzapine, plasma levels are correlated with therapeutic response; with risperidone, plasma levels are not correlated with therapeutic response but may be related to the occurrence of extrapyramidal symptoms. Information related to optimal dosing of quetiapine and ziprasidone is more limited. In clinical practice, the mean daily dose of risperidone has decreased, whereas that for olanzapine is increasing. The percentage of patients receiving quetiapine at doses above the manufacturer's recommended maximum is higher than would be expected, further illustrating that dosing ranges established during registration studies may not reflect the needs of day-to-day practice.
Introduction Quetiapine is effective and well tolerated in the treatment of schizophrenia at doses up to 800 mg/day, but data on its use at doses above this level are limited. Methods In this open-label study, 35 hospitalised patients with schizophrenia, schizoaffective disorder, bipolar disorder or alcohol-induced psychosis, who received quetiapine at doses up to 1600 mg/day in a 4-week acute phase, were followed for up to 14 months as outpatients. The primary efficacy measure was the Clinical Global Impression of Improvement (CGI-I) scale. Results At the end of the 4-week hospitalisation period, overall 94.3% of patients had experienced improvements in symptoms, with 37.1% “very much improved”, 37.1% “much improved”, and 20% “minimally improved”, according to the CGI-I scale. No patient experienced a worsening of symptoms during quetiapine treatment and there was no change in two (5.7%) patients. Among the 12 patients receiving >800 mg/day, 10 (83.3%) were “very much” or “much improved”. Quetiapine was well tolerated: no increase in extrapyramidal symptoms or other adverse events was observed even at doses above 800 mg/day, with no changes in safety parameters. Conclusion Results indicate that short-term quetiapine therapy at doses up to 1600 mg/day, with maintenance doses up to 1000 mg/day, may be an effective and well-tolerated treatment for patients with psychoses who require high doses of antipsychotics for difficult-to-treat symptoms. However, large randomised, controlled trials are required to confirm these findings.
Five fixed doses of the atypical antipsychotic "Seroquel" (quetiapine) were evaluated to delineate a dose–response relationship and to compare efficacy and tolerability opposite placebo and haloperidol. This was measured by changes from baseline responses in the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI), and Modified Scale for the Assessment of Negative Symptoms (SANS) summary scores. 361 18–64 yr olds hospitalized with schizophrenia completed a single-blind, placebo washout phase and were randomized to double-blind treatment with quetiapine (75, 150, 300, 600, or 750 mg daily), haloperidol, or placebo and evaluated weekly for 6 wks. Differences in adjusted mean changes from baseline were identified between the 4 highest doses of quetiapine and placebo for BPRS total, BPRS positive-symptom cluster, and CGI Severity of Illness item scores and between quetiapine 300 mg and placebo for SANS summary score. Dose-response modeling showssignificant linear and quadratic functions of quetiapine dose for all primary efficacy variables. Quetiapine is both superior to placebo and comparable to haloperidol in reducing positive symptoms at doses ranging from 150 to 750 mg/day and in reducing negative symptoms at a dose of 300 mg/day. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Objective. To evaluate dosing and time to efficacy of atypical antipsychotics in an acute inpatient unit. Methods. Admissions during 2001 were reviewed. Patients primarily treated with an atypical antipsychotic (including those simultaneously commenced on a mood stabiliser and/or antidepressant or receiving benzodiazepines) were evaluated. Non-acute patients, those without medical records or transferred to other hospitals were excluded. Medication details were noted. Results. A total of 137 patients were evaluated; 56 (41%) had received risperidone, 38 (28%) olanzapine, and 37 (27%) quetiapine. Mean doses (mg/day) at discharge were risperidone 4.1±2.3, olanzapine 22.5±10.2, quetiapine 576±472. Dose ranges (mg/day) were risperidone 0.5–12, olanzapine 5–40, quetiapine 50–1800. No differences between atypicals in time to efficacy/concomitant anticholinergics/mood stabilisers were observed. Benzodiazepine use was more frequent with risperidone and olanzapine than quetiapine. No serious side effects with any drug were noted. Quetiapine was rapidly titrated in 20 patients (up to 400 mg on Day 1). In 18 of these, acute disturbance was controlled. Two patients were switched for lack of efficacy, one due to persistent tachycardia, and five for concern about early postural hypotension. Conclusion. These data provide further evidence concerning dose and dose range of atypicals required for optimal clinical outcome. More rapid initiation with quetiapine may be of benefit to some patients in the acute inpatient setting.
