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2.
Int Clin Psychopharmacol ; 32(1): 41-48, 2017 01.
Article in English | MEDLINE | ID: mdl-27583543

ABSTRACT

Generalized anxiety disorder (GAD), a common mental disorder, has several treatment options including pregabalin. Not all patients respond to treatment; quickly determining which patients will respond is an important treatment goal. Patient-level data were pooled from nine phase II and III randomized, double-blind, short-term, placebo-controlled trials of pregabalin for the treatment of GAD. Efficacy outcomes included the change from baseline in the Hamilton Anxiety Scale (HAM-A) total score and psychic and somatic subscales. Predictive modelling assessed baseline characteristics and early clinical responses to determine those predictive of clinical improvement at endpoint. A total of 2155 patients were included in the analysis (1447 pregabalin, 708 placebo). Pregabalin significantly improved the HAM-A total score compared with the placebo at endpoint, treatment difference (95% confidence interval), -2.61 (-3.21 to -2.01), P<0.0001. Pregabalin significantly improved HAM-A psychic and somatic scores compared with placebo, -1.52 (-1.85 to -1.18), P<0.0001, and -1.10 (-1.41 to -0.80), P<0.0001, respectively. Response to pregabalin in the first 1-2 weeks (≥20 or ≥30% improvement in HAM-A total, psychic or somatic score) was predictive of an endpoint greater than or equal to 50% improvement in the HAM-A total score. Pregabalin is an effective treatment option for patients with GAD. Patients with early response to pregabalin are more likely to respond significantly at endpoint.


Subject(s)
Anti-Anxiety Agents/therapeutic use , Anxiety Disorders/diagnosis , Anxiety Disorders/drug therapy , Pregabalin/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Anxiety Disorders/epidemiology , Clinical Trials, Phase II as Topic/methods , Clinical Trials, Phase III as Topic/methods , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Randomized Controlled Trials as Topic/methods , Statistics as Topic/methods , Time Factors , Treatment Outcome , Young Adult
3.
J Clin Psychiatry ; 77(3): 371-8, 2016 Mar.
Article in English | MEDLINE | ID: mdl-27046309

ABSTRACT

BACKGROUND: Cariprazine is an atypical antipsychotic currently under investigation as adjunctive therapy in patients with major depressive disorder (MDD) who have inadequate response to standard antidepressant therapy. METHOD: A randomized, double-blind, placebo-controlled, flexible-dose study was conducted from December 2011 to December 2013 in adults who met DSM-IV-TR criteria for MDD and had an inadequate antidepressant response. Eligible patients were randomized to 8-week adjunctive treatment with placebo (n = 269), cariprazine 1-2 mg/d (n = 274), or cariprazine 2-4.5 mg/d (n = 276). The primary efficacy parameter was change from baseline to week 8 in Montgomery-Asberg Depression Rating Scale (MADRS) total score; P values were adjusted for multiple comparisons. Safety assessments included adverse events, clinical laboratory tests, vital signs, electrocardiograms (ECGs), and suicidality. RESULTS: Compared with placebo, reduction in MADRS total score at week 8 was significantly greater with adjunctive cariprazine 2-4.5 mg/d (least squares mean difference [LSMD] = -2.2; adjusted P = .0114), but not with cariprazine 1-2 mg/d (LSMD = -0.9; adjusted P = .2404). Significant LSMDs for MADRS total score change were detected at all earlier study visits (weeks 2, 4, 6) in the 2- to 4.5-mg/d group and at weeks 2 and 4 in the 1- to 2-mg/d group (all P values < .05). Treatment-emergent adverse events reported in ≥ 10% of patients in either cariprazine dosage group were akathisia (22.3%), insomnia (13.6%), and nausea (12.8%) (all in 2- to 4.5-mg/d group). Mean changes in metabolic parameters, vital signs, and ECG parameters were generally similar between groups. No suicide-related adverse events were reported. DISCUSSION: These results show that adjunctive cariprazine 2-4.5 mg/d was effective and generally well tolerated in adults with MDD who had inadequate responses to standard antidepressants. Further clinical studies to confirm these results are warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01469377.


Subject(s)
Antidepressive Agents/therapeutic use , Antipsychotic Agents/adverse effects , Antipsychotic Agents/therapeutic use , Depressive Disorder, Major/drug therapy , Drug Resistance/drug effects , Piperazines/adverse effects , Piperazines/therapeutic use , Adolescent , Adult , Aged , Dose-Response Relationship, Drug , Double-Blind Method , Drug Therapy, Combination/adverse effects , Female , Humans , Male , Middle Aged , Young Adult
4.
World Psychiatry ; 14(3): 303-4, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26407781
5.
CNS Spectr ; 20(2): 148-56, 2015 Apr.
Article in English | MEDLINE | ID: mdl-24902007

