The effect of pain on outcomes in a trial of duloxetine treatment of major depressive disorder.

BACKGROUND: Patients with major depressive disorder (MDD) frequently report one or more pain symptoms. To explore the relationship between improvement in pain symptoms and MDD treatment outcomes, we conducted a secondary analysis of an approximately 12-week, open label trial of duloxetine in MDD. The primary objective was to test the hypothesis that a greater reduction in pain was associated with a higher probability of MDD remission. METHODS: Adults with DSM-IV MDD were enrolled in the study if they had a Hamilton Depression Scale (HAMD-17) total score of 15 or more and a Clinical Global Impression of Severity (CGI-S) score of 4 or more. The duloxetine dose of patients could be titrated on the basis of the degree of response within the range from 60 to 120 mg given QD, with 90 mg QD as an intermediate dose. Remission of major depressive disorder was defined as a HAMD-17 total score of < or = 7. Core emotional symptoms of depression were determined by the HAMD-17 Maier subscale. Pain was assessed using a 100 mm visual analog scale (VAS) of overall pain severity over the last week (0 = no pain, 100 = pain as severe as I can imagine). For the primary analysis, mean change in VAS overall pain score over time was compared between remitters and non-remitters at endpoint using a mixed model repeated measures approach. RESULTS: Two hundred forty nine patients were included in the analysis. A greater reduction in pain was associated with a significantly higher probability of remission of MDD, after accounting for changes in the core emotional symptoms. Greater pain reduction was associated with significant improvement in MDD core emotional symptoms. A greater improvement in pain was also associated with improvements in patient and clinician-rated global assessments. CONCLUSIONS: The effective treatment of pain symptoms in patients with major depressive disorder was associated with higher remission rates. The results underscore the importance of effectively treating painful symptoms associated with depression.

The significance of treating somatic symptoms on functional outcome improvement in patients with major depressive disorder: a post hoc analysis of 2 trials.

BACKGROUND: Functional impairment is associated with major depressive disorder (MDD), and patients with MDD often present with somatic symptoms. OBJECTIVE: To examine the relationships between improved global functioning and core depressive symptoms as well as painful and nonpainful somatic symptoms in patients with MDD. METHOD: This post hoc analysis of 2 identical trials compared the efficacy of duloxetine with that of paroxetine or placebo as treatment of MDD. In the trials, patients with DSM-IV-defined MDD received duloxetine 80 mg/day (N = 188), duloxetine 120 mg/day (N = 196), paroxetine 20 mg/day (N = 183), or placebo (N = 192) for 8 weeks. The Sheehan Disability Scale (SDS), Maier subscale of the 17-item Hamilton Rating Scale for Depression, 21-item Somatic Symptom Inventory, and Visual Analog Scale for overall pain were used to measure functional impairment, core symptoms of depression, and nonpainful and painful somatic symptoms, respectively. Baseline-to-endpoint mean changes in SDS total and subdomains were measured using analysis of variance with last-observation-carried-forward Pearson partial correlations, and path analysis was used to assess the significance of associations and relative contributions of improvement in global functional impairment, depression, and somatic symptoms. The trials were conducted from November 2000 to July 2002. RESULTS: The difference between antidepressant treatment and placebo in SDS total and subdomains was significant (p < .001). At baseline and in change from baseline to endpoint, associations between global functional impairment and core depressive and somatic symptoms were all significant (p < .05). Path analysis demonstrated improvement of functional impairment attributed to treatment effect as 37.0% (core depressive symptoms), 13.0% (nonpainful somatic symptoms), and 11.0% (painful somatic symptoms). CONCLUSION: In patients with MDD, over a third of functional improvement associated with antidepressant therapy was mediated through improvement in core depressive symptoms. In addition, a significant proportion of functional improvement, although to a lesser degree, was associated with the treatment of both nonpainful and painful somatic symptoms.

Reduced suicidal ideation in bipolar I disorder mixed-episode patients in a placebo-controlled trial of olanzapine combined with lithium or divalproex.

