Rumination is a significant cognitive symptom of depression. As rumination is strongly related to altered memory function we selected two genes previously described as important candidates for both depression and memory processing to assess their contribution to rumination. Based on a possible functional role for cAMP-dependent protein kinase in the mechanism of action antidepressants, we studied the association between G protein-activated K+ channel 2 (GIRK2) and cAMP-response element binding (CREB) protein genes and rumination in two independent European samples.

We genotyped an exonic SNP (rs2070995) in GIRK2 gene and a promoter SNP (rs2253206) in CREB gene of 611 individuals from Budapest and 1174 individuals from Manchester. Rumination was measured by Ruminative Response Scale (RRS) of Response Style Questionnaire. Generalized linear models (GLMs) were performed for single marker associations. Likelihood ratio tests were used for interactions between genetic markers on RRS.

Single marker associations did not provide any significant individual effect of the two SNPs on rumination. However, interaction analyses revealed a strongly significant interaction between the rs2070995 and rs2253206 on RRS in both European samples (pBudapest=0.00099; pManchester=0.0027). Homozygous TT individuals for rs2070995 in interaction with homozygous GG for rs2253206 scored significantly higher on RRS compared with other genotypes.

Our results suggest that two key post-receptor signalling proteins, GIRK2 and CREB, interact with each other in regulating the process of rumination which may have relevance for depression and its treatment.

These studies were supported by the Sixth Framework Programme of the EU, LSHM-CT-2004-503474, HRF T03298/2000.

The safety and tolerability of aripiprazole as adjunctive treatment was examined in patients with major depressive disorder (MDD) without psychotic features who had a major depressive episode and who did not respond adequately to standard antidepressant therapy (ADT).

Data from three identical short-term, double-blind, placebo-controlled studies (CN138139, CN138163, CN138165) were pooled. After a prospective phase with placebo plus ADT, patients without adequate response entered a 6-week, double-blind phase with placebo or aripiprazole plus ADT. Safety endpoints included death, serious adverse events (SAEs), treatment-emergent adverse events (AEs), Simpson-Angus Scale (SAS), Barnes Akathisia Global Clinical Assessment, Abnormal Involuntary Movement Scale (AIMS), clinical laboratory tests, vital signs and electrocardiograms.

In total, 538 patients were randomized to adjunctive placebo and 547 to adjunctive aripiprazole. AEs with an incidence ≥5% and at least twice the rate of placebo were akathisia (adjunctive aripiprazole, 22.7%; adjunctive placebo, 4.1%), restlessness (12.4% vs 2.2%), fatigue (8.6% vs 4.3%), insomnia (8.2% vs 3.2%), vision blurred (6.2% vs 1.5%), somnolence (5.9% vs 2.6%), and constipation (4.9% vs 2.4%). AEs that had a treatment difference of ≥2% included akathisia, somnolence, sedation, dizziness, disturbance in attention, extrapyramidal disorder, restlessness, insomnia, constipation, dyspepsia, fatigue, feeling jittery, vision blurred, weight increased, and dyspnea. SAEs occurred in 0.7% of patients in each treatment group. There were no deaths during the studies.

In this pooled analysis of patients with MDD and an inadequate response to ADT, adjunctive aripiprazole showed consistently high study completion rates and low discontinuation rates resulting from adverse events.

Poor sleep is a common complaint in postpartum depression (PPD). Depression as well as sleep disturbances may affect parenting functions and mother-infant relationship. The purpose of this study was to examine the relationship between objective sleep data, parenting stress and bonding in PPD.

Forty-five mothers (age: 34.5 ± 5.4 years SD) suffering from PPD were examined 212 ± 156 days (SD) after parturition. Depression was measured by Hamilton Depression Rating Scale (HDRS-ADS) and Beck Depression Inventory (BDI). Parenting stress and bonding were assessed by self report scales, i.e. Parenting Stress Index (PSI) and Postpartum Bonding Questionnaire (PBQ). In a subsample of 10 participants sleep parameters were assessed by actigraphy and sleep logs during seven consecutive days. Actigraphic sleep parameters were put in relation to severity of depression, PSI and PBQ scores.

Poor sleep, i.e. low total sleep time (TST) was negatively correlated to depression (HRDS-ADS) (r = -.63; p < .05). Low TST was associated with poor bonding (r = -.82; p = .02), especially attitudes of “rejection and anger”. Severity of depression (BDI) was correlated with parenting stress (r =.50; p =.005). Mothers with high parenting stress tended to have more difficulties in bonding (r =.65; p =.016). Neither sleep parameters nor parenting stress and bonding were correlated with the infant's age.