Traditionally, conventional antipsychotics, often administered intramuscularly, are used to reduce hostility and aggression in the emergency setting. This study investigated the efficacy of quetiapine, an oral atypical antipsychotic, in managing aggressive psychosis. Methods Adult hospitalized patients (n=36) with an Overt Aggression Scale (OAS) total score ≥1 and a Brief Psychiatric Rating Scale-derived Psychosis Index score ≥6 received 100–800 mg/day flexibly dosed quetiapine and were monitored daily for a maximum of 5 days. The OAS total score and Physical Aggression Against Others subscale score were primary efficacy assessments. Tolerability was assessed with the Udvalg for Kliniske Undersogelser Side Effects Rating Scale. Results An 83% decrease in the OAS Physical Aggression Against Others subscale score occurred from Day 1 (baseline) to Day 2, which was generally maintained to Day 5; a 39% reduction in OAS total score was observed by Day 2. The OAS total score decreased from a mean baseline of 3.3 to 1.5 at Day 5, a significant decrease for Days 2–4 (P < 0.01) and of borderline significance on Day 5 (P=0.059). Adverse events were mostly mild to moderate with concentration difficulties and somnolence the most common. Conclusion These results from an uncontrolled trial suggest that quetiapine may be helpful for some aggressive patients in the emergency setting.
The variable results of positive-negative research with schizophrenics underscore the importance of well-characterized, standardized
measurement techniques. We report on the development and initial standardization of the Positive and Negative Syndrome Scale
(PANSS) for typological and dimensional assessment. Based on two established psychiatric rating systems, the 30-item PANSS
was conceived as an operationalized, drug-sensitive instrument that provides balanced representation of positive and negative
symptoms and gauges their relationship to one another and to global psychopathology. It thus constitutes four scales measuring
positive and negative syndromes, their differential, and general severity of illness. Study of 101 schizophrenics found the
four scales to be normally distributed and supported their reliability and stability. Positive and negative scores were inversely
correlated once their common association with general psychopathology was extracted, suggesting that they represent mutually
exclusive constructs. Review of five studies involving the PANSS provided evidence of its criterion-related validity with
antecedent, genealogical, and concurrent measures, its predictive validity, its drug sensitivity, and its utility for both
typological and dimensional assessment.
A 6-week, double-blind, randomized, multicentre, parallel-group study was conducted to compare the efficacy of quetiapine ('Seroquel') (n=101) with that of chlorpromazine (n=100) in hospitalized patients with acute exacerbation of subchronic or chronic schizophrenia, or schizophreniform disorder. The tolerabilities of the two treatments were also compared. The mean daily doses of quetiapine and chlorpromazine at the end of the study were 407 mg and 384 mg, respectively. Both treatments were effective in the treatment of positive and negative symptoms, with a trend towards superior efficacy for quetiapine. The quetiapine group had a lower incidence of adverse events than the chlorpromazine group, and a low incidence of treatment-emergent extrapyramidal symptoms. Quetiapine was not associated with a sustained increase in serum prolactin. These clinical data support the preclinical profile of quetiapine as an atypical antipsychotic agent.
Quetiapine ('Seroquel') is a well-tolerated, novel, atypical antipsychotic with consistent efficacy in the treatment of schizophrenia. To date, no clinical studies have evaluated the effect of quetiapine in patients who only partially respond to conventional antipsychotics, yet this type of patient is most frequently seen by psychiatrists. Therefore, this international, multicentre, double-blind study was conducted to compare the efficacy and tolerability of 8 weeks' treatment of quetiapine 600 mg/day with haloperidol 20 mg/day in 288 patients who had a history of partial response to conventional antipsychotics and displayed a partial or no response to 1 month of fluphenazine (20 mg/day) treatment. Patients on quetiapine tended to have greater improvement than those on haloperidol in the primary efficacy measure, mean Positive and Negative Symptom Scale (PANSS) score, after 4 weeks' treatment (-9.05, -5.82, respectively, P = 0.061) and at study end (-11.50, -8.87, respectively, P = 0.234). Similarly, there was a trend towards patients on quetiapine demonstrating greater improvements in the secondary efficacy measures (Clinical Global Impression, PANSS subscale and Brief Psychiatric Rating Scale scores) [week 4 (baseline) to week 12 (end)], but the difference between treatments did not reach significance. Significantly more patients on quetiapine than on haloperidol showed a clinical response-patient response rates, defined as > 20% reduction in PANSS total score between weeks 4 and 12, were 52.2% for quetiapine and 38.0% for haloperidol (P = 0.043). Patients receiving quetiapine required less anticholinergic medication (P < 0.011), had greater reduction in extrapyramidal symptoms (EPS) (P = 0.005) and fewer treatment-emergent EPS-related adverse events compared to those on haloperidol (P < 0.001). Serum prolactin concentrations were elevated at the end of fluphenazine treatment in 73% of patients. Between weeks 4 and 12, elevated serum prolactin concentrations significantly decreased in quetiapine-treated patients compared to those receiving haloperidol (P < 0.001). At the end of quetiapine treatment, 83% of patients had normal prolactin levels while only 21% of patients receiving haloperidol were within the normal range. These results suggest that quetiapine may make a valuable contribution to the management of patients with a history of partial response to conventional antipsychotics.