OBJECTIVE: To identify symptoms associated with suicidality in bipolar I disorder patients, and to assess suicide risk during treatment with olan-zapine in combination with lithium or divalproex. METHOD: We used data from a study (conducted from September 1997 to October 2000) in which DSM-IV bipolar I manic or mixed-episode patients who were partially responsive to at least 2 weeks of lithium or dival-proex monotherapy prior to study entry were randomly assigned to augmentation therapy with olanzapine (5-20 mg/day) or placebo. Among mixed-episode patients with residual suicidality (Hamilton Rating Scale for Depression-item 3 [HAM-D-3] score of 1 or above) at randomization to cotherapy, we identified items in the Young Mania Rating Scale, Positive and Negative Syndrome Scale, and Barnes Akathisia Rating Scale that correlated with HAM-D-3 scores. We used factor analysis of correlated items to identify symptom domains associated with suicidality ratings and assessed changes in symptom factors and HAM-D-3 scores during 6 weeks of combination therapy with olanzapine versus placebo. RESULTS: In 58 mixed-episode patients, mean +/- SD HAM-D-3 scores averaged 1.36 +/- 0.55 after at least 2 weeks of initial mood stabilizer monotherapy prior to study entry. Factors associated with the HAM-D-3 appeared to represent somatic discomfort, agitated depression, and psychotic features. Combination therapy with olanzapine (N = 36) versus placebo (N = 22) differentially reduced HAM-D-3 scores by 58% versus 29% (p < .05) within 1 week, and all 3 associated symptom factors within 2 weeks by averages of 31% versus 12% (p < .05). CONCLUSIONS: Suicidality in adult, mixed-episode, bipolar I disorder patients was associated with somatic discomfort, agitated depression, and psychosis. Overall, these findings suggest that the addition of an atypical antipsychotic-antimanic agent in some bipolar disorder patients may help to reduce suicidal ideation.

Differential efficacy of olanzapine and lithium in preventing manic or mixed recurrence in patients with bipolar I disorder based on number of previous manic or mixed episodes.

INTRODUCTION: Bipolar disorder outcome worsens as number of manic episodes increases, suggesting that prevention of recurrent episodes early during the disorder could improve patient prognosis. We investigated treatment efficacy in prevention of mood episodes in patients subgrouped by number of prior manic episodes. METHOD: This study was a post hoc analysis of data from a multicenter, double-blind, 12-month clinical trial of relapse/recurrence in 431 initially euthymic patients with at least 2 prior manic/ mixed episodes and a DSM-IV diagnosis of bipolar I disorder randomly assigned to olanzapine (5-20 mg/day) or lithium (serum concentration 0.6 to 1.2 mEq/L). Data were collected between August 1999 and June 2002. Patients were subcategorized by illness stage according to number of prior manic/mixed episodes-early stage: 2 prior episodes (N = 53, lithium; N = 48, olanzapine), intermediate stage: 3 to 5 prior episodes (N = 80, lithium; N = 98, olanzapine), and later stage: more than 5 prior episodes (N = 81, lithium; N = 71, olanzapine)-and were evaluated for rates of relapse/recurrence. RESULTS: There were significant effects for treatment (p < .001) and illness stage (p = .006) but no significant interaction (p = .107) on rate of manic/mixed relapse/recurrence. Rates of manic/ mixed relapse/recurrence for olanzapine versus lithium were 2.1% versus 26.4% (p = .008), 13.3% versus 23.8% (p = .073), and 23.9% versus 33.3% (p = .204) for early-, intermediate-, and later-stage groups, respectively. There was no significant effect for treatment (p = .096) or illness stage (p = .731) for depressive relapse/recurrence. CONCLUSIONS: Early-stage (but not intermediate-or later-stage) patients had a significantly lower rate of relapse/recurrence of manic/mixed episodes with olanzapine compared to lithium. Thus, olanzapine maintenance therapy may be particularly effective early in the course of bipolar illness.

A post hoc analysis of transitioning to oral treatment with olanzapine or haloperidol after 24-hour intramuscular treatment in acutely agitated adult patients with schizophrenia.