ABSTRACT

INTRODUCTION/OBJECTIVE: Post hoc analyses were conducted to evaluate the efficacy of levomilnacipran extended-release (ER) in subgroups of patients with major depressive disorder (MDD). METHODS: Data were pooled from 5 completed Phase II/III studies. Patients were categorized by sex, age, MDD duration, recurrence of MDD, current episode duration, number of prior episodes, and baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score. Efficacy was evaluated by MADRS least squares (LS) mean change from baseline, response (MADRS improvement ≥50%), and remission (MADRS ≤10). RESULTS: In the pooled population, treatment with levomilnacipran ER versus placebo resulted in greater improvement in MADRS score (-15.8 versus -12.9; LS mean difference, -2.9; P < .001) and higher response rates (44.7% versus 34.5%; P < .001). Comparable treatment effects were found in most subgroups. Remission rates in the overall population were higher for levomilnacipran ER versus placebo (27.7% versus 21.5%; P < .05); notably high remission rates were seen in patients with baseline MADRS score < 30 (48.8% versus 28.9%; P < .001). Discussion Clinically meaningful improvements in depressive symptoms were found across subgroups, including statistically significant outcomes for both response and remission. CONCLUSION: Levomilnacipran ER was efficacious across a wide range of MDD patients, including men and women, ages 18-78, with varying histories and symptom severity.


Subject(s)
Antidepressive Agents/administration & dosage , Antidepressive Agents/therapeutic use , Cyclopropanes/administration & dosage , Cyclopropanes/therapeutic use , Depressive Disorder, Major/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Delayed-Action Preparations , Depressive Disorder, Major/psychology , Double-Blind Method , Female , Humans , Male , Middle Aged , Milnacipran , Treatment Outcome , Young Adult
6.
Int J Neurosci ; 125(5): 336-43, 2015 May.
Article in English | MEDLINE | ID: mdl-24955721

ABSTRACT

PURPOSE: Mood disorders are present in more than 90% of suicides, and a genetic vulnerability to suicidality is well established. Numerous lines of evidence relate the transcription factor Cyclic adenosine monophosphate Response Element Binding protein (CREB1) to suicide, and to the aetiology of major depressive disorder (MDD). Our aim was to test for association between CREB1 single nucleotide polymorphisms (SNPs) and both suicide risk (SR) and a personal history of suicide attempt (SA) in MDD patients. MATERIALS AND METHODS: A sample of 250 MDD patients collected in the context of a European multicenter resistant depression study and treated with antidepressants over a period of at least 4 weeks were genotyped for five CREB1 SNPs (rs2709376, rs2253206, rs7569963, rs7594560, and rs4675690). To assess suicidality, the Mini International Neuropsychiatric Interview (MINI) and the Hamilton Rating Scale for Depression (HAM-D) were applied. RESULTS: Neither single-marker nor haplotypic association were found between SR and/or a personal history of SA with any of the investigated SNPs after multiple testing correction. For females, an association between rs2709376 and a personal history of SA was found (p = 0.016), however not resisting multiple testing correction. CONCLUSIONS: Although we found significant CREB1 single marker association with a personal history of SA in female MDD patients, this finding could not be confirmed in haplotypic analyses after multiple testing correction. Larger well-defined cohorts are required to confirm or refute a possible association of CREB1 and SA in female MDD patients.


Subject(s)
Cyclic AMP Response Element-Binding Protein/genetics , Depressive Disorder, Major/genetics , Depressive Disorder, Major/psychology , Polymorphism, Single Nucleotide/genetics , Suicide, Attempted/psychology , Adult , Aged , Europe/epidemiology , Female , Genetic Association Studies , Genotype , Humans , Male , Middle Aged , Psychiatric Status Rating Scales , Risk , Sex Characteristics , Suicide, Attempted/statistics & numerical data
7.
Hum Psychopharmacol ; 29(5): 470-82, 2014 Sep.
Article in English | MEDLINE | ID: mdl-25087600

ABSTRACT

OBJECTIVE: This randomised, double-blind, 12-week study compared efficacy and tolerability of flexible-dose treatment with vortioxetine(10-20 mg/day) versus agomelatine (25-50 mg/day) in major depressive disorder patients with inadequate response to selective serotonin reuptake inhibitor (SSRI)/serotonin-noradrenaline reuptake inhibitor (SNRI) monotherapy. METHODS: Patients were switched directly from SSRI/SNRI to vortioxetine or agomelatine. Primary endpoint was change from baseline to week 8 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score analysed by mixed model for repeated measurements, using a noninferiority test followed by a superiority test. Secondary endpoints included response and remission rates, anxiety symptoms(Hamilton Anxiety Rating Scale), Clinical Global Impression, overall functioning (Sheehan Disability Scale), health-related quality of life(EuroQol 5 Dimensions), productivity (work limitation questionnaire) and family functioning (Depression and Family Functioning Scale). RESULTS: Primary endpoint noninferiority was established and vortioxetine (n = 252) was superior to agomelatine (n = 241) by 2.2 MADRS points (p<0.01). Vortioxetine was also significantly superior in response and remission rates at weeks 8 and 12; MADRS, Hamilton Anxiety Rating Scale, Clinical Global Impression, Sheehan Disability Scale and EuroQol 5 Dimensions scores at week 4 onwards; work limitation questionnaire at week 8 and Depression and Family Functioning Scale at weeks 8 and 12. Fewer patients withdrew because of adverse events with vortioxetine (5.9% vs 9.5%). Adverse events (incidence ≥5%) were nausea, headache, dizziness and somnolence. CONCLUSIONS: Vortioxetine was noninferior and significantly superior to agomelatine in major depressive disorder patients with previous inadequate response to a single course of SSRI/SNRI monotherapy. Vortioxetine was safe and well tolerated.


