Efficacy of risperidone augmentation to antidepressants in the management of suicidality in major depressive disorder: a randomized, double-blind, placebo-controlled pilot study. Placebo-controlled study of relapse prevention with risperidone augmentation in older patients with resistant depression. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression. Amisulpride versus imipramine and placebo in dysthymia and major depression. Amisulpride Study Group. Faster response on amisulpride 50 mg versus sertraline 50-100 mg in patients with dysthymia or double depression: a randomized, double-blind, parallel group study. Amisulpride versus fluoxetine in patients with dysthymia or major depression in partial remission: a double-blind, comparative study. Amisulpride versus amineptine and placebo for the treatment of dysthymia. Quetiapine adjunct to selective serotonin reuptake inhibitors or venlafaxine in patients with major depression, comorbid anxiety, and residual depressive symptoms: a randomized, placebo-controlled pilot study. Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance. Efficacy and safety of amisulpride 50 mg versus paroxetine 20 mg in major depression: a randomized, double-blind, parallel group study. A novel augmentation strategy for treating resistant major depression. A double-blind, randomized study of olanzapine and olanzapine/fluoxetine combination for major depression with psychotic features. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, and fluoxetine in treatment-resistant major depressive disorder. Amisulpride in medium-term treatment of dysthymia: a six-month, double-blind safety study versus amitriptyline. AMILONG investigators. Aripiprazole augmentation in major depressive disorder: a double-blind, placebo-controlled study in patients with inadequate response to antidepressants. Extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in major depressive disorder (MDD) in patients with an inadequate response to ongoing antidepressant treatment: a multicentre, randomized, double-blind, placebo-controlled study. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a second multicenter, randomized, double-blind, placebo-controlled study. Risperidone for treatment-refractory major depressive disorder: a randomized trial. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. Extended release quetiapine fumarate monotherapy in major depressive disorder: a placebo- and duloxetine-controlled study. A randomized, placebo-controlled trial of risperidone augmentation for patients with difficult-to-treat unipolar, non-psychotic major depression.
Major depressive disorder (MDD) is a severe mental illness with high risk of suicidality. Antidepressant treatment alone is not sufficient for the acute management of risk-taking symptoms of depression. This pilot study was designed to investigate the efficacy of risperidone augmentation to antidepressants in the acute management of suicidality and other core symptoms in MDD with suicidality.
                Twenty-four adult men and women diagnosed with MDD (DSM-IV), having a depressive episode with suicidality despite taking an antidepressant, were enrolled in an 8-week double-blind, placebo-controlled study. Subjects were randomly assigned to receive risperidone (0.25-2 mg/day) or placebo while continuing on their antidepressant therapy. Clinical efficacy in suicidality, depressive symptoms, and impulsivity were assessed after treatment with study drugs for 4 days, weekly for 4 weeks, then every other week for 4 weeks. Adverse events were also recorded at each visit. The study was conducted from June 2004 to April 2007.
                Risperidone significantly reduced suicidal ideations in MDD patients, and the overall effect of risperidone appeared to be superior to placebo. The effect of risperidone was rapid, with onset at 2 weeks' treatment, and was sustained along the course of 8 weeks' treatment. Furthermore, risperidone demonstrated superiority to placebo in improving other symptoms related to suicidality and having better trial completion rate, and the low dose risperidone was well tolerated by subjects in this study.
                Data from this pilot study suggest that risperidone is beneficial as an augmenting treatment in MDD patients who have developed high-risk suicidal ideation during a depressive episode. The antisuicidality effect of risperidone is especially valuable in the acute management of severe depressive symptoms. Although the pilot study is limited by small sample size, the promising results warrant further larger scale investigation in the efficacy of atypical antipsychotics in the treatment of severe depression with suicidality.
                clinicaltrials.gov Identifier: NCT00167154. The effect of risperidone augmentation of citalopram for relapse prevention in older patients with antidepressant-resistant depression was evaluated.
                Patients with major depression aged > or =55 years who had failed at least one adequate trial of an antidepressant received citalopram monotherapy (20-40 mg) for 4 to 6 weeks to confirm nonresponse (<50% reduction in Hamilton Rating Scale for Depression [HAM-D] scores). Those who achieved remission (HAM-D score < or =7 or Clinical Global Impressions severity score 1 or 2) after 4 to 6 weeks of open-label risperidone augmentation (0.25-1 mg) then entered a 24-week double-blind maintenance phase during which they received citalopram augmented with risperidone or placebo.