In PPD poor sleep should be recognized and treated early, because it is associated to parenting stress and disturbed bonding, which might have a detrimental impact on mother-infant relationship.

Evaluate the effects of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in patients with major depressive disorder (MDD) according to disease severity.

Pooled data (quetiapine XR 50, 150 and 300mg/day doses combined) from four 6- or 8-week placebo-controlled quetiapine XR monotherapy studies (D1448C00001, D1448C00002, D1448C00003, D1448C00004) were analysed. Key inclusion criterion for all 4 studies: HAM-D total score ≥22. Primary endpoint: change from randomisation in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. A post-hoc analysis assessed change from randomisation in MADRS total score and MADRS response (≥ 50% reduction in MADRS total score) at endpoint (Week 6 or Week 8) in 6 severity cohorts (defined by a MADRS total score at randomisation ≥24, ≥26, ≥28, ≥30, ≥32 or ≥34).

1752 patients (comprising the l’ all patients’ group) were evaluated (MADRS score ≥24 at randomisation, n=1601; ≥26, n=1467; ≥28, n=1269; ≥30, n=1038; ≥32, n=745; ≥34, n=500). Quetiapine XR significantly reduced mean MADRS total score at endpoint in lrsquo;all patients’ (p< 0.001 vs placebo) and in all 6 severity cohorts (≥24, ≥26, ≥28, ≥30 and ≥32, p< 0.001 vs placebo; ≥34, p< 0.01 vs placebo). MADRS response rates were significantly higher in the quetiapine XR group vs placebo in the ‘all patients’ group (p< 0.001 vs placebo) and in all 6 severity cohorts (≥24, ≥26, ≥28, ≥30 and ≥32, p< 0.001 vs placebo; ≥34, p=0.001 vs placebo).

Quetiapine XR monotherapy significantly improved depressive symptoms in patients with MDD irrespective of disease severity, including the most severe levels of depression.

AstraZeneca funded

To evaluate once-daily extended release quetiapine fumarate (quetiapine XR) as monotherapy (50, 150 and 300mg/day) (acute and maintenance treatment) or adjunct treatment (150 and 300mg/day) in patients with MDD.

Eight (7 acute, 1 maintenance) placebo-controlled studies were analysed. Primary endpoints: change from randomisation in Montgomery-Åsberg Depression Rating Scale (MADRS) scores (acute); time from randomisation to depressed event (maintenance). Statistical analyses: ANCOVA for difference between quetiapine XR and placebo in LSM change in MADRS total score from randomisation to study end (LOCF; acute); hazard ratio (HR) for time to recurrence of a depressed event (maintenance).

Figure 1 shows treatment differences (95% CIs) for primary efficacy variable for the seven acute studies. Four monotherapy studies (D1448C00001, D1448C00002, D1448C00003, D1448C00014) were significant in favour of quetiapine XR; Study D1448C00004 (monotherapy) was not. Studies D1448C00006 and D1448C00007 were significant in favour of adjunct quetiapine XR. Time from randomisation to depressed event (Study D1448C00005) significantly increased with quetiapine XR; HR (95% CI): 0.34(0.25, 0.46); p< 0.001; number of depressed events: 55, quetiapine XR; 132, placebo. Safety findings were consistent with the known tolerability profile of quetiapine.

Quetiapine XR consistently demonstrated antidepressant efficacy, with 6/7 acute studies positive in favour of quetiapine XR (monotherapy or adjunct). Quetiapine XR maintenance therapy significantly reduced risk of a depressed event, demonstrating relapse prevention. AstraZeneca funded

Impaired sleep quality and dyssomnia disorders in particular have repeatedly been linked to affective symptoms. However reports about systematic assessments in larger study samples are generally lacking. Furthermore the associative relationships of fatigue and sleepiness complaints to sleep quality and affective symptoms are poorly described.

During a one-year period we recruited 570 patients (mean age 28(0.26), 287 males) attending the sleep laboratory of a general University Hospital. Psychometrics were performed using the Pittsburgh Sleep Quality Index (PSQI), the Hospital Anxiety and Depression Scale (HAD), the Fatigue Severity Scale (FSS) and the Epworth Sleepiness Scale (ESS). All patients underwent two consecutive nights of full polysomnographic recording (PSG).