This review describes dosing strategies used to optimize the beneficial effects of atypical antipsychotic medications. Differences between manufacturers' recommended dosing and actual clinical practice are reconciled using evidence from pivotal double-blind randomized registration studies, other randomized clinical trials, case series, and case reports. With clozapine and perhaps olanzapine, plasma levels are correlated with therapeutic response; with risperidone, plasma levels are not correlated with therapeutic response but may be related to the occurrence of extrapyramidal symptoms. Information related to optimal dosing of quetiapine and ziprasidone is more limited. In clinical practice, the mean daily dose of risperidone has decreased, whereas that for olanzapine is increasing. The percentage of patients receiving quetiapine at doses above the manufacturer's recommended maximum is higher than would be expected, further illustrating that dosing ranges established during registration studies may not reflect the needs of day-to-day practice.
A growing number of atypical antipsychotics are available for clinicians to choose from in the treatment of psychotic disorders. However, a number of important questions concerning medication selection, dosing and dose equivalence, and the management of inadequate response, compliance problems, and relapse have not been adequately addressed by clinical trials. To aid clinical decision-making, a consensus survey of expert opinion on the pharmacologic treatment of psychotic disorders was undertaken to address questions not definitively answered in the research literature.
Based on a literature review, a written survey was developed with 60 questions and 994 options. Approximately half of the options were scored using a modified version of the RAND 9-point scale for rating the appropriateness of medical decisions. For the other options, the experts were asked to write in answers (e.g., average doses) or check a box to indicate their preferred answer. The survey was sent to 50 national experts on the pharmacologic treatment of psychotic disorders, 47 (94%) of whom completed it. In analyzing the responses to items rated on the 9-point scale, consensus on each option was defined as a non random distribution of scores by chi-square "goodness-of-fit"test. We assigned a categorical rank (first line/preferred choice,second line/alternate choice, third line/usually inappropriate) to each option based on the 95% confidence interval around the mean rating. Guideline tables indicating preferred treatment strategies were then developed for key clinical situations.
The expert panel reached consensus on 88% of the options rated on the 9-point scale. The experts overwhelmingly endorsed the atypical antipsychotics for the treatment of psychotic disorders. Risperidone was the top choice for first-episode and multi-episode patients, with the other newer atypicals rated first line or high second line depending on the clinical situation. Clozapine and a long-acting injectable atypical (when available)were other high second line options for multi-episode patients. The expert's dosing recommendations agreed closely with the package inserts for the drugs, and their estimates of dose equivalence among the antipsychotics followed a linear pattern. The experts considered 3-6 weeks an adequate antipsychotic trial, but would wait a little longer (4-10 weeks) before making a major change in treatment regimen if there is a partial response. The experts recommended trying to improve response by increasing the dose of atypical and depot antipsychotics before switching to a different agent; there was less agreement about increasing the dose of conventional antipsychotics before switching, probably because of concern about side effects at higher doses. If it is decided to switch because of inadequate response, risperidone was the expert's first choice to switch to, no matter what drug was initially tried. Although there was some disparity in the expert's recommendations concerning how many agents to try before switching to clozapine, the expert's responses suggest that switching to clozapine should be Clozapine was also the antipsychotic of choice for patients with suicidal behavior. When switching oral antipsychotics,the experts considered cross-titration the preferred strategy. When switching to an injectable antipsychotic, the experts stressed the importance of continuing the oral antipsychotic until therapeutic levels of the injectable agent are achieved. The experts considered psychosocial interventions the first choice strategy for partially compliant patients, with pharmacologic interventions the first choice for patients with clear evidence of noncompliance. However, because it can be difficult to distinguish partially compliant from noncompliant patients, the editors recommended combining psychosocial and pharmacologic interventions to improve compliance whenever possible. When patients relapse because of compliance problems or if there is any doubt about compliance, the experts recommended the use of a long-acting injectable antipsychotic and would select an injectable atypical when this option becomes available. The experts would also consider using an injectable atypical antipsychotic (when available) in many clinical situations that do not involve compliance problems. The experts stressed the importance of monitoring for health problems-especially obesity, diabetes, cardiovascular problems,HIV risk behaviors, medical complications of substance abuse, heavy smoking and its effects, hypertension, and amenorrhea-in patients being treated with antipsychotics. Although many patients are prescribed adjunctive treatments,multiple antipsychotics, and combinations of different classes of drugs (e.g., antipsychotics plus mood stabilizers or antidepressants) in an effort to enhance response, the experts gave little support to any of these strategies, with the exception of antidepressants for patients with dysphoria/depression, antidepressants or ECT for patients with suicidal behavior, and mood stabilizers for patients with aggression/violence. When asked about indicators of remission and recovery, the experts considered acute improvement in psychotic symptoms the most important indicator of remission, whereas they considered more sustained improvement in multiple outcome domains (e.g., occupational/educational functioning, peer relationships,independent living) important in assessing recovery.