                The patients' mean age was 63.4 +/- 7.9 years; 58% were women; 61% had received two or more antidepressants during the current episode; 93 met the criterion for citalopram nonresponse and entered open-label risperidone augmentation. Of the 89 patients who completed risperidone augmentation, 63 achieved symptom resolution and entered the 6-month double-blind maintenance phase: 32 received risperidone augmentation and 31 received placebo augmentation. The median time to relapse (Kaplan-Meier estimates) was 105 days in the risperidone group and 57 days in the placebo group (Wilcoxon chi(2): 3.2, df = 1, p = 0.069). Overall, 18 of 32 (56%) from the risperidone group and 20 of 31 (65%) from the placebo group relapsed. Treatment was well tolerated.
                In older patients with resistant depression and poor response to standard treatments, risperidone augmentation resulted in symptom resolution in a substantial number of patients and a nonsignificant delay in time to relapse. Based on preliminary evidence of its usefulness in treatment-resistant depression (TRD), an olanzapine/fluoxetine combination (OFC) was examined in comparison with olanzapine, fluoxetine, and venlafaxine in a TRD population. In this 12-week double-blind study, 483 subjects with unipolar, nonpsychotic TRD, with historic failure on a selective serotonin reuptake inhibitor (SSRI) and prospective failure on open-label venlafaxine, were randomized to an OFC or to an olanzapine, fluoxetine, or venlafaxine monotherapy group. Venlafaxine was continued randomly in the double-blind acute phase to explore the benefits of continuation versus switching therapy. The Montgomery-Asberg Depression Rating Scale (MADRS) total change score at end point was the primary outcome measure. The OFC group had significantly greater improvement in depressive symptoms by week 1 of treatment (MADRS mean change =-7.2, baseline =29.6), in comparison to olanzapine (-4.8, P=.03), fluoxetine (-4.7, P=.03), or venlafaxine (-3.7, P=.002) groups and maintained its statistical separation from all three monotherapy groups through week 6. At end point, the OFC group was significantly different only from the olanzapine group (-14.1 vs. -7.7, P<.001). Analysis of a subgroup of subjects who had an SSRI failure in their current depressive episode (n=334) revealed statistical separation from both olanzapine and fluoxetine (but not venlafaxine) at end point: OFC (-14.6) versus olanzapine (-9.4, P<.001) versus fluoxetine (-10.7, P=.006) versus venlafaxine (-14.7, P=.98). The OFC had a safety profile comparable to its component monotherapies (i.e., olanzapine and fluoxetine), showed a rapid onset of antidepressant effect, and was effective in this TRD sample. At the study end point, OFC, fluoxetine, venlafaxine, and low-dose OFC all appeared to be similarly effective. Amisulpride, a selective antagonist of D2 and D3 dopamine receptors, acts preferentially on presynaptic receptors increasing dopaminergic transmission at low doses. In a multicentre, 6 months, placebo-controlled trial, amisulpride (50 mg/daily) was compared to imipramine (100 mg/daily) in the treatment of patients with DSM-III-R criteria for primary dysthymia, dysthymia with major depression or major depression in partial remission. A total of 219 patients were included. Both analyses (intention-to-treat and "per protocol' analysis) detected significant differences between groups (active treatment vs. placebo) on all main rating scales (CGI, MADRS, ERD, and SANS). The number of patients reporting at least one adverse event was higher in the imipramine group than in the two other, mainly due to anticholinergic effects. Endocrine symptoms were more frequent in female patients treated with amisulpride. These results confirm the interest of a drug acting on dopaminergic transmission such as amisulpride in the treatment of depressed patients. Amisulpride (50 mg o.d.) was compared with sertraline (50-100 mg o.d.) for 12 weeks in a double-blind, parallel-group study in 313 outpatients with dysthymia (DSM-IV +/- episode of major depression). Full response rate [> or = 50% decrease in Hamilton Depression Rating Scale (HAMD) total score] was higher with amisulpride after 4 weeks (63% versus 50%, P < 0.02) and 8 weeks (82% versus 69%, P < 0.009). Time to initial improvement (> or = 25% decrease in HAMD total score) and to > or = 50% HAMD decrease were significantly shorter with amisulpride (P < 0.0033 and P < 0.0080, respectively). A faster response was also present in the subgroup of patients with pure dysthymia. The improvement in HAMD, Montgomery and Asberg Depression Rating Scale and Social and Occupational Assessment Scale total scores, as