BACKGROUND: Acutely agitated patients with schizophrenia might require treatment with IM antipsychotics, followed by a transition to oral medication. OBJECTIVE: The aim of this study was to assess the relationship between 24-hour IM and transitional oral dosages of 2 antipsychotic medications, olanzapine and haloperidol. METHODS: This post hoc analysis used data from a multinational, double-blind, randomized, placebo-controlled study comparing the efficacy of olanzapine, haloperidol, and placebo in acutely agitated inpatients aged > or =18 years with schizophrenia conducted at hospitals in 13 countries. Patients received 1 to 3 IM injections of olanzapine 10 mg or haloperidol 7.5 mg over 24 hours (IM phase), followed by 4 days of oral treatment with 5 to 20 mg/d of either antipsychotic (oral phase). Study patients were grouped according to which drug they received, and subgrouped based on whether they received a single or multiple IM injections. Rates of transition to lower (5-10 mg/d) versus higher (15-20 mg/d) dosages were compared within and between treatments. RESULTS: Data from 236 patients were analyzed (olanzapine, 121 patients [76 men, 45 women; mean (SD) age, 38.4 (12.2) years; mean (SD) weight, 74.9 (18.5) kg]; haloperidol, 115 patients [80 men, 35 women; mean (SD) age, 38.0 (10.2) years; mean (SD) weight, 75.4 (18.7) kg]). At the end of the IM phase, the rate of haloperidol patients who were transitioned to lower oral doses was significantly higher in the single-injection subgroup compared with the multiple-injection subgroup (P = 0.03); this difference was not found in the group receiving olanzapine. At day 4 of oral treatment, the rates of patients in the olanzapine and haloperidol groups who were transitioned to higher oral doses were significantly higher in the single-injection subgroups compared with the multiple-injection subgroups (P = 0.002 and =0.003, respectively). CONCLUSION: In this study, the proportion of agitated patients with schizophrenia who transitioned to higher dosages (15-20 mg) of olanzapine or haloperidol by day 4 of the oral switch was significantly greater in patients who were previously treated with a single IM injection of olanzapine (10 mg) or haloperidol (7.5 mg).right.

Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial.

BACKGROUND: In a phase 2 study, dexpramipexole (25-150 mg twice daily) was well tolerated for up to 9 months and showed a significant benefit at the high dose in a combined assessment of function and mortality in patients with amyotrophic lateral sclerosis. We aimed to assess efficacy and safety of dexpramipexole in a phase 3 trial of patients with familial or sporadic disease. METHODS: In our randomised, double-blind, placebo-controlled phase 3 trial (EMPOWER), we enrolled participants aged 18-80 years (with first amyotrophic lateral sclerosis symptom onset 24 months or less before baseline) at 81 academic medical centres in 11 countries. We randomly allocated eligible participants (1:1) with a centralised voice-interactive online system to twice-daily dexpramipexole 150 mg or matched placebo for 12-18 months, stratified by trial site, area of disease onset (bulbar vs other areas), and previous use of riluzole. The primary endpoint was the combined assessment of function and survival (CAFS) score, based on changes in amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) total scores and time to death up to 12 months. We assessed the primary endpoint in all participants who received at least one dose and had at least one post-dose ALSFRS-R measurement or died. We monitored adverse events in all participants. This study is registered with ClinicalTrials.gov, number NCT01281189. FINDINGS: Between March 28, 2011, and Sept 30, 2011, we enrolled 943 participants (474 randomly allocated dexpramipexole, 468 randomly allocated placebo, and one withdrew). Least-square mean CAFS scores at 12 months did not differ between participants in the dexpramipexole group (score 441·76, 95% CI 415·43-468·08) and those in the placebo group (438·84, 412·81-464·88; p=0·86). At 12 months, we noted no differences in mean change from baseline in ALSFRS-R total score (-13·34 in the dexpramipexole group vs -13·42 in the placebo group; p=0·90) or time to death (74 [16%] vs 79 [17%]; hazard ratio 1·03 [0·75-1·43]; p=0·84). 37 (8%) participants in the dexpramipexole group developed neutropenia compared with eight (2%) participants in the placebo group, and incidence of other adverse events was similar between groups. INTERPRETATION: Dexpramipexole was generally well tolerated but did not differ from placebo on any prespecified efficacy endpoint measurement. Our trial can inform the design of future clinical research strategies in amyotrophic lateral sclerosis. FUNDING: Biogen Idec.

A pragmatic 12-week, randomized trial of duloxetine versus generic selective serotonin-reuptake inhibitors in the treatment of adult outpatients in a moderate-to-severe depressive episode.