Subject(s)
Acetamides/therapeutic use , Antidepressive Agents/therapeutic use , Depressive Disorder, Major/drug therapy , Depressive Disorder, Treatment-Resistant/drug therapy , Piperazines/therapeutic use , Sulfides/therapeutic use , Acetamides/adverse effects , Adolescent , Adrenergic Uptake Inhibitors/therapeutic use , Adult , Aged , Antidepressive Agents/adverse effects , Double-Blind Method , Female , Humans , Male , Middle Aged , Piperazines/adverse effects , Psychiatric Status Rating Scales , Selective Serotonin Reuptake Inhibitors/therapeutic use , Sulfides/adverse effects , Treatment Outcome , Vortioxetine , Young Adult
8.
Int Clin Psychopharmacol ; 29(6): 339-43, 2014 Nov.
Article in English | MEDLINE | ID: mdl-24859491

ABSTRACT

'Recurrent brief depression' (RBD) is a common, distressing and impairing depressive disorder for which there is no current proven pharmacological or psychological treatment. This multicentre, randomized, fixed-dose, parallel-group, placebo-controlled study of the reversible inhibitor of monoamine oxidase moclobemide (450 mg/day) and the tricyclic antidepressant imipramine (150 mg/day) evaluated the potential efficacy of active medication, when compared with placebo, in patients with recurrent brief depression, recruited in the mid-1990s. After a 2-4-week single-blind placebo run-in period, a total of 35 patients were randomized to receive double-blind medication for 4 months, but only 16 completed the active treatment period. An intention-to-treat analysis of the 34 evaluable patients found no evidence for the efficacy of moclobemide or imipramine, when compared with placebo, in significantly reducing the severity, duration or frequency of depressive episodes. A total of 28 patients experienced at least one adverse event, and four patients engaged in nonfatal self-harm. Limitations of the study include the small sample size and the high rate of participant withdrawal. The lack of efficacy of these antidepressant drugs and the previous finding of the lack of efficacy of the selective serotonin reuptake inhibitor fluoxetine together indicate that medications other than antidepressant drugs should be investigated as potential treatments for what remains a common, distressing and potentially hazardous condition.


Subject(s)
Antidepressive Agents/therapeutic use , Depressive Disorder/drug therapy , Imipramine/therapeutic use , Moclobemide/therapeutic use , Adolescent , Adult , Antidepressive Agents/adverse effects , Double-Blind Method , Female , Humans , Imipramine/adverse effects , Male , Middle Aged , Moclobemide/adverse effects , Recurrence , Young Adult
9.
J Clin Psychiatry ; 75(5): 520-7, 2014 May.
Article in English | MEDLINE | ID: mdl-24816198

ABSTRACT

OBJECTIVE: To prospectively analyze effects of extended release quetiapine fumarate (quetiapine XR) on suicidality in major depressive disorder (MDD). METHOD: Data were pooled from randomized, acute studies (4 monotherapy; 2 adjunct therapy) in adult patients with a DSM-IV diagnosis of MDD who were considered not to be at high risk of suicide at baseline and were receiving quetiapine XR 50 mg/d (n = 181), 150 mg/d (n = 910), or 300 mg/d (n = 685) or placebo (n = 957). Data from 1 acute monotherapy study in elderly patients receiving quetiapine XR (50-300 mg/d; n = 166) or placebo (n = 172) and maintenance data (up to 52 weeks) for patients receiving quetiapine XR (50-300 mg/d; n = 391) or placebo (n = 385) were also evaluated. Overall incidences and relative risks for suicidality (suicidal behavior/ideation) were assessed by Columbia-type review and classification. The proportion of patients with Montgomery-Asberg Depression Rating Scale (MADRS) item 10 (suicidal thoughts) score ≥ 4 was analyzed. RESULTS: Incidence of suicidality during acute treatment in adults was 1.1%, 0.7%, 0.7%, and 0.7% with quetiapine XR 50 mg/d, 150 mg/d, and 300 mg/d and placebo, respectively. The proportion of patients with MADRS item 10 score ≥ 4 during acute treatment in adults was 1.8% with quetiapine XR (all doses combined) and 2.4% with placebo. In elderly patients, the incidence of suicidality during acute treatment was 0.6% in both treatment groups; the proportion of patients with MADRS item 10 score ≥ 4 was 0% with quetiapine XR (all doses combined) and 1.2% with placebo. During maintenance treatment, the incidence of suicidality was 0.3% (n = 1) and 0.5% (n = 2) for quetiapine XR and placebo, respectively. The proportion of patients with MADRS item 10 score ≥ 4 was 4.1% with quetiapine XR in the open-label stabilization period and 0.3% with quetiapine XR and 0.5% with placebo during the randomized period. CONCLUSIONS: This analysis suggests that there is no evidence of treatment-emergent suicidality with quetiapine XR therapy in patients with MDD considered not to be at high suicide risk at baseline.


Subject(s)
Antipsychotic Agents/adverse effects , Depressive Disorder, Major/drug therapy , Dibenzothiazepines/adverse effects , Randomized Controlled Trials as Topic/statistics & numerical data , Suicide/statistics & numerical data , Adult , Antipsychotic Agents/administration & dosage , Delayed-Action Preparations , Depressive Disorder, Major/complications , Dibenzothiazepines/administration & dosage , Female , Humans , Male , Middle Aged , Psychiatric Status Rating Scales , Quetiapine Fumarate , Risk , Treatment Outcome , Young Adult
10.
Int Clin Psychopharmacol ; 29(4): 185-96, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24424469

ABSTRACT

It is known that newer antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), provide advantages in tolerability over antidepressants such as the tricyclics. However, even within the SSRI class, differences in efficacy or tolerability exist between the individual drugs. Among the three most widely prescribed SSRIs are paroxetine, sertraline, and escitalopram. Escitalopram is commonly referred to as an SSRI, but also has well-documented allosteric properties, and thus can be further classed as an allosteric serotonin reuptake inhibitor. All three antidepressants are efficacious compared with placebo, but there is evidence that escitalopram is more effective than a range of other antidepressants. There are no direct data to regard either paroxetine or sertraline as a superior antidepressant. Escitalopram is superior compared with paroxetine, which has a less favorable tolerability profile. Paroxetine is associated with cholinergic muscarinic antagonism and potent inhibition of CYP2D6, and sertraline has moderate drug interaction issues in comparison with escitalopram. Overall, as an allosteric serotonin reuptake inhibitor that is somewhat different from classical SSRIs, escitalopram is the first choice judged by combined efficacy and tolerability, and nonclinical data have offered possible mechanisms through which escitalopram could be more efficacious, based on its interaction with orthosteric and allosteric binding sites at the serotonin transporter.


Subject(s)
Antidepressive Agents, Second-Generation/therapeutic use , Citalopram/therapeutic use , Evidence-Based Medicine , Models, Biological , Paroxetine/therapeutic use , Selective Serotonin Reuptake Inhibitors/therapeutic use , Sertraline/therapeutic use , Allosteric Site , Animals , Antidepressive Agents, Second-Generation/adverse effects , Antidepressive Agents, Second-Generation/pharmacokinetics , Antidepressive Agents, Second-Generation/pharmacology , Citalopram/adverse effects , Citalopram/pharmacokinetics , Citalopram/pharmacology , Depression/drug therapy , Depression/metabolism , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/metabolism , Drug Interactions , Humans , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/chemistry , Nerve Tissue Proteins/metabolism , Paroxetine/adverse effects , Paroxetine/pharmacokinetics , Paroxetine/pharmacology , Serotonin Plasma Membrane Transport Proteins/chemistry , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/adverse effects , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Selective Serotonin Reuptake Inhibitors/pharmacology , Sertraline/adverse effects , Sertraline/pharmacokinetics , Sertraline/pharmacology
11.
Int Clin Psychopharmacol ; 29(5): 252-62, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24394383

ABSTRACT

This study is a pooled, post-hoc analysis evaluating once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in patients with generalized anxiety disorder (GAD). Three previously reported positive, 8-week, randomized, double-blind, placebo-controlled studies evaluated quetiapine XR therapy (50, 150, 300 mg/day) in patients with GAD [Hamilton Anxiety Rating Scale (HAM-A) total score ≥ 20]. Patients were stratified by baseline severity: HAM-A total score ≥ 22, ≥ 24, < 26, ≥ 26, ≥ 28. We report HAM-A total score change, response (≥ 50% reduction in HAM-A total score), and remission (HAM-A total score ≤ 7 and ≤ 9). Quetiapine XR significantly improved HAM-A total scores compared with placebo at Weeks 1 and 8 in the HAM-A ≥ 22, ≥ 24, and ≥ 26 cohorts (all doses), at Week 1 (all doses) and Week 8 (quetiapine XR 150 mg/day) in the < 26 cohort, and at Week 1 (all doses) and Week 8 (quetiapine XR 50 and 150 mg/day) in the HAM-A ≥ 28 group (P<0.05). Week 8 effect sizes for 50, 150, and 300 mg/day were as follows: 0.29, 0.47, 0.17 (HAM-A ≥ 22); 0.35, 0.55, 0.22 (HAM-A ≥ 24); 0.18, 0.32, 0.10 (HAM-A < 26); 0.41, 0.59, 0.24 (HAM-A ≥ 26); 0.60, 0.64, 0.22 (HAM-A ≥ 28), respectively. Acute quetiapine XR monotherapy significantly improves anxiety compared with placebo in patients with moderate or severe GAD, with symptom improvements seen as early as Week 1.


Subject(s)
Anti-Anxiety Agents/therapeutic use , Anxiety Disorders/drug therapy , Dibenzothiazepines/therapeutic use , Adolescent , Adult , Aged , Anti-Anxiety Agents/administration & dosage , Anti-Anxiety Agents/adverse effects , Anxiety Disorders/physiopathology , Anxiety Disorders/psychology , Cohort Studies , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/adverse effects , Delayed-Action Preparations/therapeutic use , Diagnostic and Statistical Manual of Mental Disorders , Dibenzothiazepines/administration & dosage , Dibenzothiazepines/adverse effects , Dose-Response Relationship, Drug , Double-Blind Method , Female , Follow-Up Studies , Humans , Male , Middle Aged , Psychiatric Status Rating Scales , Quetiapine Fumarate , Severity of Illness Index , Time Factors , Young Adult
12.
Int Clin Psychopharmacol ; 29(2): 93-105, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24162081