well as Clinical Global Impression improvement, was significantly greater with amisulpride after 4 weeks. Both drugs were equally effective at week 12. The tolerability of both drugs was satisfactory. Amisulpride is significantly more effective than sertraline during the first weeks of treatment in dysthymia. In a multicentre, double blind, parallel group study 281 patients with DSM III-R diagnosis of dysthymia or a single episode of major depression in partial remission were randomised to 3 months of treatment with amisulpride 50 mg/day or fluoxetine 20 mg/day. The baseline Montgomery and Asberg Depression Rating Scale (MADRS) total score was reduced by at least 50% in 74.1% of patients (103/139) with amisulpride and 67.4% (87/129) with fluoxetine (P =0.230). No significant differences between treatment groups were found in the reductions in mean total score with the MADRS, Widlöcher psychomotor retardation scale, Sheehan disability scale, and CGI. Anxiety measured by HAM-A total mean score decreased significantly more with amisulpride (63%) than with fluoxetine (54%; P = 0.021). There were 13 dropouts due to adverse events with amisulpride and ten with fluoxetine. The number of patients reporting at least one adverse event was similar in the two groups (amisulpride 47.5%; fluoxetine 40.9%). As expected, in the amisulpride group endocrine-like adverse events in female patients were the most common, while nausea, dyspepsia, anorexia and insomnia occurred more frequently with fluoxetine. Amisulpride, a selective antagonist for D2 and D3 dopamine receptors, acts preferentially on presynaptic receptors increasing dopaminergic transmission at low doses. In a multicentre, 3-month, placebo-controlled study, amisulpride (50 mg/day) was compared to amineptine (200 mg/day) in the treatment of primary dysthymia. A total of 323 patients were enrolled. Amisulpride and amineptine were found to be statistically superior to placebo (p < 0.0001) on the Clinical Global Impression (item 2): 63, 64 and 33% responders, respectively; improvement of Montgomery-Asberg Depression Rating Scale and Scale for the Assessment of Negative Symptoms scores following amisulpride or amineptine treatment was twice as high as with placebo (p < 0.0001). The adverse event profile of amisulpride was similar to that of placebo except for endocrine symptoms in female patients; amineptine showed mainly events linked to psychic activation (insomnia, nervousness). Results show that amisulpride can improve symptoms of chronic depression in dysthymia. This double-blind, placebo-controlled study examined the efficacy and tolerability of quetiapine in combination with selective serotonin reuptake inhibitors (SSRIs)/venlafaxine in 58 patients with major depressive disorder, comorbid anxiety symptoms (HAM-A-14 score > or =14), and residual depressive symptoms (HAM-D-17 score > or =18, CGI-S score > or =4). Patients had received an SSRI/venlafaxine (at a predefined therapeutic dose) for > or =6 weeks. Overall, 62% (18/29) of quetiapine- and 55% (16/29) of placebo-treated patients completed the study. The mean change in HAM-D and HAM-A total scores from baseline to Week 8 (primary endpoint) was significantly greater with quetiapine (mean dose 182 mg/day) than placebo: -11.2 vs. -5.5 (P=.008) and -12.5 vs. -5.9 (P=.002), respectively. The onset of quetiapine efficacy (HAM-D/HAM-A/CGI-I) was rapid (by Week 1) and continued through to Week 8. Significant differences (P<.05) from baseline to Week 8 were observed between groups in 7/17 HAM-D (including feelings of guilt, suicide) and 6/14 HAM-A items (including tension, cardiovascular symptoms). Response (> or =50% decrease in total score) was higher for quetiapine than placebo: HAM-D, 48% vs. 28% (not significant, NS); HAM-A, 62% vs. 28% (P=.02). Remission (total score < or =7) was higher for quetiapine than placebo: HAM-D, 31% vs. 17% (NS); HAM-A, 41% vs. 17% (NS). CGI-S, CGI-I, and the Global Assessment Scale showed that quetiapine was significantly more effective than placebo. For quetiapine, adverse events (AEs) were similar to those previously observed; sedation/somnolence/lethargy was the most commonly reported. Here quetiapine was shown to be effective as augmentation of SSRI/venlafaxine therapy in patients with major depression, comorbid anxiety, and residual depressive symptoms, with no unexpected tolerability issues. Further studies are warranted.
                2006 Wiley-Liss, Inc This 8-week, double-blind, multicenter study was undertaken to replicate, in a larger sample of patients with treatment-resistant major depressive disorder (MDD; DSM-IV criteria), the results of a pilot study of the olanzapine/fluoxetine combination.