Both fatigue (FSS) and sleepiness (ESS) were related to affective symptoms (HAD, p< 0.001 and p=0.012 respectively). Fatigue and affective symptom intensity but not sleepiness, were correlated to sleep quality (p< 0.001). The HAD was related to REM-Sleep Latency (HAD, p=0.017). Slow Wave Sleep duration of the second night was negatively correlated to affective symptoms (p=0.21). Body mass index (BMI) was correlated to fatigue (p< 0.001), sleepiness (p=0.18) and to sleep quality (p=0.006) but not to affective symptoms.

These results confirm the tight relations between sleep quality, daytime fatigue or sleepiness and affective symptoms. Residual fatigue is a common and invalidating complaint in mental disorders as major depression. Achievement of clinical remission can be compromised because of residual treatment resistant symptoms. PSG might be useful in certain conditions to rule out co-morbid sleep disorders and to orientate treatment attitudes.

Clinical studies demonstrate that quetiapine is efficacious in schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder. The pharmacological basis for this broad range of clinical effects is not completely understood. The current experiments evaluated pharmacological assays investigating the receptor-binding characteristics of quetiapine and norquetiapine (the major human metabolite) and compared these with other atypical antipsychotics and standard antidepressants.

In vitro receptor-binding assays utilized cloned human targets including norepinephrine transporter (NET), dopamine D2 receptor, and serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors stably expressed in CHO or HEK cell lines. In vitro functional studies included uptake-inhibition assays for NET and GTPgammaS assays for D2/D3 antagonist and 5-HT1A agonist activity.

Norquetiapine demonstrated high affinity at 5-HT2A receptors (5 nM) and moderate/high affinity at NET (29 nM) and 5-HT2C receptors (76 nM), while quetiapine had moderate affinity at 5-HT2A receptors (29 nM), weak affinity at 5-HT2C receptors (2800 nM), and lacked appreciable affinity at NET. Both quetiapine and norquetiapine showed moderate affinity at D2 receptors (56 nM and 59 nM, respectively) with moderate/low-potency antagonist activity. Both quetiapine and norquetiapine exhibited low affinity at 5-HT1A receptors (1800 nM and 570 nM, respectively) with low-potency agonist activity.

These experiments confirm that quetiapine-norquetiapine have multiple pharmacological effects at targets associated with psychotropic drug action. This combination of effects by quetiapine-norquetiapine at dopaminergic, serotonergic, and noradrenergic targets may explain the antipsychotic, antidepressant, and anxiolytic properties of quetiapine.

Supported by funding from AstraZeneca Pharmaceuticals LP.

Asenapine is indicated in adults for acute treatment of schizophrenia and bipolar I disorder. We describe the efficacy and tolerability of adjunctive asenapine in bipolar patients showing incomplete response to lithium or valproate monotherapy.

In a 12-week core study, patients were randomized to flexible-dose asenapine (5 or 10 mg BID) or placebo as an adjunct to continued mood stabilizer therapy. Patients completing the core study without protocol violations could enter a 40-week extension. Changes from core study baseline on the Young Mania Rating Scale (YMRS) and Montgomery-Asberg Depression Rating Scale (MADRS) total scores were assessed at week 3 of the core study and at week 52 in the extension. Efficacy in the core study was assessed using ANCOVA with LOCF to impute missing data. The extension was not powered for statistical comparisons; descriptive statistics were employed.

The intent-to-treat population comprised 318 patients (asenapine, 155; placebo, 163) in the core study and 71 (38; 33) in the extension. Mean±SD changes at week 3 with asenapine and placebo, respectively, were -9.7±10.1 versus -7.7±9.6 (P=0.0257) on YMRS and -2.8±7.2 versus -2.2±6.8 (P=0.3684) on MADRS. Mean±SD changes at week 52 with asenapine and placebo were -17.2±13.7 versus -19.7±11.8 on YMRS and -3.3±9.8 versus -3.9±7.7 on MADRS. The incidence of treatment-emergent AEs with asenapine and placebo was 73% and 69% in the core study, 78% and 69% in the extension.

Asenapine was effective as an adjunct to mood stabilizer in bipolar I disorder and was well tolerated.

Bipolar Disorder treatment includes not only the remission of Major Depressive or Manic/Hypomanic Episodes, but also the prevention of recurrences. Purpose of this trial is to evaluate the effectiveness of Mood Stabilizers and Atypical Antipsychotics in preventing recurrences.

67 patients with a diagnosis of Bipolar Disorder type 1 and 2 were followed retrospectively for a period of 48 months. Clinical and demographic information were collected by clinical charts and interviews with patients. A survival analysis was performed considering death events change of treatment, a Major Depressive or Hypomanic/Manic Episode or a hospitalization.

Patients treated with Lithium survived longer than patients treated with Valproate (Log Rank: χ2=3.86, p=0.05) which resulted to be superior in terms of recurrence prevention compared to Atypical Antipsychotics in monotherapy (Olanzapine, Quetiapine or Risperidone) (Log Rank: χ2=4.54, p=0.03). Lithium association with an Atypical Antipsychotic resulted more efficacious in terms of recurrence prevention compared to Lithium (Log Rank: χ2=7.01, p=0.008) or Atypical Antipsychotics in monotherapy (Log Rank: χ2=8.61, p=0.003).

These preliminary data would indicate that Lithium association with an Atypical Antipsychotic would be more effective in preventing Major Depressive or Hypomanic/Manic recurrences in bipolar patients.

An undiagnosed bipolarity may be one of the reasons connected with treatment resistance in major depressive disorder. In recent years, the tools have been introduced helping to assess the bipolarity such as the Hypomania Checklist (HCL-32) and the Mood Disorder Questionnaire (MDQ). The objective of the study was to compare scores of bipolarity measured with these scales between patients with treatment-resistant and treatment non-resistant depression within the framework of all-Poland multi-center study TRES-DEP.

One-thousand and fifty-one patients recruited from 150 outpatient psychiatric clinics in Poland and fulfilling DSM-IV criteria for single or recurrent major depressive episode were studied. Five-hundred and sixty-nine patients were identified as having treatment-resistant depression on account of non-obtaining remission in recent depressive episode after minimum of two courses of adequate treatment with antidepressant drugs. They were compared with 482 patients with non-treatment-resistant depression. All patients were assessed using the structured demographic and clinical data interview, as well as the Polish version of HCL-32 and MDQ

Patients with treatment-resistant depression scored significantly higher compared with non-resistant depression both on HCL-32 and MDQ (11.9+8.3 vs 8.5±7.7 and 4.3±3.5 vs 2.7±2.9, respectively). Independent risk factors of treatment resistance were scoring of14 or higher on HCL-32, and 6 or higher on MDQ.

Higher scoring by patients with treatment-resistant depression on both HCL-32 and MDQ may suggest a possible association between bipolarity and worse response to antidepressant drugs in patients with major depressive disorder.

In patients with major depression (MD), mean BDNF serum concentration increases during antidepressant treatment. This increase has been associated with symptom amelioration. In a previous analysis of the time course of BDNF serum concentration, we could show a high association between early and final changes of BDNF levels during antidepressant treatment. The aim of this study was to analyse the predictive value of early BDNF changes for BDNF changes after 4 to 6 weeks of antidepressant treatment in individual patients with MD.

Forty-six patients with MD according to DSM-IV were included in this study. All patients were treated as clinically indicated. Depression severity was assessed by HAMD-17 by trained raters from baseline to week 6 in weekly intervals. Serum at each visit (baseline, V1-V6) was obtained from whole blood after centrifugation with 1.000 × g for 10 minutes. Aliquots were frozen at -80°C until analysis. BDNF serum concentration was determined with ELISA (R&D Systems). We determined sensitivity and specificity of early changes (from baseline to weeks 1 and 2) of BDNF serum concentration to BDNF changes in the later course (from baseline to weeks 4 to 6) of treatment.

BDNF increase from BL to week 2 predicted BDNF increase from baseline to week 5 with high sensitivity (81%) and specificity (73%). Further analyses revealed comparable results (data not shown).

These results suggest that early BDNF increase is predictive for final BDNF increase in individual patients with MD during antidepressant treatment.

Oral isotretinoin is presently regarded as the drug of choice for the treatment of severe and recalcitrant acne.

Although its use has been associated with various psychiatric side effects, the casual relationship between these manifestations and oral isotretinoin still remains in dispute.

The purpose of this study was to investigate the incidence of psychopathological reactions in patients with severe acne orally treated with isotretinoin.

Seventy-two (72) patients with severe acne and thirty-six (36) healthy volunteers acne enrolled in the study from January 2003 and August 2009. Acne patients were allocated either to oral isotretinoin (1mg/kg/day) (N=36) or to topical treatment (N=36). All patients and controls were separately interviewed by two psychiatrists before and 1, 3 and 6 months after onset of treatment. Their psychological status was evaluated using SCID-I, SCID-II (DSM-IV) and Hamilton Scale for Depression and Anxiety.

A statistical significant increase in the incidence of depression, mood and/or anxiety disorders was observed in the group of isotretinoin-treated acne patients as compared to the group of those topically treated and to healthy controls. No association between development of symptoms of mental disorder and duration of treatment with isotretinoin was detected.

In view of the above findings it seems reasonable to suggest that oral isotretinoin may be capable of causing anxiety and/or depressive or other mood disorders in patients with severe acne. Close psychiatric monitoring should be included in the investigations that are routinely performed throughout oral isotretinoin treatment of these patients.

The rate of manifestation of depressive episodes can vary appreciably. The complete development of a depressive episode may be very rapid, taking less than one hour or be very slow, taking up to one month. Altough this clinical observation suggests different neurobiological pathomechanisms, the onset speed of depressive episodes in different affective disorders has not been investigated systematically up to now. The objective of this study was to establish the onset speed of depressive episodes in patients with a history of at least one depressive episode and to compare the onset speed in unipolar with that in bipolar affective disorders.

A group of 96 inpatients was investigated consecutively using the structured patient interview “Onset of Depression Inventory” (ODI). In 76 patients, there was a unipolar depressive disorder and 20 patients suffered from a bipolar depressive disorder.

The onset speed of the current depressive episode in patients with effective disorders correlated significantly with the onset speed of the previous depressive episodes (p < 0.001). Furthermore, there was a significant difference in the onset of the depressive episodes between unipolar and bipolar affective disorders (p < 0.001). In 55% of patients with a bipolar disorder, the depressive episode was manifested within one week whereas this was the case in only 22,37% of the patients with a unipolar affective disorder.

The rate of manifestation of depressive episodes differs between unipolar and bipolar disorders. The clinical observation reported here can support the diagnostic appraisal of depressive episodes.

Considering the effects of the level of social support and self-esteem as risk factors in the onset and continuation of depression, the purpose of the current study (in addition to studying the demographic items of depression) was to investigate the correlation between depression and level of social support and self-esteem in Iranian university students studying non medical majors.

The study was a cross-sectional descriptive-analytic research carried out on the students of Ferdowsi University of Mashhad in 2006. Self administered questionnaires on socio-demographic information (age, gender, marital status, and educational level), Eysenk self-esteem scale, Beck Depression Inventory and Cassidy social support scale were randomly given out to students who were selected by multi stage randomized sampling. The data were analyzed using SPSS version 14 using the χ2-test.

1200 students responded to the anonymous questionnaires. A total of 57.2% of the participants had depression (36.3% mild, 14.4% moderate and 6.5% severe). Depression was significantly higher in males, singles and in 25-29-year-old students. Results showed that 9.4%, 18.3% and 72.3% of the participants reported low, moderate and high levels of social support respectively. 1.8% and 6.3% of the participants reported low and moderate levels of self-esteem respectively; while 91.9% reported high levels of self-esteem.

Depression has a higher rate in non-medical university students of Iran than general population. Levels of social support and self-esteem were negatively associated with frequency of depression.

Mixed Bipolar patients are those who have co-existing depressive symptoms during mania. These patients are supposed to have a worse evolution.

The objective of this study was to compare the long-term outcomes of patients who had at least one mixed episode with those who experienced only pure manic episodes.

169 outpatients diagnosed of Bipolar I disorder and treated at least during two years were included. 120 patients (71%) complited the follow-up over 10 years. Baseline demographic and clinical variables were included.

The patients with mixed episodes (37%) had a significantly younger mean age at onset comparing with those with manic episodes (25.3 years vs. 30.8 years; p=0.025) they also had more previous mood- incongruent psychotic symptoms χ2= 6.77, p=0.034), more number of hospitalizations (OR= 1.36, 95% CI = 1.14; -1.63; p< 0.001), and more number of episodes (OR= 1.21, 95% CI = 1.10-1.31; p< 0.001). There were no significant differences relating to depressive episodes, alcohol use, drug abuse, suicidal behaviour and suicide attempts.

Age at onset differed significantly between the mixed episode and pure mania groups, with mixed episode patients having a younger age of onset. This is interesting as one of the major results of the study we have found that age at onset mediates some of the factors classically related to outcome in mixed episodes like alcohol abuse and suicide attempts. However, independently of age at onset, these patients represent a especially severe type of bipolar disorder.

To evaluate the long-term tolerability and effectiveness of aripiprazole adjunctive to lithium or valproate in bipolar mania.

