glikosilasi hemoglobin; HDL, high density lipoprotein; LDL, low density lipoprotein.

sebuah
faktor risiko diabetes didefinisikan sebagai (a) Z5.5 glukosa puasa dan o6.93 mmol / L (Z100
dan o126 mg / dL) di pengacakan (pasien diminta untuk berpuasa selama 8 jam sebelum darah
hasil imbang karena statusnya puasa dianggap tetapi tidak dikonfirmasi), (b) riwayat diabetes
atau obesitas atau, (c) BMIZ35 kg / m2.
kelompok perlakuan (Tabel 3). Patients in the quetiapine XR group showed a slight increase in
mean triglyceride levels vs a slight decrease in the placebo group. For total cholesterol, a greater
proportion of patients in the quetiapine XR group (7.1%) than in the placebo group (2.8%),
showed a shift to clinically important values (Z6.21 mmol/L) at Week 8. For triglycerides, the
propor- tion of patients with a shift to a clinically important value (Z2.26 mmol/L) at Week 8 was
similar between treatment groups (8.3% and 7.5%, respectively).
4. Discussion
This is the first randomized, parallel-group, placebo-controlled study to evaluate the efficacy
and safety of the extended release formulation of quetiapine in bipolar depression. Quetiapine
extended release monotherapy at a dose of 300 mg once daily was significantly more effective
than placebo in the treatment of acute episodes of bipolar depression, both in the primary and
several secondary outcome measures. The rapidity of effect asso- ciated with quetiapine XR is
notable given that antidepressants typically take longer to significantly improve mood symptoms
(Rosenzweig-Lipson et al., 2007).
Quetiapine XR 300 mg once daily demonstrated efficacy that was consistent with previous
bipolar depression studies of similar duration that used the quetiapine immediate release (IR)
formula- tion and adds to an overall strong set of studies supporting efficacy (Calabrese et al.,
2008, 2005; Thase et al., 2008, 2006; Young et al., 2008; McElroy et al., 2008). This evidence
base contrasts with studies of antidepressants in major depression where only a relatively few
studies show evidence in favor of the medication over placebo (Turner et al., 2008).
The consistent effectiveness of quetiapine in bipolar depression may be attributable to its
putative mechanism of action. It has been postulated that one of the potential antidepressant
mechan- isms exhibited by quetiapine is the competitive inhibition of norepinephrine reuptake by
norquetiapine, an active quetiapine metabolite that exhibits a high affinity for the norepinephrine
transporter (NET) (Goldstein et al., 2007).
 The incidence of AEs observed in this study following treat- ment with quetiapine extended
release was consistent with the known tolerability profile of quetiapine in bipolar depression
(Calabrese et al., 2005; Thase et al., 2006). The incidence of AEs potentially associated with EPS
was higher following treatment with quetiapine XR 300 mg once daily than with placebo, though
use of anticholinergic medications was similar and the majority of patients showed no change in
SAS or BARS scores. This is similar to a study of quetiapine XR in bipolar mania (Cutler et al.,
2008).
A significant drawback associated with the use of antidepres- sant medication in the treatment
of bipolar disorder is the risk of switching to mania or hypomania (Leverich et al., 2006).
Consis- tent with the known profile of quetiapine in bipolar depression (Calabrese et al., 2005;
Thase et al., 2006), in this study, treatment with quetiapine XR 300 mg once daily was not
associated with treatment-emergent mania or hypomania.
Patients treated with quetiapine XR 300mg once daily reported higher weight gain than those
treated with placebo; though none of the patients reported withdrawing from treatment as a direct
result. Mean changes in serum glucose levels from baseline to study end were similar between
treatment groups. However, higher mean changes in HbA
1c
, triglycerides, and insulin were noted in the quetiapine XR
treatment group compared with the placebo group.
Further prespecified secondary safety analyses were carried out in a subgroup of patients
defined as potentially at higher risk for changes in metabolic parameters. This subgroup was
identified by fasting glucose levels Z5.5 and o6.93 mmol/L (Z100 and o126 mg/dL) at
randomization, a history of diabetes or obesity, or BMIZ35 kg/m2. Mean changes in serum
glucose levels from baseline to study end were analyzed in this subgroup of patients who were
classified at risk for diabetes according to pretreatment parameters, and a subgroup considered
not at risk for diabetes. In “at risk” patients, higher mean changes in the quetiapine XR treatment
group were observed for laboratory parameters of glucose regulation compared with the placebo
group. In patients “not at risk” for diabetes based on these criteria, mean changes in serum
glucose levels were lower in the quetiapine XR group than in the placebo group. Overall mean
changes in HbA
1c
and insulin were higher in the quetiapine group when
compared with the placebo group.
Confirmation of fasting status was reliant on the patient- reported last meal which may not
have identified other caloric intake that could have affected the patient's fasting status such as
smaller snacks or beverages. However, these results are generally consistent with two long-term
studies that evaluated the main- tenance effect of quetiapine, in combination with lithium or
divalproex, in which the incidence density of a single emergent fasting blood glucose value
Z6.93 mmol/L (Z126 mg/dL) was higher in the quetiapine group compared with placebo (Vieta
et al., 2008; Suppes et al., 2009).
This study had a number of methodological limitations. A majority of patients (approximately
80%) enrolled in this study were patients with bipolar I disorder thereby limiting the avail-
ability of information about patients with bipolar II disorder. Although quetiapine XR 300mg
once daily was not associated with an increased risk of suicidality, the exclusion of patients with
a current suicidal or homicidal risk limits the generalizability of these findings.
While doses of 300 and 600 mg once daily of quetiapine IR have been shown to be effective
for treatment of bipolar depres- sion, only a fixed dose of 300 mg once daily was evaluated in
this study. This is the lowest dose studied for this indication and the recommended dose of
quetiapine for the treatment of bipolar depression. Further study will be needed to assess the
potential efficacy of lower doses for treatment of acute bipolar depression.
T. Suppes et al. / Journal of Affective Disorders 168 (2014) 485–493 492
Another limiting factor of this study was the absence of an active comparator. Finally, while
metabolic parameters were examined more thoroughly in this study relative to other studies with
second generation antipsychotics, results should be inter- preted along with the limitations
inherent in outpatient studies, specifically uncertain fasting status and variable time of day for
collecting blood and patient weights.
5. Conclusions
The results of this trial demonstrate that quetiapine XR 300 mg once daily monotherapy is an
effective treatment for acute bipolar depression. Significant improvement in symptoms were seen
after 1 week of treatment and continued throughout the 8 week study. Quetiapine XR 300 mg
once daily was equally effective in patients with bipolar I and II disorder and rapid or nonrapid
cycling, although efficacy in bipolar II disorder and the rapid or nonrapid cycling subpopulations
require further confirmation in future studies due to the smaller number of patients in these
subpopula- tions in this study. Treatment with quetiapine XR 300 mg once daily monotherapy
was overall well tolerated. Additional studies on this new formulation may lead to further
understanding of its effects on adherence and patient acceptability.
Role of funding source
This study was supported by AstraZeneca Pharmaceuticals LP, Wilmington, Delaware, USA
(Study D144CC00002).
Conflict of interest
Dr. Suppes has received funding or medications for clinical studies in the last 12 months from
Abbott, AstraZeneca, GlaxoSmithKline, JDS, National Institute of Mental Health, Novartis,
Pfizer, and The Stanley Medical Research Institute. Dr. Suppes has had one advisory board with
Orexigen and no speaking bureau activity within the last 12 months and has no conflicting
financial interests or stock ownership. Royalties are received from Compact Clinical Publishers.
Drs. Darko, Datto, Minkwitz, and Mr. Walker are employees of AstraZeneca Pharmaceuticals
LP, USA. Dr. Nordenhem is a former employee of AstraZeneca R&D, Sweden.
Acknowledgment
We thank Jaya Gagwani, MS, and Aruna Seth, Ph.D. from PAREXEL, who provided medical
writing and editing support funded by AstraZeneca.
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