                The study was begun in August 1999. The primary entry criterion was a history of failure to respond to a selective serotonin reuptake inhibitor (SSRI). Patients (N = 500) who subsequently failed to respond to nortriptyline during an open-label lead-in phase were randomly assigned to 1 of 4 treatment groups: olanzapine (6-12 mg/day) plus fluoxetine (25-50 mg/day) combination, olanzapine (6-12 mg/day), fluoxetine (25-50 mg/day), or nortriptyline (25-175 mg/day). The primary outcome measure was baseline-to-endpoint mean change in score on the Montgomery-Asberg Depression Rating Scale (MADRS).
                At the 8-week study endpoint, MADRS total scores decreased by a mean 8.7 points from baseline (28.5) with the olanzapine/fluoxetine combination, 7.0 points from baseline (28.4) with olanzapine (p = .08), 8.5 points from baseline (28.4) with fluoxetine (p = .84), and 7.5 points from baseline (28.8) with nortriptyline (p = .30), with no significant differences among the therapies. The olanzapine/fluoxetine combination was associated with significantly (p < or = .05) greater improvement (decrease) in MADRS scores than olanzapine at weeks 2, 4, 6, and 7; than fluoxetine at weeks 2 through 5; and than nortriptyline at weeks 1 through 4. A post hoc analysis of a subgroup of patients who had an SSRI treatment failure during their current MDD episode (N = 314) revealed that the olanzapine/fluoxetine combination group had a significantly (p = .005) greater decrease in MADRS scores than the olanzapine group at endpoint. Safety data for the olanzapine/fluoxetine combination were similar to those for its component monotherapies.
                The olanzapine/fluoxetine combination did not differ significantly from the other therapies at endpoint, although it demonstrated a more rapid response that was sustained until the end of treatment. The results raised several methodological questions, and recommendations are made regarding the criteria for study entry and randomization. The efficacy of amisulpride in depressive disorders has been demonstrated in dysthymia and in double depression. Limited data are available in major depression. A randomized, double-blind, parallel group, multicentre study was set up to compare the efficacy and tolerability of amisulpride (50 mg o.d.) and paroxetine (20 mg o.d.) for 8 weeks in 272 patients with major depression (DSM-IV and baseline Hamilton Depression Rating Scale (HAMD) score > or = 18). The study was designed as a non-inferiority trial based on the proportion of responders (> or = 50% decrease in HAMD total score) at end-point, with a maximal allowable difference of 15%; secondary end-points included HAMD total and cluster scores, Montgomery and Asberg Depression Rating Scale score and responders rates and Clinical Global Impression improvement. The tolerability evaluation was based on incidence of adverse events and routine laboratory tests. The results did not disclose statistically significant differences between treatments, although the hypothesis of an efficacy difference between the two treatments within the set limit at day 56 could not be accepted. The issue of non-inferiority trials is discussed. Treatment-resistant depression is a significant public health concern; drug switching or augmentation often produce limited results. The authors hypothesized that fluoxetine could be augmented with olanzapine to successfully treat resistant depression.
                An 8-week double-blind study was conducted with 28 patients who were diagnosed with recurrent, nonbipolar, treatment-resistant depression without psychotic features. Subjects were randomly assigned to one of three groups: olanzapine plus placebo, fluoxetine plus placebo, or olanzapine plus fluoxetine.
                Fluoxetine monotherapy produced minimal improvement on various scales that rate severity of depression. The benefits of olanzapine monotherapy were modest. Olanzapine plus fluoxetine produced significantly greater improvement than either monotherapy on one measure and significantly greater improvement than olanzapine monotherapy on the other measures after 1 week. There were no significant differences between treatment groups on extrapyramidal measures nor significant adverse drug interactions.
                Olanzapine plus fluoxetine demonstrated superior efficacy for treating resistant depression compared to either agent alone. The purpose of this study was to compare the efficacy and safety of olanzapine (OLZ) monotherapy and an olanzapine/fluoxetine combination (OFC) with placebo (PLA) for unipolar major depression with psychotic features. Under a single protocol, two 8-week, double-blind trials were conducted at 27 sites. Patients (n = 124 trial 1, n = 125 trial 2) were randomized to 1 of 3 treatment groups: OLZ (5 to 20 mg/d), PLA, or OFC (olanzapine 5 to 20 mg/d + fluoxetine 20 to 80 mg/d). The primary outcome measure was the 24-item Hamilton Depression Rating Scale total score. For trial 1, endpoint improvement for the OLZ group (-14.9) was not significantly different from the PLA or OFC groups. The OFC group had significantly greater endpoint improvement (-20.9) than the PLA group (-10.4, P = 0.001); this significant difference was present within 7 days of therapy and maintained at every subsequent visit. The OFC group also had significantly higher response rate (63.6%) than the PLA (28.0%, P = 0.004) or OLZ (34.9%, P = 0.027) groups. For trial 2, there were no significant differences among treatment groups on the 24-item Hamilton Depression Rating Scale total scores or response rates. The combination exhibited a comparable safety profile with OLZ monotherapy and no significant increases in extrapyramidal symptoms compared with placebo. Patients with major depression with psychotic features treated with OLZ monotherapy did not demonstrate significant depressive symptom improvement compared with placebo in either trial; however, an olanzapine/fluoxetine combination was associated with significant improvement compared with placebo in one trial and was well tolerated.
