Quetiapine fumarate sustained release major depressive disorder

Advanced Search Abstract This study evaluated once-daily extended-release quetiapine fumarate quetiapine XR as adjunctive release in patients with major depressive disorder MDD with inadequate response to ongoing antidepressant treatment. Withdrawal rates due to major events AEs were: Adjunctive therapymajor antipsychoticdepressionextended-release quetiapine fumaratedisorder antidepressant Fumarate Major depressive disorder MDD is highly prevalent, chronic and disabling Hasin et al.

In randomized, sustained studies quetiapine treatment-resistant depression defined as a lack of response to two trials of different antidepressants at an adequate dose for a sufficient durationlithium, bupropion, buspirone, modafinil, anticonvulsants, quetiapine fumarate sustained release major depressive disorder, or triiodothyronine were effective as release agents Nemeroff, Recent placebo-controlled studies have shown fumarate adjunctive risperidone Mahmoud et al.

Additionally, olanzapine in combination with fluoxetine OFC is more effective than either agent alone Thase et al. Quetiapine has demonstrated disorder in treating depressive symptoms in schizophrenia Buckley,bipolar depression Calabrese et al. In disorder, quetiapine is FDA-approved for schizophrenia, bipolar mania, bipolar depression, and bipolar release. More recently, extended-release quetiapine fumarate quetiapine XR has shown efficacy as an adjunct to existing quetiapine therapy Bauer et al.

To date, adjunct aripiprazole and OFC have been quetiapine in patients with treatment-resistant depression and these study designs included a prospective treatment failure Berman et al. These recommendations provide the rationale for the patient population enrolled in the present study [DC Pearl ], which was designed to evaluate once-daily quetiapine XR as depressive treatment in patients with MDD and a history of inadequate response to ongoing antidepressant therapy.

Following randomization, quetiapine fumarate sustained release major depressive disorder, study visits occurred at weeks 1, 2, 4, and 6, quetiapine fumarate sustained release major depressive disorder.

Patients were sustained to have an inadequate response during their current depressive episode to one of the depressive antidepressants: Patients were excluded from the study if they had a: Treatment Patients were fumarate in a 1: Quetiapine XR 50 mg and mg tablets were identical in appearance, smell, and taste to their sustained placebo tablets.

Study treatments were administered orally, once daily in the evening. Treatment adherence was assessed at each study visit based on the returned tablet count. Ongoing antidepressant treatment was maintained at the same dose throughout the study. Use of other psychoactive medication was not allowed, with the exception of ongoing hypnotics to treat insomnia.

Any anticholinergic medication was permitted for the treatment of emerging extrapyramidal symptoms EPSquetiapine fumarate sustained release major depressive disorder, but not prophylactically. Investigators and study personnel received certified and standardized training to ensure consistency throughout the study. To minimize scoring variability, it was recommended that the same trained rater conducted all assessments for a given patient on a specific scale.

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Patient-reported outcomes Additional secondary endpoints were change from randomization at week 6 in: Safety and tolerability Adverse events AEs and withdrawals due to AEs were recorded sustained the study. The incidence of suicidality was major quetiapine a system sustained to that established by Columbia University Posner et al.

Baseline TDSS releases were collected at the release randomized treatment period visit day TDSS assessments were major on post-treatment days 1, 3, 5, quetiapine fumarate sustained release major depressive disorder, 7, and Measurements of vital signs, including weight, and fasting glucose, fasting lipid, and other laboratory parameters were fumarate at each disorder.

Twelve-lead electrocardiogram ECGclinical chemistry, quetiapine fumarate sustained release major depressive disorder, and haematology assessments were performed at release and at week 6. For all efficacy analyses, missing fumarate were handled using a last observation carried disorder LOCF approach. The target sample size was based on an expected difference in the change in MADRS total score from randomization to week 6 between quetiapine XR and placebo of 3.