ABSTRACT

This study evaluated extended release quetiapine fumarate (quetiapine XR) monotherapy in elderly patients with major depressive disorder (MDD) according to baseline levels of anxiety, sleep disturbance, and pain. Post-hoc analyses of data from an 11-week (9-week randomized-treatment, 2-week post-treatment phase), double-blind, placebo-controlled study of quetiapine XR (50-300 mg/day) monotherapy in elderly (≥66 years) patients (n=338) with MDD were carried out. Outcomes included randomization to week 9 change in Montgomery Åsberg Depression Rating Scale (MADRS) score and week 9 response (≥50% MADRS score reduction) rates. Post-hoc analyses were carried out to assess subgroups of patients with MDD according to baseline levels in terms of the following: higher or lower anxiety (Hamilton Rating Scale for Anxiety total score≥20 or < 20, respectively); high or low sleep disturbance [Hamilton Rating Scale for Depression sleep disturbance factor (items 4+5+6) score≥5 or <5, respectively]; and pain visual analog scale total score 40 mm or higher or less than 40 mm. At week 9, quetiapine XR reduced the MADRS total score compared with placebo in the higher anxiety (least squares mean change -17.8 vs. -8.5; P<0.001) and lower anxiety (-14.8 vs. -8.8; P<0.001) subgroups. MADRS total score was also reduced with quetiapine XR compared with placebo in the high (-17.6 vs. -8.7; P<0.001) and low (-14.4 vs. -9.2; P<0.001) sleep disturbance subgroups, as well as in the pain visual analog scale subgroups [≥40 mm (-16.6 vs. -8.9; P<0.001) and <40 mm (-15.7 vs. -8.7; P<0.001)]. Quetiapine XR response rates were higher than those of placebo in all subgroups analyzed. In this study, quetiapine XR (50-300 mg/day) monotherapy was shown to be effective against depressive symptoms in elderly patients with MDD, irrespective of baseline levels of anxiety, sleep disturbance, and pain.


Subject(s)
Antipsychotic Agents/therapeutic use , Anxiety/drug therapy , Depressive Disorder, Major/drug therapy , Dibenzothiazepines/therapeutic use , Pain/drug therapy , Sleep Wake Disorders/drug therapy , Aged , Antipsychotic Agents/adverse effects , Anxiety/complications , Anxiety/psychology , Delayed-Action Preparations , Depressive Disorder, Major/complications , Depressive Disorder, Major/psychology , Diagnostic and Statistical Manual of Mental Disorders , Dibenzothiazepines/adverse effects , Double-Blind Method , Female , Humans , Male , Pain/complications , Pain/psychology , Psychiatric Status Rating Scales , Quetiapine Fumarate , Sleep Wake Disorders/complications , Sleep Wake Disorders/psychology
13.
Int Clin Psychopharmacol ; 29(1): 26-35, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24172160

ABSTRACT

Levomilnacipran (1S, 2R-milnacipran) is a potent and selective serotonin and norepinephrine reuptake inhibitor that is Food and Drug Administration approved for once-daily treatment of major depressive disorder in adults. Secondary and post-hoc analyses were carried out on data from a positive 10-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter, proof-of-concept trial (EudraCT Number: 2006-002404-34) on 75 or 100 mg/day levomilnacipran extended release (ER). Included outpatients (18-70 years) met the criteria for a major depressive episode. There was a statistically significant difference in favor of levomilnacipran ER versus placebo in change from baseline to week 10 on every Montgomery Åsberg Depression Rating Scale (MADRS) single item (mixed-effects model for repeated measures; P<0.05) and most Hamilton Depression Rating Scale (HAMD17) single items. Significantly more levomilnacipran ER versus placebo patients (P < 0.05) achieved 'complete' (MADRS ≤ 5; 24 vs. 10%) and 'sustained' (MADRS ≤ 10 in Weeks 4-10; 16 vs. 10%) remission, Sheehan Disability Scale (SDS) response (total score ≤ 12 and each item score ≤ 4; 52 vs. 35%) and remission (total score ≤ 6 and each item score ≤ 2; 26 vs. 17%), and combined symptomatic (MADRS) and functional (SDS) remission (19 vs. 8%). Treatment effects of similar magnitude were observed in the severe depression subgroup (MADRS ≥ 30). These results demonstrate the benefit of levomilnacipran ER over placebo for patients with symptomatic and functional impairment associated with major depressive disorder.


Subject(s)
Antidepressive Agents, Second-Generation/therapeutic use , Cyclopropanes/therapeutic use , Depressive Disorder, Major/drug therapy , Adolescent , Adult , Aged , Antidepressive Agents, Second-Generation/administration & dosage , Cyclopropanes/administration & dosage , Delayed-Action Preparations , Depressive Disorder, Major/psychology , Double-Blind Method , Female , Humans , Male , Middle Aged , Milnacipran , Prospective Studies , Psychiatric Status Rating Scales , Treatment Outcome , Young Adult
14.
J Affect Disord ; 151(1): 209-19, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23810357

ABSTRACT

BACKGROUND: Patients with treatment-resistant major depressive disorder (MDD) remain a common clinical challenge. METHODS: This 6-week, randomised, open-label, rater-blinded trial evaluated once-daily extended-release quetiapine fumarate (quetiapine XR; 300 mg/day) as add-on to ongoing antidepressant and quetiapine XR monotherapy (300 mg/day) compared with add-on lithium (0.6-1.2 mmol/L) in patients with treatment-resistant MDD. Primary efficacy measure: change in Montgomery Åsberg Depression Rating Scale (MADRS) total score from randomisation to week 6 with a pre-specified non-inferiority limit of 3 points on the MADRS. RESULTS: At week 6, both add-on quetiapine XR (n=231) and quetiapine XR monotherapy (n=228) were non-inferior to add-on lithium (n=229); least squares means (LSM) differences (97.5% CI) in MADRS total score changes were -2.32 (-4.6, -0.05) and -0.97 (-3.24, 1.31), respectively. LSM MADRS total score change was numerically greater at day 4 for both quetiapine XR groups (add-on and monotherapy; p<0.01) compared with add-on lithium. At week 6, the differences between groups for the secondary endpoints of MADRS response (≥ 50% reduction in total score), MADRS remission (total score ≤ 10, add-on quetiapine XR only) and Clinical Global Impressions ('much'/'very much' improved) were numerically similar. Overall tolerability was consistent with the known profiles of both treatments. LIMITATIONS: Limitations included the open-label study design (although MADRS and laboratory measurements were performed by treatment-blinded raters) and relatively short study duration with no assessments in the continuation phase. CONCLUSIONS: Add-on quetiapine XR (300 mg/day) and quetiapine XR monotherapy (300 mg/day) are non-inferior to add-on lithium in the management of patients with treatment-resistant MDD.


Subject(s)
Antidepressive Agents/administration & dosage , Antipsychotic Agents/administration & dosage , Depressive Disorder, Major/drug therapy , Depressive Disorder, Treatment-Resistant/drug therapy , Dibenzothiazepines/administration & dosage , Lithium Compounds/administration & dosage , Adolescent , Adult , Aged , Antidepressive Agents/therapeutic use , Antipsychotic Agents/therapeutic use , Delayed-Action Preparations , Dibenzothiazepines/therapeutic use , Drug Therapy, Combination , Female , Humans , Lithium/administration & dosage , Lithium/therapeutic use , Lithium Compounds/therapeutic use , Male , Middle Aged , Psychiatric Status Rating Scales , Quetiapine Fumarate , Treatment Outcome , Young Adult
15.
J Clin Psychiatry ; 74(4): 363-9, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23656841

ABSTRACT

OBJECTIVE: To investigate the efficacy and safety of levomilnacipran sustained release (SR), an antidepressant candidate in late-stage development, in major depressive disorder (MDD). METHOD: Between December 2006 and October 2007, a 10-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter, flexible-dose trial assessed once-daily levomilnacipran SR (75 mg or 100 mg) in outpatients (18-70 years) meeting DSM-IV criteria for a major depressive episode (duration ≥ 1 month) with a 17-item Hamilton Depression Rating Scale (HDRS17) score > 22 and Sheehan Disability Scale (SDS) score ≥ 10. Levomilnacipran SR dose was increased to 100 mg/d over 12 days. The primary efficacy measure was Montgomery Asberg Depression Rating Scale (MADRS) score change from baseline to week 10; secondary efficacy measures were the HDRS17, SDS, Clinical Global Impressions-Improvement scale, and MADRS response (≥ 50% decrease from baseline) and remission (score ≤ 10). Safety was evaluated according to adverse events, laboratory investigations, and vital signs/physical findings. RESULTS: Efficacy analyses included 276 levomilnacipran SR-treated patients and 277 placebo-treated patients. Levomilnacipran SR was significantly superior to placebo on MADRS total score change from baseline to week 10 (least squares mean difference [LSMD] = -4.2 [95% CI, -5.7 to -2.6]; P < .0001). Statistical significance in favor of levomilnacipran SR was demonstrated on change from baseline to week 10 in HDRS17 total score (LSMD = -3.4 [95% CI, -4.7 to -2.2]; P < .0001) and SDS total score (LSMD = -3.4 [95% CI, -4.6 to -2.2]; P < .0001) and subscales. Significantly more levomilnacipran SR patients versus placebo patients achieved MADRS response (59.1% vs 42.2%; P < .0001) and remission (46.4% vs 26.0%; P < .0001). Levomilnacipran SR was generally safe and well tolerated; more levomilnacipran SR patients (9.4%) versus placebo patients (6.5%) discontinued due to adverse events, but more placebo patients versus levomilnacipran SR patients discontinued overall (24.9% vs 20.2%). CONCLUSIONS: Levomilnacipran SR demonstrated robust efficacy on all measures and was generally well tolerated. TRIAL REGISTRATION: EudraCT number: 2006-002404-34


Subject(s)
Antidepressive Agents/administration & dosage , Cyclopropanes/administration & dosage , Depressive Disorder, Major/drug therapy , Adolescent , Adult , Aged , Antidepressive Agents/adverse effects , Cyclopropanes/adverse effects , Double-Blind Method , Female , Humans , Male , Middle Aged , Milnacipran , Severity of Illness Index , Treatment Outcome , Young Adult
16.
Int Clin Psychopharmacol ; 28(1): 12-9, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23023074

ABSTRACT

Pooled analysis of individual patient data was used to compare the antidepressant efficacy of agomelatine with that of selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs). We sought head-to-head, double-blind, randomized studies without a placebo arm using antidepressant doses in the licensed range and primary evaluation on the Hamilton scale (HAM-D(17)). Six studies were identified versus venlafaxine, sertraline, fluoxetine, paroxetine or escitalopram. Estimates of differences between treatments were calculated on parameters expressed as the last postbaseline value (6, 8 or 12 weeks). A total of 2034 patients were randomized (age 47.6 ± 14.9 years; 73% women; HAM-D(17) total score 26.9 ± 3.0). The full analysis set included 1997 patients (1001 agomelatine; 996 SSRI/SNRI). There was a significant difference between HAM-D(17) total scores, with a greater reduction with agomelatine than with SSRI/SNRI [E(SE), 0.86 (0.35), 95% confidence interval 0.18-1.53, P=0.013], and better rates of response on the HAM-D(17) (P=0.012) and the Clinical Global Impression-Improvement scales (P=0.032). Similar results were found in patients with severe depression. Agomelatine was associated with better tolerability than SSRI/SNRI. Agomelatine has favourable efficacy and tolerability versus a range of SSRIs and SNRIs - including agents considered to have superior efficacy - and may deserve benefit-risk analysis as a first-line treatment of major depressive disorder.


Subject(s)
Acetamides/therapeutic use , Adrenergic Uptake Inhibitors/therapeutic use , Antidepressive Agents/therapeutic use , Depressive Disorder, Major/drug therapy , Selective Serotonin Reuptake Inhibitors/therapeutic use , Acetamides/adverse effects , Adrenergic Uptake Inhibitors/adverse effects , Adult , Antidepressive Agents/adverse effects , Depressive Disorder, Major/diagnosis , Depressive Disorder, Major/psychology , Female , Humans , Male , Middle Aged , Randomized Controlled Trials as Topic , Selective Serotonin Reuptake Inhibitors/adverse effects , Time Factors , Treatment Outcome
17.
Int Clin Psychopharmacol ; 27(5): 249-55, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22869009

ABSTRACT

The aim of this study was to evaluate, in patients with coronary artery disease (CAD), factor structure and psychometric properties of the Montgomery Åsberg Depression Rating Scale (MADRS) to identify patients with current major depressive episode (MDE). The construct validity of the MADRS against self-rating scales was also evaluated. Consecutive 522 CAD patients at admission to the cardiac rehabilitation program were interviewed for the severity of depressive symptoms using the MADRS and for current MDE using the structured MINI International Neuropsychiatric Interview. Also, all patients completed the Hospital Anxiety and Depression Scale and the Beck Depression Inventory-II. The MADRS had one-factor structure and high internal consistency (Cronbach's coefficient α=0.82). Confirmative factor analysis indicated an adequate fit: comparative fit index=0.95, normed fit index=0.91, and root mean square error of approximation=0.07. At a cut-off value of 10 or higher, the MADRS had good psychometric properties for the identification of current MDE (positive predictive value=42%, with sensitivity=88% and specificity=85%). There was also a moderate to strong correlation of MADRS scores with scores on self-rating depression scales. In sum, in CAD patients undergoing rehabilitation, the MADRS is a unidimensional instrument with high internal consistency and can be used for the identification of depressed CAD patients. The association between MADRS and self-rating depression scores is moderate to strong.


Subject(s)
Coronary Artery Disease/psychology , Coronary Artery Disease/rehabilitation , Depressive Disorder, Major/complications , Depressive Disorder, Major/diagnosis , Aged , Angina Pectoris/psychology , Angina Pectoris/rehabilitation , Anxiety/complications , Anxiety/diagnosis , Cohort Studies , Cross-Sectional Studies , Depression/complications , Depression/diagnosis , Depressive Disorder, Major/epidemiology , Depressive Disorder, Major/physiopathology , Female , Hospitals, University , Humans , Lithuania/epidemiology , Male , Middle Aged , Myocardial Infarction/psychology , Myocardial Infarction/rehabilitation , Prevalence , Psychiatric Status Rating Scales , Self Report , Sensitivity and Specificity , Severity of Illness Index
18.
Int Clin Psychopharmacol ; 27(1): 27-39, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22027845

ABSTRACT

Prospectively planned pooled analysis evaluating the efficacy of quetiapine extended release (XR) monotherapy in major depressive disorder (MDD). Data were pooled from two 6-week, randomized, double-blind, placebo-controlled studies of quetiapine XR in outpatients with MDD. The primary endpoint was Montgomery-Åsberg Depression Rating Scale (MADRS) total score change from randomization at week 6. Other evaluations were MADRS response/remission, Hamilton Rating Scale for Anxiety, and subgroup analyses. A total of 968 patients were randomized to quetiapine XR, 150 mg/day (n=315), 300 mg/day (n=323), or placebo (n=330). The mean MADRS total score reductions from randomization were significant at week 6 with quetiapine XR, 150 mg/day (-14.7; P<0.001) and 300 mg/day (-14.7; P<0.001) versus placebo (-11.1), with significant reductions versus placebo from week 1 onward. Response rates (week 6): 52.7% (P<0.001) quetiapine XR 150 mg/day and 49.5% (P<0.001) quetiapine XR 300 mg/day versus placebo (33.0%). MADRS remission (score≤8; week 6): 23.5% (P=0.208) quetiapine XR 150 mg/day and 28.8% (P<0.01) quetiapine XR 300 mg/day versus placebo (19.4%). Quetiapine XR (both doses) significantly improved eight of 10 MADRS items versus placebo at week 6. The therapeutic effect of quetiapine XR was neither limited to nor driven by factors such as sex, age, or severity of depression. In patients with MDD, quetiapine XR (150 and 300 mg/day) monotherapy reduced depressive symptoms, with significant improvements compared with placebo from week 1 onward.


Subject(s)
Antidepressive Agents/therapeutic use , Depressive Disorder, Major/drug therapy , Dibenzothiazepines/therapeutic use , Adolescent , Adult , Aged , Antidepressive Agents/adverse effects , Clinical Trials, Phase III as Topic , Delayed-Action Preparations , Depressive Disorder, Major/diagnosis , Depressive Disorder, Major/psychology , Dibenzothiazepines/adverse effects , Double-Blind Method , Female , Humans , Logistic Models , Male , Middle Aged , Multicenter Studies as Topic , Placebos , Predictive Value of Tests , Prospective Studies , Psychiatric Status Rating Scales , Quetiapine Fumarate , Randomized Controlled Trials as Topic , Time Factors , Treatment Outcome , United States , Young Adult
19.
World J Biol Psychiatry ; 11(1): 36-44, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20146649

ABSTRACT

OBJECTIVE: To examine suicidal behaviour risk in the short-term placebo-controlled studies of mirtazapine in Major Depressive Disorder (MDD). METHOD: Longitudinal Generalized Estimating Equations analyses were performed on pooled data from 15 placebo-controlled, randomized, double-blind, short-term trials of mirtazapine, using the suicide item scores from the Hamilton Depression Rating Scale (HAMD) as a proxy outcome measure for suicidality risk. RESULTS: The overall analysis using the convention that a patient is at risk if the HAMD suicide item score is > or =3, and excluding patients at risk at baseline, demonstrated a statistically significantly lower risk for mirtazapine- compared to placebo-treated patients on the HAMD (odds ratio mirtazapine versus placebo 0.38; 95% confidence interval 0.21-0.66; P= 0.0008). CONCLUSION: Our results based on pooled data from 15 placebo-controlled, short-term studies of mirtazapine in MDD using the suicide item scores from the HAMD as a proxy outcome measure for suicidality risk, demonstrate that mirtazapine was associated with statistically significantly lower suicidality risk compared to placebo.


Subject(s)
Antidepressive Agents, Tricyclic/therapeutic use , Depressive Disorder, Major/drug therapy , Mianserin/analogs & derivatives , Suicide, Attempted/psychology , Suicide, Attempted/statistics & numerical data , Adult , Depressive Disorder, Major/diagnosis , Diagnostic and Statistical Manual of Mental Disorders , Double-Blind Method , Female , Follow-Up Studies , Humans , Male , Mianserin/therapeutic use , Mirtazapine , Placebo Effect , Severity of Illness Index
20.
J Clin Psychopharmacol ; 30(1): 18-24, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20075643

ABSTRACT

OBJECTIVES: To compare the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) with placebo in reducing relapse rate in patients with major depressive disorder (MDD). METHODS: This phase 3, multicenter, randomized trial included a 12-week, open-label (OL) treatment phase (intent-to-treat population, n = 575) followed by a 6-month, double-blind (DB) relapse prevention phase. Patients who responded to the OL treatment (17-item Hamilton Rating Scale for Depression total score or= 16 at any visit, Clinical Global Impression-Improvement score >or= 6 at any visit, or discontinuation due to unsatisfactory response). RESULTS: Patients receiving desvenlafaxine (n = 189) experienced significantly longer times to relapse of MDD versus patients receiving placebo (n = 185) during the DB period (log-rank test, P < 0.0001). The percentages of patients relapsing were 42% (78/185) and 24% (45/189) for placebo and desvenlafaxine, respectively (P < 0.001). The most common primary reason cited for discontinuation in the OL period was adverse events (19%), which consisted of nausea, dizziness, and insomnia. A total of 159 patients (42%) discontinued treatment during the DB period, including 101 placebo- (55%) and 58 desvenlafaxine-treated patients (31%). The most frequent adverse event reported as reason for treatment discontinuation in the DB period was depression, reported by 14 placebo- (8%) and 7 desvenlafaxine-treated patients (4%). CONCLUSIONS: Desvenlafaxine effectively prevented relapse of MDD during 6 months of DB treatment in patients who had responded to 12 weeks of OL desvenlafaxine therapy.


Subject(s)
Antidepressive Agents/therapeutic use , Cyclohexanols/therapeutic use , Depressive Disorder, Major/drug therapy , Adult , Antidepressive Agents/adverse effects , Cyclohexanols/adverse effects , Depressive Disorder, Major/prevention & control , Depressive Disorder, Major/psychology , Desvenlafaxine Succinate , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Male , Psychiatric Status Rating Scales , Secondary Prevention , Treatment Outcome
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