Completers of a 6-week double-blind comparison of adjunctive aripiprazole versus placebo in bipolar mania partially responsive to monotherapy were followed up over 46-weeks on open-label aripiprazole plus lithium (ARI+LI) or valproate (ARI+VAL).

283 (ARI+LI n=108; ARI+VAL n=175) patients entered and 146 (ARI+LI n=55; ARI+VAL n=91) completed the 46-week extension. Safety results for both combinations were consistent with the known tolerability profile of aripiprazole, lithium and valproate. No clinically significant changes in lipids or glucose were observed with either ARI+LI or ARI+VAL. Mean (SE) weight change from double-blind endpoint to Week 46 (LOCF) was 2.3 (0.6) kg with ARI+LI and 2.0 (0.4) kg with ARI+VAL. Temporal analysis of the time of first onset of adverse events showed that akathisia and insomnia tended to occur early in treatment, with few new cases in patients previously treated with aripiprazole during the 6-week study.

Significant improvements from baseline in YMRS total score and MADRS total score were sustained over the 52 weeks with both ARI+LI and ARI+VAL treatment.

Long-term aripiprazole adjunctive to lithium/valproate in bipolar mania was safe and well-tolerated. Improvements in manic and depressive symptoms observed during the first 6 weeks of treatment were maintained.

To determine the efficacy of QTP in patients with bipolar I disorder with mixed symptoms.

Data from 2 phase III studies (D1447C00126 and D1447C00127) were pooled. Unlike previous analyses of these studies, mixed events were analyzed separately. Patients received QTP (400-800 mg/d)+Li/DVP to achieve ≥12 weeks of clinical stability followed by double-blind treatment with QTP (400-800 mg/d)+Li/DVP or PBO+Li/DVP for up to 104 weeks. Primary endpoint was time to first mood event post-randomization.

1326 patients were included in the ITT population. Relative to PBO, QTP significantly increased time to recurrence of mixed events (P< 0.0001). 445 ITT patients had a most recent mixed episode at study entry. In these patients, mood events were reported by fewer patients on QTP+Li/DVP (21.0%) than on PBO+Li/DVP (53.9%). These events included mixed (6.4% vs 22.1%), pure manic (5.0% vs 13.3%), and pure depressed events (9.6% vs 18.6%). Time to recurrence of mood events was significantly longer for patients on QTP+Li/DVP than for those on PBO+Li/DVP for mixed (HR, 0.23, 95% CI, 0.13-0.42, P< 0.0001), pure manic (HR, 0.30, 95% CI, 0.15-0.60, P=0.0007), and pure depressed events (HR, 0.38, 95% CI, 0.22-0.64, P=0.0003). No new safety concerns were noted.

In stable patients with bipolar I disorder, QTP+Li/DVP significantly increased: a) time to recurrence of mood events compared with PBO in patients with mixed symptoms at study entry; and b) time to occurrence of mixed mood events in patients with any mood episode at study entry.

Supported by funding from AstraZeneca Pharmaceuticals.

Combined data are presented from 2 long-term studies (D1447C00126; D1447C00127) of QTP in combination with Li or DVP in the prevention of mood events in bipolar I disorder. Data from Li and DVP treatment groups are analyzed separately to determine the added benefit of QTP.

Patients received QTP (400-800 mg/d)+Li/DVP to achieve ≥12 weeks of clinical stability followed by double-blind treatment with QTP (400-800 mg/d)+Li/DVP or PBO+Li/DVP for up to 104 weeks. Li or DVP treatment was openly assigned at the discretion of the investigator. Primary endpoint was time to first mood event post-randomization.

1326 patients were included in the ITT population. In both Li and DVP groups, the risk of recurrence of any mood event was significantly reduced following treatment with QTP relative to placebo (HR, 0.32, 95% CI, 0.24-0.44 and HR, 0.28, 95% CI, 0.21-0.37; for Li and DVP, respectively; P< 0.0001 for both). This trend was repeated for risk of recurrence of mania and depression events (P< 0.0001 vs placebo). Comparison of QTP+Li versus QTP+DVP groups revealed no differences in the risk of recurrence of mood, mania, or depression events. Safety data were generally consistent with the recognized safety profiles of QTP, Li, and DVP.

In stable patients with bipolar I disorder, treatment with QTP, in combination with either Li or DVP, resulted in similar significant increases in the time to recurrence of a mood event (mania or depression) compared with placebo, regardless of Li or DVP co-treatment.

Supported funding from AstraZeneca Pharmaceuticals.