The experts reached a high level of consensus on many of the key treatment questions in the survey. Within the limits of expert opinion and with the expectation that future research data will take precedence, these guidelines provide direction for addressing common clinical dilemmas that arise in the pharmacologic treatment of psychotic disorders. They can be used to inform clinicians and educate patients regarding the relative merits of a variety of interventions. Clinicians should keep in mind that no guidelines can address the complexities involved in the care of each individual patient and that sound clinical judgment based on clinical experience should be used in applying these recommendations.
Tardive dyskinesia is a potentially permanent and disfiguring side effect associated with the use of conventional, or first generation, antipsychotics. Quetiapine is a second generation antipsychotic with transient dopamine receptor occupancy, a property shared with clozapine. Quetiapine was administered to a patient who had persistent choreoathetoid movements that developed during treatment with conventional antipsychotics and remained unimproved during longterm treatment with risperidone. During 10 weeks of monotherapy with quetiapine, his Abnormal Involuntary Movement Scale score fell from 11 to 3. He was subsequently switched back to risperidone and his movements returned. The addition of quetiapine to his risperidone regimen once again resulted in a decrease of his tardive dyskinesia symptoms. The mechanism by which quetiapine improved tardive dyskinesia symptoms in this patient is not known, but differential treatment effects between the novel antipsychotics may exist. Controlled trials of quetiapine in the treatment of tardive dyskinesia should be pursued.
Previous studies suggested that African American patients with psychotic disorders receive higher doses of antipsychotic medication than white patients, are more likely to receive depot antipsychotics, and are less likely to be prescribed second-generation antipsychotics. African-American men in particular may be most likely to receive excessive doses of antipsychotics and depot antipsychotics, although this is less clear. Few studies have examined how sex and ethnicity interactions affect treatment of psychotic disorders. In this study, we examined whether the interaction of sex and ethnicity predicted the use of depot antipsychotics and the dosing of antipsychotics in a sample of inpatients with psychotic disorders. The inpatient records of 167 patients with psychotic disorders were evaluated for type and dose of medication at discharge. African-American men received depot antipsychotic medication more frequently than African-American women and white patients. This difference persisted after controlling for sociodemographic and clinical variables. African-American men and women with psychotic mood disorders were also more likely to be discharged on high antipsychotic doses compared with white patients. There were no ethnic or sex differences in the dosing of antipsychotics for the treatment of schizophrenia spectrum disorders. There were also no ethnic or sex differences in the use of second-generation antipsychotics.
Understanding common pharmacologic and clinical "class" actions associated with atypical antipsychotics certainly reveals how these agents are alike, but what about unique differences from one agent to another? Atypical antipsychotics are also a heterogeneous group of agents that have complex pharmacologic entities, acting upon multiple dopamine receptors (D2, D1, D3, and D4) and multiple serotonin receptors (5-HT2A, 5-HT2C, 5-HT1A, and 5-HT1D, among others). Atypical antipsychotics also interact with noradrenergic (alpha 1- and alpha 2-adrenergic receptor blockade), histaminergic (H1-receptor blockade), and cholinergic (muscarinic M1 blockade) neurotransmitter systems as well as with monoamine (D, 5-HT, and norepinephrine reuptake blockade) transporters. However, no two atypical antipsychotics possess the same portfolio of actions upon all of these additional neurotransmitter systems.
Physicians' Desk Reference
- Seroquel
Seroquel (quetiapine fumarate). Physicians' Desk Reference, 59th
Edition. Montvale, NJ: Thomson PDR; 2005:662-667
Presented at the 154th annual meeting of the American Psychiatric Association
- M J Reinstein
- J G Sonnenberg
- M A Chasanov
Reinstein MJ, Sonnenberg JG, Chasanov MA, et al. Comparative
efficacy and tolerability of quetiapine at high and low doses [poster].
Presented at the 154th annual meeting of the American Psychiatric
Association; May 5-10, 2001; New Orleans, La. NR353