                Copyright 2004 Lippincott Williams and Wilkins Two parallel, 8-week double-blind studies compared olanzapine/fluoxetine combination, olanzapine, and fluoxetine in outpatients with treatment-resistant depression (TRD).
                Treatment-resistant depression was defined as a documented history of current-episode antidepressant failure plus a prospective failure on fluoxetine. Following an 8-week fluoxetine lead-in, 605 nonresponders with DSM-IV major depressive disorder were randomly assigned to olanzapine/fluoxetine combination, olanzapine, or fluoxetine. The primary outcome measure was baseline-to-endpoint mean change on the Montgomery-Asberg Depression Rating Scale (MADRS). The study was conducted from April 2002 to May 2005.
                After 8 weeks of double-blind treatment, Study 1 revealed no statistically significant therapy differences in MADRS mean change (olanzapine/fluoxetine combination: -11.0, fluoxetine: -9.4, olanzapine: -10.5). In Study 2, olanzapine/fluoxetine combination demonstrated significantly greater MADRS improvement (-14.5) than fluoxetine (-8.6, p < .001) and olanzapine (-7.0, p < .001). Pooled study results revealed significant differences for olanzapine/ fluoxetine combination (-12.7) versus fluoxetine (-9.0, p < .001) and olanzapine (-8.8, p < .001). Pooled remission rates were 27% for olanzapine/ fluoxetine combination, 17% for fluoxetine, and 15% for olanzapine. Adverse events were consistent with previous studies. Cholesterol mean change (mg/dL) was +15.1 for olanzapine/ fluoxetine combination, +0.8 for fluoxetine, and +2.7 for olanzapine. Mean weight change (kg) was +4.9 for olanzapine/fluoxetine combination, +0.4 for fluoxetine, and +5.5 for olanzapine. Nonfasting glucose mean change (mg/dL) was +11.4 for olanzapine/fluoxetine combination, +4.9 for fluoxetine, and +9.9 for olanzapine.
                Patients with TRD (defined as treatment failure on 2 antidepressants) taking olanzapine/fluoxetine combination demonstrated significantly greater improvement in depressive symptoms than patients taking olanzapine or fluoxetine in 1 of 2 studies and in the pooled analysis. When considered within the context of all available evidence, olanzapine/fluoxetine combination is an efficacious therapy for patients with TRD.
                ClinicalTrials.gov identifier: NCT00035321. Two hundred and fifty patients participated in a 6-month, double-blind study to evaluate safety and efficacy of a medium-term treatment with amisulpride 50 mg/day versus amitriptyline 25-75 mg/day in dysthymia. Patients in treatment groups (165 amisulpride; 85 amitriptyline) were well balanced for demographic and baseline characteristics. A total of 139 patients (93 amisulpride, 46 amitriptyline) completed the study with no statistically significant differences in reasons for premature termination between the two groups. A tendency towards a higher incidence of treatment-emergent adverse events with amitriptyline was observed (73% versus 64% amisulpride). In the amitriptyline group, a statistically significantly higher incidence of central nervous system (41% versus 24%, p=0.004) and autonomic nervous system disorders (45% versus 16%, p < 0.0001) was reported. Conversely, endocrine disorders were more frequent with amisulpride (18% versus 7%, p=0.023). Efficacy was a secondary end-point. Results of the symptom rating scales indicate that both drugs were equally effective: 60% and 62% of patients under amisulpride and amitriptyline, respectively, achieved a reduction > or = 50% of the Montgomery and Asberg Rating Scale total score at end-point. On the item 'global improvement' of the Clinical Global Impression, 67% of amisulpride and 68% of amitriptyline patients were rated as 'very much' or 'much' improved. Results of the present study in a large patient population further confirm the safe use of amisulpride in dysthymia and support its administration upon a medium-term treatment period. Effective management of major depressive disorder (MDD) continues to be a challenging task for psychiatrists and primary care physicians. This trial evaluated the efficacy and safety of adjunctive aripiprazole versus antidepressant monotherapy in patients with MDD and independently replicated the positive findings of two similar trials.