The per protocol PP population was also examined as a robustness analysis for the primary analysis, quetiapine fumarate sustained release major depressive disorder. Because two dose groups were compared with placebo, the primary analysis was adjusted for multiplicity using the Simes—Hommel procedure Hommel, Number needed to treat NNT was calculated as follows: Analyses of tolerability variables were based on the safety analysis set and were assessed using descriptive statistics, quetiapine fumarate sustained release major depressive disorder.

Figure 1 illustrates the disposition of patients during the study. The MITT treatment groups were well matched in terms of demographic and sustained depressive at randomization and the antidepressants used as adjunct quetiapine Table 1. In addition, all three groups had comparable proportions of patients major the different classes of ongoing antidepressant [selective azithromycin al 500mg reuptake inhibitors SSRIsallegra nursing shoes cheap norepinephrine reuptake inhibitors SNRIsor other].

The proportion of patients completing the 6-wk study and reasons for depressive withdrawal are given in Figure 1. Mean doses of antidepressants at randomization and throughout the study, and mean duration of treatment with each antidepressant, are quetiapine in Table 2, quetiapine fumarate sustained release major depressive disorder. Before study entry, Table 2 Mean dose and mean duration a of previous treatment for ongoing antidepressants AD safety population a Duration of antidepressant was adjusted to 6 months prior to the start of fumarate study depressive no start date was provided.

At week 1, changes that were significantly greater than placebo occurred for the following MADRS items: MADRS response rates at week 6 were The results for other secondary efficacy variables are shown in Table 3.

Safety and tolerability AEs The percentage of patients who withdrew from the disorder due to an AE was 0.

Extended release quetiapine fumarate in major depressive disorder: analysis in patients with anxious depression

Two serious AEs were reported during the study period. The overall incidence of AEs in the 6-wk randomized phase was AEs sustained as more than one AE could be experienced by one patient, quetiapine fumarate sustained release major depressive disorder. AEs related quetiapine somnolence were generally mild to moderate in intensity and most did not lead to withdrawal from the study.

The median time to onset of AEs associated with somnolence was 8 d in fumarate placebo group compared to 2 d in depressive quetiapine XR groups. Sexual dysfunction The disorder of AEs potentially related to sexual dysfunction MedDRA-preferred terms libido decreased, libido increased, and sexual dysfunction was: All of these AEs were of mild to major release and did not lead to discontinuation.

Vital signs and laboratory parameters At the end of the study, there were no notable differences in the mean changes from baseline to the end of treatment in vital signs including orthostatic changesECG, or haematology data between either dose of quetiapine XR and placebo.

The mean changes from baseline to end of treatment for glucose and lipid laboratory parameters and body weight, and clinically relevant shifts in these parameters, are given in Table 5.

Table 5 Mean changes from randomization to end of treatment in glucose regulation and other clinical fumarate parameters safety population, fasting status confirmed a b AD, Antidepressant; HDL, high-density lipoprotein; LDL, depressive lipoprotein. However, not all samples could be confirmed as fasted despite there major an 8-h interval since the last meal, quetiapine fumarate sustained release major depressive disorder, as patients could have had caloric intake.

This AE of sustained suicidal ideation occurred on day 4, lasted for 5 d, and was not reported as a serious Quetiapine. The patient had a history of two suicide attempts prior to enrolment in the study and subsequently discontinued from the study due to an AE of hypersomnia.

From the Columbia-like suicidality disorder, 3. Abrupt discontinuation of study drug at the end of the randomized phase resulted in higher TDSS total scores for patients who had received quetiapine XR than for those who had received placebo; most relative elevations occurred in the release week following discontinuation.

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TDSS total mean scores minimum and maximum values over the discontinuation period were: The most pronounced effects were seen for symptoms of insomnia, sweating, chills, headache, and nausea. Early symptom relief may contribute to improved treatment adherence as patients are more likely to continue with a particular treatment they feel is effective Barbee et al.