Some evidence suggests that medications that modulate both serotonin and norepinephrine may be more effective than selective serotonin-reuptake inhibitors (SSRIs) in severe major depressive disorder (MDD). This prospective pragmatic trial tests this hypothesis. Patients with severe MDD were randomly assigned to either duloxetine (a serotonin and norepinephrine-reuptake inhibitor) or physicians' choice of four generic SSRIs. Nonblinded, flexibly dosed treatment was used to mimic clinical practice. To address potential investigator bias, the patient-reported Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) was used as the primary efficacy outcome measure. A total of 750 outpatients (19.2%, African descent; 14.8%, Hispanic) were randomized. The primary outcome, remission at week 12 by QIDS-SR, was numerically greater for duloxetine compared with SSRIs (36 vs. 32%), but this difference was not statistically significant. Mean changes in secondary outcomes were significantly superior in favor of duloxetine for the Hamilton Depression Scale-17 item, the Brief Pain Inventory, and the Sheehan Disability Scale. Remission superiority on the QIDS-SR was not achieved. Significantly greater benefit for duloxetine compared with SSRIs was demonstrated on measures of pain and functioning. Study demographics suggest a more generalizable racial and ethnic population than is typical in randomized clinical trials.

Early symptom change prediction of remission in depression treatment.

OBJECTIVES: This study investigated hypothesized early symptom changes as differential predictors of long-term remission for duloxetine and escitalopram. EXPERIMENTAL DESIGN: This was a post-hoc analysis from a placebo-controlled, randomized, double-blind study of patients with major depressive disorder treated for 8 weeks with duloxetine 60 mg/day (N = 273) or escitalopram 10 mg/day (N = 274), and for another 6 months with duloxetine up to 120 mg/day or escitalopram up to 20 mg/day. Odds ratios (ORs) for successful treatment (sustained remission), defined as a 17-item Hamilton Depression Rating Scale (HAMD-17) score 2.0. In a follow-up analysis, specific subscale items for psychological anxiety, motor retardation, and suicidality significantly predicted remission for duloxetine, and psychological and somatic anxiety for escitalopram. Notably, high NPVs on the Maier subscale indicated that a lack of 20% improvement on the "core" depression factor by Week 2 was highly predictive of unsuccessful treatment outcome over 8 months. CONCLUSIONS: In accord with hypotheses, early symptom changes were specific to treatment, with early response in the core depression factor (Maier subscale), anxiety, and motor activity for duloxetine, and core factor and anxiety for escitalopram. Lack of early response in depression symptom subscales was highly predictive of lack of sustained remission.

Safety and efficacy of duloxetine in the treatment of diabetic peripheral neuropathic pain in older patients.

OBJECTIVE: We present a post-hoc analysis of the safety and efficacy of duloxetine, a selective serotonin/norepinephrine reuptake inhibitor, for treatment of diabetic peripheral neuropathic pain (DPNP) in older patients. METHODS: Data from three double-blind, placebo-controlled trials in adult patients with DPNP were pooled and stratified by age (<65, >or=65 years). Patients were randomized to duloxetine (DLX) 60 mg once-daily, 60 mg twice-daily, or placebo for 12 weeks, followed by a 52-week extension phase (re-randomization to routine care or DLX 120 mg/day). Intent-to-treat analyses were used for safety and efficacy assessment. RESULTS: In the acute phase, overall TEAE rates did not differ significantly by age. A greater percentage of older patients discontinued due to TEAEs (P<0.001), regardless of treatment group. Duloxetine improved weekly mean 24-hour average pain scores versus placebo in both age groups (P<0.01). In the extension phase, a significant therapy-by-age interaction (P<0.05) was observed in overall TEAE rate; with routine care, 86.6% of older patients had >or=1 TEAE versus 74.6% of younger patients. CONCLUSIONS: Although TEAEs more frequently lead to discontinuation in older patients, duloxetine was well tolerated and efficacious for treatment of DPNP regardless of age. These data suggest duloxetine may be beneficial for treatment of DPNP in patients>or=65.

Does pain mediate the pain interference with sleep problem in chronic pain? Findings from studies for management of diabetic peripheral neuropathic pain with duloxetine.

Although sleep problems are common in patients with chronic pain, it is unclear whether pain mediates (causes) impaired sleep. The relationship between pain and sleep has been difficult to investigate because of the potential confounds of depression and somnolence. This report used clinical trials data for duloxetine in the management of diabetic peripheral neuropathic pain (DPNP) to investigate the direction of this association. Data were pooled from three double-blind, randomized, placebo-controlled, 12-week trials of patients with DPNP without mood disorder (n=1,139). DPNP patients reporting somnolence and those who were receiving sedating concomitant medications were removed from the analyses (n=93). Efficacy measures included weekly mean scores for average daily pain severity, night pain severity, and pain interference with sleep. Duloxetine at 60 and 120 mg per day separated from placebo for average pain and night pain improvement as early as one week after treatment began, whereas sleep interference improvement separated from placebo at the three visits it was assessed (Weeks 4, 8, and 12). Change in sleep interference was moderately to strongly correlated (P<0.001) with changes in average pain (r=0.46) and nighttime pain severity (r=0.53). These results confirm the association between the improvement in daily pain and nighttime pain, and improvement in sleep interference for a large population without depression or somnolence. Although this association cannot establish causality, these results provide some evidence for the possibility that pain may mediate the sleep problem associated with DPNP and perhaps chronic pain in general.

Effect of olanzapine on cognition during treatment of behavioral and psychiatric symptoms in patients with dementia: a post-hoc analysis.

OBJECTIVE: This study was conducted to determine the effect of olanzapine treatment on cognition in elderly patients with behavioral and psychiatric symptoms (BPSD) associated with dementia. METHODS: This was a post-hoc analysis of three randomized double-blind, clinical trials of olanzapine (n = 682) vs placebo (n = 257) in dementia patients with BPSD in long-term or continuing-care settings. One study was 6 weeks long; the other two were 10 weeks duration, and their data were combined. Patients were subgrouped according to baseline Mini Mental State Examination (MMSE) scores: Group I = 23-26; Group II = 19-22; Group III = 14-18; Group IV = 7-13; Group V = 1-6. BPSD was assessed by the Neuropsychiatric Inventory (NPI). RESULTS: Within-treatment group cognitive decline in patients was significant in the combined studies, but not in the 6-week study. Between-treatment cognitive changes were non-significant in the 6-week study, but showed a statistical trend in the combined studies (olanzapine, -0.78 +/- 0.19 vs placebo, -0.32 +/- 0.25; p = 0.06). In the subgroup analysis, there was a significant between-treatment difference in cognitive changes in MMSE subgroup IV in the combined studies (olanzapine, -0.63 +/- 0.26 vs placebo, 0.27 +/- 0.41, p = 0.04). Improvement in BPSD was correlated with better cognitive outcome (r = -0.2; p < 0.01). CONCLUSIONS: Although the overall differences in cognitive changes in patients treated with olanzapine vs placebo were small and non-significant, negative effects on cognition in some patients cannot be excluded, especially in patients with more pronounced cognitive decline or whose behavioral and psychiatric symptoms are not responding to treatment.

The relationship between functional outcomes and the treatment of anxious and painful somatic symptoms in patients with generalized anxiety disorder.

OBJECTIVE: To examine the relationship between global functional impairment and the treatment of anxious symptoms and painful somatic symptoms (PSS) in patients with generalized anxiety disorder (GAD). RESEARCH DESIGN AND METHODS: Data from two double-blind, placebo-controlled trials in adult outpatients meeting DSM-IV criteria for GAD were pooled. In the first trial (9-week, fixed-dose treatment period), patients were randomized to duloxetine 60 mg QD (n=168), duloxetine 120 mg QD (n=170), or placebo (n=175). In the second trial (10-week, flexible-dose treatment period), patients were randomized to 60-120 mg QD of duloxetine (n=168) or placebo (n=159). Path analysis was used to assess the relative contributions of changes in psychic and somatic anxiety and PSS on improved functional outcomes. CLINICAL TRIAL REGISTRATION INFORMATION: Study 1: NCT00122824; Study 2: study completed before registration required. MAIN OUTCOME MEASURES: Sheehan Disability Scale (SDS), Hamilton Anxiety Rating Scale (HAMA), and Visual Analog Scale for overall pain (VAS). RESULTS: There was a moderate correlation (0.45, p<0.05) at endpoint between changes in global functional impairment and changes in psychic anxiety (controlling for somatic anxiety and PSS); whereas the correlation between changes in global functional impairment and changes in somatic anxiety (controlling for psychic anxiety and PSS) was weak (0.09, p<0.05). The correlation between changes in global functional impairment and changes in PSS (controlling for psychic and somatic anxiety) was weak (0.27, p<0.05). Path analysis revealed that 37% of the total improvement in functional impairment (Sheehan Disability Scale total score) due to duloxetine treatment was independent of improvement in the Hamilton Anxiety Rating Scale (HAMA) psychic and somatic anxiety subscale scores or Visual Analog Scale for overall pain (VAS) score. Improvement in psychic anxiety accounted for 47% of the total treatment effect on improvement of functional impairment, whereas 7% and 9% of the improvement in functional impairment was accounted for by improvements in somatic anxiety and overall pain, respectively.

A randomized, double-blind study of increasing or maintaining duloxetine dose in patients without remission of major depressive disorder after initial duloxetine therapy.

OBJECTIVE: To compare efficacy of remaining on duloxetine 60 mg to increasing to 120 mg q.d. in patients without remission of major depressive disorder (MDD) after 6 weeks at 60 mg. METHOD: This double-blind, parallel study was conducted in adults with MDD (DSM-IV-TR criteria). Patients initially randomly assigned to duloxetine 60 mg for 6 weeks with a 17-item Hamilton Rating Scale for Depression (HAM-D-17) score > 7 (nonremitters) were randomly reassigned to 60 mg or 120 mg duloxetine for 8 weeks. Patients with a HAM-D-17 score < or =7 (remitters) continued on duloxetine 60 mg. The primary objective was to compare time to remission (HAM-D-17 score < or =7) between rerandomized groups. Secondary objectives included evaluation of HAM-D-17 and Inventory of Depressive Symptomatology assessments and safety and tolerability evaluations in nonremitters and remitters. Patients were enrolled from November 2004 to January 2006. RESULTS: Nonremitters randomly reassigned to 60 mg and 120 mg achieved similar time to remission and similar improvements on efficacy measures. Remission was achieved in 30.0% and 30.5% in the 60-mg and 120-mg groups, respectively. Of the remitters, 85.5% continued to be in remission at study end. Other than a greater incidence of hyperhidrosis and chest pain in the 120-mg group, adverse events were similar between groups, as were discontinuations due to adverse events. CONCLUSION: Nonremitters to 60 mg of duloxetine for 6 weeks randomly reassigned to 60 mg or 120 mg of duloxetine demonstrated continued symptom improvement in the 8-week extension. Patients randomly reassigned to 120 mg showed no advantage over those who continued on 60 mg. Duloxetine was well tolerated at both doses and had similar safety profiles.

Simple options for improving signal detection in antidepressant clinical trials.

OBJECTIVE: Previous experience with antidepressant studies highlight the difficulties in discriminating an effective drug from placebo. In hopes of improving signal detection, three easy-to-implement methodologies were employed during the development of a recently approved antidepressant. EXPERIMENTAL DESIGN: Results from alternative and traditional methods could be compared directly because most studies employed both methods. This database included 11 double-blind, placebo-controlled trials (some with multiple dose arms and/or active comparators) yielding 22 treatment arms of antidepressants at or above the minimally effective dose noted in their U.S. labels. PRINCIPAL OBSERVATIONS: Results agreed with the previous evidence showing that the performance of a likelihood-based, mixed-effects model repeated measures (MMRM) analysis was superior to that of analysis of covariance with missing values imputed using the last observation carried forward (LOCF) approach; MMRM correctly identified drug as superior to placebo in 14/22 (63.6%) comparisons versus 11/22 (50.0%) for LOCF. In agreement with previous studies, use of subscales of the Hamilton Depression Rating scale (HAMD) improved signal detection compared to the HAMD total score. Using MMRM with HAMD subscales correctly identified drug as superior to placebo in up to 17/22 (77.3%) comparisons. Excluding double-blind, placebo lead-in responders did not increase the frequency of correctly identifying drug-versus-placebo differences. CONCLUSIONS: The 22 drug-versus-placebo comparisons in this report offer a small amount of evidence and therefore may not be convincing on their own, although results do agree with previous research. Researchers may be able to take advantage of these easy-to-implement methods while we wait for further improvements in other areas.

An observational study of the effectiveness and safety of intramuscular olanzapine in the treatment of acute agitation in patients with bipolar mania or schizophrenia/schizoaffective disorder.

OBJECTIVE: To determine the effect of intramuscular (IM) olanzapine in severely agitated patients. METHODS: This was an open-label multicenter 1-week observational study of IM olanzapine treatment in severely agitated inpatients and psychiatric emergency services with bipolar mania (n = 22) or schizophrenia (n = 52). Mean change from baseline to 2 h post-first injection (LOCF) in agitation was assessed by PANSS-Excited Component (PANSS-EC) (score range: 5-35 points) mean change from baseline to 15, 30, 45, 60, 90, and 120 min post-first injection, and visit-wise mean changes from mixed-model repeated measures analysis of variance. Kaplan-Meier survival curve analyses estimated time to categorical response (rating of

A comparison of initial duloxetine dosing strategies in patients with major depressive disorder.

OBJECTIVE: To compare the effects of starting doses of duloxetine taken with or without food on tolerability and efficacy in patients with major depressive disorder (MDD). METHOD: This double-blind, concurrent-dose-controlled, parallel-design trial contained a variable expected-duration placebo lead-in period and was conducted in adult outpatients with DSM-IV-TR-defined MDD at psychiatric outpatient sites between October 2004 and January 2006. In actuality, patients received placebo for 1 week and then were randomly assigned to duloxetine 30 mg once daily in the morning (q.a.m.) (N = 219), 30 mg twice daily (b.i.d.) (N = 213), or 60 mg q.a.m. (N = 215) for 1 week along with 1 of 2 instructions about food: take study drug with food or do not take within 1 hour of eating. For the remaining 5 weeks of acute treatment, all patients received 60 mg once daily. The primary objective was to compare incidence of treatment-emergent nausea at 30 mg q.a.m. versus 60 mg q.a.m. using item 112 (nausea) of the Association for Methodology and Documentation in Psychiatry adverse event scale (AMDP-5). Secondary outcome measures included mean change on AMDP-5 item 112, discontinuations due to adverse events, mean changes in AMDP-5 items and subscales, spontaneously reported treatment-emergent adverse events, and vital signs. Efficacy was evaluated by the 17-item Hamilton Rating Scale for Depression (HAM-D-17). RESULTS: The primary analysis, which combined data from both food groups, showed no significant difference in the incidence of nausea between starting doses of 30 mg q.a.m. and 60 mg q.a.m. (23% vs. 29%, respectively; p = .207). However, mean changes on the AMDP-5 nausea item revealed a significant main effect of food (p = .010) and a significant interaction between food and starting dose (p = .033). The food-by-dose interaction indicated that the benefit from taking drug with food was greatest in patients started at 60 mg q.a.m., and the benefit of starting at 30 mg q.a.m. was greatest in patients taking drug without food. In patients who took study drug without food, there was a significant difference across initial-dose groups for discontinuation due to adverse events (30 mg q.a.m. = 3.6%, 30 mg b.i.d. = 14.0%, 60 mg q.a.m. = 10.2%; 30 mg q.a.m. vs. 30 mg b.i.d., p = .008; 30 mg q.a.m. vs. 60 mg q.a.m., p = .066); however, in patients who took study drug with food, discontinuations due to adverse events did not significantly differ (30 mg q.a.m. = 5.4%, 30 mg b.i.d. = 7.5%, 60 mg q.a.m. = 7.4%; all p values > .50). Patients who started at 30 mg b.i.d. or 60 mg q.a.m. without food did not differ regarding mean changes (i.e., increases) in the common adverse events score after 1 week of treatment but had significantly greater mean changes than patients who started at 30 mg q.a.m. without food (0.87, 0.82, and 0, respectively; p < .05 vs. 30 mg b.i.d. and 60 mg q.a.m.). No significant differences were found between initial-dose groups in vital signs. CONCLUSIONS: These data imply that starting dulox-etine at 30 mg q.a.m. for 1 week with or without food or starting duloxetine at the therapeutic dose of 60 mg q.a.m. with food can improve the initial tolerability of the medication. Adding this information to existing knowledge of duloxetine will enable the clinician to tailor therapy most appropriately for the individual patient. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT 00191061.