                Patients (N=1,147) with MDD experiencing a major depressive episode and a history of inadequate response to antidepressant monotherapy were enrolled (week 0); 827 received single-blind adjunctive placebo plus open-label antidepressant (escitalopram, fluoxetine, paroxetine controlled release, sertraline, or venlafaxine extended release) for 8 weeks to confirm inadequate response to antidepressants; 349 patients with inadequate response were randomized (1:1) to double-blind, adjunctive placebo (n=172) or adjunctive aripiprazole (n=177; 2-20 mg/day). Primary outcome was the mean change in Montgomery-Asberg Depression Rating Scale (MADRS) Total score from baseline (week 8) to endpoint (week 14).
                Clinically significant improvements in depressive symptoms as assessed by decreases in the MADRS Total score were greater with adjunctive aripiprazole (-10.1) than placebo (-6.4; P<.001). Remission rates were greater for adjunctive aripiprazole than for adjunctive placebo (week 14, 36.8% vs 18.9%; P<.001). Completion rates with adjunctive aripiprazole and placebo were high (83% vs. 87%) and discontinuations due to adverse events were low (6.2% vs 1.7%).
                For some patients with MDD who do not obtain adequate symptom relief with antidepressant monotherapy, adjunctive therapies can significantly improve depressive symptoms. As reported, adjunctive aripiprazole was associated with a two-fold higher remission rate than adjunctive placebo. This, and previous studies, have shown that discontinuations due to adverse events were low and completion rates were high, and has indicated that both antidepressant and aripiprazole in combination were relatively well-tolerated and safe. This is the third consecutive clinical trial, in the absence of a failed trial, to demonstrate that aripiprazole augmentation to antidepressants is an efficacious and well-tolerated treatment for patients with MDD who do not respond adequately to standard antidepressant monotherapy (ClinicalTrials.gov study NCT00105196). This study evaluated once-daily extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in patients with major depressive disorder (MDD) with inadequate response to ongoing antidepressant treatment. In this 8-wk (6-wk active treatment/2-wk post-treatment drug-discontinuation/follow-up), multicentre, double-blind, placebo-controlled, Phase III study, 446 patients were randomized to quetiapine XR 150 mg/d, 300 mg/d, or placebo adjunct to ongoing antidepressant treatment. The primary endpoint was the change from randomization to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score. At week 6, MADRS total scores significantly improved with quetiapine XR 300 mg/d vs. placebo (-14.7 vs. -11.7, p<0.01). Quetiapine XR 300 mg/d showed significant improvements vs. placebo for: MADRS total score from week 1 onwards; MADRS response [(> or = 50% total score reduction) 58.9% vs. 46.2%, p<0.05] and remission [(total score < or = 8) 42.5% vs. 24.5%, p<0.01] rates; Hamilton Depression Rating Scale (HAMD) (-13.53 vs. -10.80, p<0.01) and Clinical Global Impression-Severity of illness (CGI-S) change (-1.52 vs. -1.23, p<0.05) at week 6. For quetiapine XR 150 mg/d, improvements were not significantly different vs. placebo, except for MADRS (weeks 1 and 2) and HAMD (week 6) total scores. Withdrawal rates due to adverse events (AEs) were: quetiapine XR 150 mg/d 11.5%, 300 mg/d 19.5%, and placebo 0.7%. The most common AEs (>10%) with quetiapine XR were dry mouth, somnolence, sedation, dizziness, constipation, nausea, insomnia, headache, and fatigue. In this study, quetiapine XR 300 mg/d as adjunctive therapy in patients with MDD with an inadequate response to ongoing antidepressant treatment was effective at week 6. However, the difference from placebo for quetiapine XR 150 mg/d at week 6 was not statistically significant. Both doses studied (150 and 300 mg/d) were effective at week 1 and generally well tolerated. Nonresponse to one or more antidepressants is common and an important public health problem. This study evaluated the efficacy and safety of adjunctive aripiprazole or placebo to standard antidepressant therapy (ADT) in patients with major depressive disorder who showed an inadequate response to at least 1 and up to 3 historical and 1 additional prospective ADT. The study comprised a 7-28-day screening, an 8-week prospective treatment, and a 6-week randomization phase. During prospective treatment, patients experiencing a major depressive episode (17-item Hamilton Rating Scale for Depression total score > or = 18) received single-blind adjunctive placebo plus clinicians' choice of ADT (escitalopram, fluoxetine, paroxetine controlled-release, sertraline, or venlafaxine extended-release). Subjects with inadequate response were randomized to adjunctive placebo (n = 190) or adjunctive aripiprazole (n = 191) (starting dose 5 mg/d, dose adjustments 2-20 mg/d, mean end-point dose of 11.0 mg/d). The primary efficacy endpoint was the mean change in Montgomery-Asberg Depression Rating Scale total score from end of prospective treatment phase to end of randomized treatment phase (last observation carried forward). Mean change in Montgomery-Asberg Depression Rating Scale total score was significantly greater with adjunctive aripiprazole than placebo (-8.5 vs -5.7; P = 0.001). Remission rates were significantly greater with adjunctive aripiprazole than placebo (25.4% vs 15.2%; P = 0.016) as were response rates (32.4% vs 17.4%; P < 0.001). Adverse events occurring in 10% of patients or more with adjunctive placebo or aripiprazole were akathisia (4.2% vs 25.9%), headache (10.5% vs 9.0%), and fatigue (3.7% vs 10.1%). Incidence of adverse events leading to discontinuation was low (adjunctive placebo [1.1%] vs adjunctive aripiprazole [3.7%]). Aripiprazole is an effective and safe adjunctive therapy as demonstrated in this short-term study for patients who are nonresponsive to standard ADT. Major depressive disorder has high prevalence, morbidity, and mortality. Inadequate results with antidepressants have prompts addition of a nonstandard treatment (augmentation therapy).
                To assess whether augmentation therapy with risperidone reduces symptoms and increases response to antidepressant therapy and remission of depression in adults.
                Multicenter, double-blind, placebo-controlled, randomized trial conducted from 19 October 2004 to 17 November 2005.
                75 primary care and psychiatric centers.
                274 outpatient adults with major depressive disorder that was suboptimally responsive to antidepressant therapy.
                After a 4-week run-in period to ensure insufficient response to standard antidepressants, patients were randomly assigned to receive risperidone, 1 mg/d, or placebo for 6 weeks. After 4 weeks, the dosage of risperidone was increased to 2 mg/d in some cases.
                Symptoms were measured by using the 17-item Hamilton Rating Scale for Depression (HRSD-17). Other outcomes were response to therapy, remission of depression, and various clinician- and patient-rated assessments.
                Of the intention-to-treat population (268 patients), 81% (111 of 137) who received risperidone and 87.8% (115 of 131) who received placebo completed 6 weeks of double-blind treatment. Mean (+/-SE) HRSD-17 scores improved more in the risperidone augmentation group than in the placebo group (13.4 +/- 0.54 vs. 16.2 +/- 0.53; difference, -2.8 +/- 0.72 [95% CI, -4.2 to -1.4]; P <0.001). More risperidone recipients than placebo recipients experienced remission of depression (24.5% [26 of 106] vs. 10.7% [12 of 112]; P = 0.004) and had a response (46.2% [49 of 106] vs. 29.5% [33 of 112]; P = 0.004). Headache (8.8% of risperidone recipients vs. 14.5% of placebo recipients), somnolence (5.1% vs. 1.5%), and dry mouth (5.1% vs. 0.8%) were the most frequently reported adverse events.
                Patients were receiving many different antidepressants, and the duration of augmentation therapy was limited.
                Risperidone augmentation produced a statistically significant mean reduction in depression symptoms, substantially increased remission and response, and improved other patient- and clinician-rated measures. ClinicalTrials.gov registration number: NCT00095134. To assess the efficacy and safety of aripiprazole versus placebo as adjunctive treatment to standard antidepressant therapy (ADT) in patients with major depressive disorder (MDD) who showed an incomplete response to 1 prospective and 1 to 3 historical courses of ADT within the current episode.
                The study comprised a 7- to 28-day screening phase, an 8-week prospective treatment phase, and a 6-week double-blind treatment phase. Patients with DSM-IV-TR-defined MDD were enrolled between June 16, 2004, and April 27, 2006. During prospective treatment, patients received ADT: escitalopram, fluoxetine, paroxetine controlled-release, sertraline, or venlafaxine extended-release, each with single-blind, adjunctive placebo. Incomplete responders continued ADT and were randomly assigned to double-blind, adjunctive placebo or adjunctive aripiprazole (2-15 mg/day with fluoxetine or paroxetine; 2-20 mg/day with all others). The primary efficacy endpoint was the mean change from end of prospective treatment to end of double-blind treatment (week 14, last observation carried forward) in Montgomery-Asberg Depression Rating Scale (MADRS) total score (analysis of covariance).
                A total of 178 patients were randomly assigned to adjunctive placebo and 184 to adjunctive aripiprazole. Baseline demographics were similar between groups (mean MADRS total score of 26.0). Mean change in MADRS total score was significantly greater with adjunctive aripiprazole (-8.8) than adjunctive placebo (-5.8; p < .001). Adverse events (AEs) that occurred in > or = 10% of patients with adjunctive placebo or adjunctive aripiprazole were akathisia (4.5% vs. 23.1%), headache (10.8% vs. 6.0%), and restlessness (3.4% vs. 14.3%). Discontinuations due to AEs were low with adjunctive placebo (1.7%) and adjunctive aripiprazole (2.2%); only 1 adjunctive aripiprazole-treated patient discontinued due to akathisia.
                In patients with MDD who showed an incomplete response to ADT, adjunctive aripiprazole was efficacious and well tolerated.
                ClinicalTrials.gov identifier NCT00095823. To evaluate the efficacy and tolerability of once-daily extended release quetiapine fumarate (quetiapine XR) as monotherapy treatment for major depressive disorder (MDD).
                This 8-week (6-week active-treatment, randomized phase; 2-week posttreatment drug-discontinuation/tapering phase), multicenter, double-blind, randomized, parallel-group, placebo- and active-controlled, phase 3 study was conducted between April 2006 and May 2007. In total, 612 patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-defined MDD were randomly assigned to quetiapine XR 150 mg/day or 300 mg/day, duloxetine 60 mg/day (active control), or placebo. The primary endpoint was the change from baseline to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score.
                At week 6, both doses of quetiapine XR (p < .001) and duloxetine (p < .01) significantly reduced mean MADRS total score versus placebo. A significant reduction was seen at week 1 with quetiapine XR 150 mg/day and 300 mg/day versus placebo (p < .01), but not with duloxetine. Response rates (>or= 50% reduction in MADRS total score) at week 6 were significantly higher for both doses of quetiapine XR (p < .01) and duloxetine (p < .05) versus placebo. Remission rates (MADRS score <or= 8) were significantly higher for quetiapine XR 300 mg/day and duloxetine versus placebo (p < .05), but not for quetiapine XR 150 mg/day. Hamilton Rating Scale for Depression, Hamilton Rating Scale for Anxiety, and Clinical Global Impressions-Severity of Illness total scores and the proportion of patients with Clinical Global Impressions-Improvement scores of 1 or 2 ("much/very much improved") were significantly improved with both doses of quetiapine XR and duloxetine versus placebo. The most common adverse events reported were dry mouth, sedation, and somnolence for quetiapine XR and nausea, headache, dizziness, and dry mouth for duloxetine.
                Quetiapine XR monotherapy (150 mg/day and 300 mg/day) is effective, with safety and tolerability consistent with the known profile of quetiapine XR, in the treatment of patients with MDD, with onset of symptom improvement demonstrated at week 1.
                clinicaltrials.gov Identifier: NCT00321490.
                ©Copyright 2009 Physicians Postgraduate Press, Inc. Patients (30-50%) with non-psychotic major depression will not respond despite an adequate trial of antidepressant medication. This study evaluated risperidone as an augmenting agent for patients who failed or only partially responded to an adequate trial of an antidepressant medication.
                Ninety-seven patients with unipolar non-psychotic major depression who were not responsive to antidepressant monotherapy were randomized to risperidone (0.5-3mg/day) or placebo augmentation in a four-week, double-blind, placebo controlled treatment trial. The primary outcome measure was remission defined by a score of < or =10 on the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes measures were the Hamilton Rating Scale for Depression, the Clinician Global Impression of Severity scale and the overall satisfaction item of the Quality of Life and Enjoyment Questionnaire.
                Subjects in both treatment groups improved significantly over time. The odds of remitting were significantly better for patients in the risperidone vs. placebo arm (OR=3.33, p=.011). At the end of 4 weeks of treatment 52% of the risperidone augmentation group remitted (MADRS< or =10) compared to 24% of the placebo augmentation group (CMH(1)=6.48, p=.011), but the two groups were converging. Patients in the risperidone group also reported significantly more improvement in quality-of-life than patients in the placebo group. There were no between-group differences in the number of adverse events reported, however, weight gain was significantly higher in the group receiving risperidone.
                Augmentation of an antidepressant with risperidone for patients with difficult-to-treat depression leads to more rapid response and a higher remission rate and better quality-of-life.
Quetiapine was more effective than placebo treatment. Aripiprazole and quetiapine and partly also olanzapine and risperidone augmentation showed beneficial effects compared to placebo. Some evidence indicated beneficial effects of low-dose amisulpride for dysthymic people. Most SGAs showed worse tolerability.