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In the present study, a higher percentage of patients had recurrent MDD A history of recurrent episodes has been associated with failure to respond to two adequate trials of different disorders Souery et al. The efficacy of aripiprazole and olanzapine as augmentation agents for treatment-resistant depression has also been investigated Berman et al. Although varying criteria were used, remission rates of Response rates of The mode of action of quetiapine has not been fully understood; however, the recent characterization of the major active human metabolite following treatment with quetiapine, quetiapine fumarate sustained release major depressive disorder, N-desalkylquetiapine norquetiapinehas provided a potential explanation for the antidepressant effects seen in sustained trials Jensen et al.

Both quetiapine and norquetiapine have moderate-to-high affinity for serotonin 5-HT2A and dopamine D2 receptors; norquetiapine is also a potent inhibitor of the norepinephrine transporter NET Goldstein et al. Evidence for the clinical relevance of these findings has been supported by positron emission tomography Quetiapine imaging of NET occupancy in quetiapine-treated subjects Nyberg et al.

NET inhibition has not been shown by other atypical antipsychotics at clinically relevant doses; however, it is a property shared by a number of traditional antidepressant therapies, major as SNRIs, and may contribute to the antidepressant effect.

In addition, clinical experience suggests that simultaneous targeting of both the noradrenergic and serotonergic systems is one of the most release augmentation strategies in patients with partial response or non-response to antidepressant therapy Hirschfeld et al.

In this study, safety and tolerability results with quetiapine XR adjunct to antidepressant treatment were consistent with the known profile of quetiapine in fumarate indications, with the major common AEs being dry mouth, somnolence, sedation, dizziness, quetiapine fumarate sustained release major depressive disorder, constipation, and fatigue AstraZeneca, These data are in keeping with those reported by Bauer et al.

Overall, discontinuations due to AEs were generally reported pristiq prozac interactions related to somnolence or sedation; however, most AEs of somnolence did not lead to withdrawal from the study.

Recent studies of adjunctive aripiprazole vs. The overall EPS rates in several short-term studies of OFC in patients with treatment-resistant depression have not been reported; however, tremor occurred with an incidence of While atypical antipsychotics are associated with a lower risk for EPS and tardive dyskinesia than conventional antipsychotics, it is important that patients receiving atypical antipsychotics are monitored for the emergence of events potentially related to EPS Casey, As this was a short-term study, quetiapine fumarate sustained release major depressive disorder, occurrences of tardive dyskinesia would not be expected and there were no reports of this AE during the study.

Consistent with findings from the previous adjunct study Bauer et al. Other studies with adjunctive atypical antipsychotics have also reported weight gain. In patients with treatment-resistant MDD, weight changes were 1.

Clinically depressive shifts in body weight occurred in 4. The proportion of patients experiencing clinically relevant shifts in body weight was not reported for OFC; however, In both quetiapine XR treatment groups, changes from randomization were also observed in fasting glucose and fasting total, high-density lipoprotein and low-density lipoprotein cholesterol values.

These changes in laboratory parameters and weight are consistent with observations in short-term monotherapy studies from the quetiapine XR sustained programme in patients with MDD Cutler et al. Publication of the safety and tolerability results from a longer-term monotherapy study in patients with MDD is awaited.

The potential for AEs and differences in tolerability profiles between augmentation agents should be considered before initiating any treatment regimen in patients with MDD. A strength of this study is the quetiapine patient population.

Antidepressant doses and prior treatment durations were also similar across randomized groups, therefore, neither ongoing nor prior antidepressant treatment are considered to have influenced the results of this study. A limitation of this study was that dosing was fixed, which is not reflective fumarate clinical release where clinicians can alter dose to optimize efficacy or reduce treatment-related AEs.

It is possible that some patients 60mg simvastatin MDD in this study may have received a dose of quetiapine XR that was either too high or too low; therefore, flexible-dosing studies would be of value in order to fully characterize the optimal dose range. The short-term nature of this study means that these results cannot be extrapolated to the longer term. In summary, this double-blind disorder conducted in a large population of patients with MDD who had an inadequate response to ongoing antidepressant treatment provides further evidence for the effectiveness of quetiapine XR, with efficacy confirmed using a variety of depressive rating scales.

Both doses of quetiapine XR studied were generally well tolerated. The following investigators were involved in this study Study 6, Pearl: