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During the past two decades, it has been amply documented that neuropsychiatric disorders (NPDs) disproportionately account for burden of illness attributable to chronic non-communicable medical disorders globally. It is also likely that human capital costs attributable to NPDs will disproportionately increase as a consequence of population aging and beneficial risk factor modification of other common and chronic medical disorders (e.g., cardiovascular disease). Notwithstanding the availability of multiple modalities of antidepressant treatment, relatively few studies in psychiatry have primarily sought to determine whether improving cognitive function in MDD improves patient reported outcomes (PROs) and/or is cost effective. The mediational relevance of cognition in MDD potentially extrapolates to all NPDs, indicating that screening for, measuring, preventing, and treating cognitive deficits in psychiatry is not only a primary therapeutic target, but also should be conceptualized as a transdiagnostic domain to be considered regardless of patient age and/or differential diagnosis.

Introduction The subjective experience of drug craving is a prominent and common clinical phenomenon for many individuals diagnosed with opioid use disorder (OUD), and could be a valuable clinical endpoint in medication development studies. The purpose of this scoping review is to provide an overview and critical analysis of opioid craving assessments located in the published literature examining OUD. Method Studies were identified through a search of PubMed, Embase, and PsychInfo databases and included for review if opioid craving was the focus and participants were diagnosed with or in treatment for OUD. Results Fifteen opioid craving assessment instruments were identified across the 87 studies included for review. The most common were the Visual Analog Scale (VAS, 41 studies), Desires for Drug Questionnaire (DDQ, 12 studies), Heroin Craving Questionnaire (HCQ, 10 studies), and Obsessive-Compulsive Drug Use Scale (OCDUS, 10 studies). Craving assessments varied considerably in their format, content, time frame, and underlying subscales, and only 6 of 15 had been psychometrically evaluated. Discussion This review identified a variety of opioid craving assessments, but few had been evaluated for their psychometric properties making it difficult to ascertain whether craving is being assessed optimally in studies of OUD. Thus, the development of a reliable and valid opioid craving assessment would be worthwhile and could be guided by recently published Food and Drug Administration Clinical Outcome Assessment (COA) guidelines. Importantly, a COA focused on opioid craving could be a valuable addition to research studies designed to evaluate novel treatments for OUD.

Background Potential drugdrug interactions are a concern for patients taking tamoxifen. Objective This study was designed to determine the effect of coadministering desvenlafaxine on tamoxifen pharmacokinetics. Materials and methods This open-label, 2-period inpatient and outpatient study enrolled healthy, postmenopausal women. Period 1, day 1, subjects were administered tamoxifen 40 mg followed by 23 days of blood sampling for pharmacokinetic analyses. During period 2, subjects received desvenlafaxine 100 mg/d for 28 days; a single dose of tamoxifen 40 mg was administered with desvenlafaxine 100 mg on day 7, followed by 23 days of blood sampling. Pharmacokinetics of tamoxifen and its metabolites (AUC over infinite time (AUC(inf)), AUC to the last measurable concentration (AUC(last)), peak plasma concentration (C(max)) were compared for monotherapy vs. combination therapy using the ratio of adjusted mean differences. A superposition method was used in the statistical analysis of N-desmethyl-tamoxifen and endoxifen to address the carry-over observed for those metabolites. The test for interaction was considered negative if the 90% confidence intervals (CIs) for the ratios were within 80 - 125%. Results Coadministration of tamoxifen with steady-state desvenlafaxine did not alter tamoxifen AUC(inf), AUC(last), and C(max), as reflected by the ratio of adjusted geometric means (90% CIs) of 100.7% (96.7%, 104.9%), 103.5% (100.2%, 106.9%), and 99.4% (94.0%, 105.2%), respectively. Similarly, coadministration did not alter 4-hydroxy- tamoxifen and N-desmethyl-amoxifen pharmacokinetics. The 11.8% (88.2% (82.6%, 94.2%)) and 8.0% (92.0% (84.7%, 100.0%)) decreases in endoxifen AUC(last) and C(max), respectively, were not significant (90% CIs fell wholly within the prespecified acceptance range). Conclusions Steady-state desvenlafaxine 100 mg did not affect tamoxifen pharmacokinetics. For women treated with tamoxifen, desvenlafaxine may represent a safe and effective treatment unlikely to alter tamoxifen efficacy.

The objective of this study was to determine whether the occurrence of discontinuation symptoms was equivalent for abrupt discontinuation versus 1-week taper to desvenlafaxine 25 mg/d after a 24-week treatment with desvenlafaxine 50 mg/d (administered as desvenlafaxine succinate) for major depressive disorder. Adult outpatients with major depressive disorder who completed the 24 weeks of open-label treatment with desvenlafaxine 50 mg/d were randomly assigned to no discontinuation (desvenlafaxine 50 mg/d), taper (desvenlafaxine 25 mg/d), or abrupt discontinuation (placebo) groups for the double-blind (DB) taper phase. The primary end point was Discontinuation-Emergent Signs and Symptoms (DESS) scale total score during the first 2 weeks of the DB phase. The null hypothesis that the absolute difference of greater than 2.5 in DESS scores between taper and abrupt discontinuation groups was tested by calculating the 95% 2-sided confidence interval on the mean difference between the 2 groups. Of the 480 patients enrolled in the open-label phase, 357 (≥1 postrandomization DESS record) were included in the primary analysis. Adjusted mean ± SE DESS scores were 4.1 ± 0.72 for no discontinuation (n = 72), 4.8 ± 0.54 for taper (n = 139), and 5.3 ± 0.52 for abrupt discontinuation (n = 146) groups. The difference in adjusted mean DESS total scores between the abrupt discontinuation and taper groups was 0.50 (95% confidence interval, -0.88 to 1.89) within the prespecified margin (±2.5) for equivalence. The number of patients who discontinued because of adverse events or discontinuation symptoms during the DB period was similar between the taper (2.8%) and abrupt discontinuation (2.1%) groups. These findings indicate that an abrupt discontinuation of desvenlafaxine 50 mg/d produces statistically equivalent DESS scores compared with the 1-week taper using 25 mg/d.

Objective: The purpose of this post hoc analysis was to evaluate the incidence and timing of taper/posttherapy–emergent adverse events (TPAEs) following discontinuation of long-term treatment with desvenlafaxine (administered as desvenlafaxine succinate). Method: This was a phase 4, randomized, double-blind, placebo-controlled study conducted at 38 research centers within the United States between March 2010 and February 2011. Adult outpatients with major depressive disorder (MDD; DSM-IV-TR criteria) who completed 24 weeks of open-label treatment with desvenlafaxine 50 mg/d were randomly assigned to 1 of 3 groups for the double-blind taper phase: desvenlafaxine 50 mg/d for 4 weeks (no discontinuation), desvenlafaxine 25 mg/d for 1 week followed by placebo for 3 weeks (taper), or placebo for 4 weeks (abrupt discontinuation). The primary endpoint, Discontinuation-Emergent Signs and Symptoms Scale (DESS) score over the first 2 weeks of the taper phase, was described previously. Secondary assessments included incidence and timing of TPAEs (any adverse event that started or increased in severity during the double-blind phase) and the percentage of patients who could not continue the taper phase due to discontinuation symptoms. The Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16) assessed MDD status. Results: A total of 480 patients enrolled in the open-label phase; the full analysis set included 357 patients (taper, n = 139; abrupt discontinuation, n = 146; no discontinuation, n = 72). TPAEs occurred in all groups through week 4. The incidence of any TPAE was lower for taper versus abrupt discontinuation at week 1 (P < .001), similar at week 2, and lower for taper versus abrupt discontinuation at weeks 3 and 4 (P ≤ .034). The most common TPAEs (incidence ≥ 3%) in the taper group were nausea and headache (3% each) at week 1 and dizziness (5%) and headache (4%) at week 2. The most common TPAEs in the abrupt discontinuation group were dizziness (8%), headache (8%), nausea (4%), irritability (3%), and diarrhea (3%) at week 1 and headache (3%) at weeks 2 and 3. The most common TPAE in the no discontinuation group was nausea (6%) at week 2. Conclusion: The overall incidence of any TPAE was lower in the taper versus abrupt discontinuation groups. Trial Registration: ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT01056289","term_id":"NCT01056289"}}NCT01056289

This randomized, double-blind, placebo-controlled trial evaluated the efficacy of CP-601,927, an α4β2 nicotinic acetylcholine receptor partial agonist and an augmenting agent of antidepressants in major depressive disorder patients with insufficient response to selective serotonin reuptake inhibitors (SSRIs). After open-label treatment with an SSRI for 8 weeks, subjects with a Hamilton Depression Scale 17 score greater than or equal to 16 were entered into a double-blind phase and randomized to CP-601,927 2 mg twice daily or placebo for 6 weeks. The primary end point was the change in Montgomery-Asberg Depression Rating Scale (MADRS) score from double-blind baseline to week 14. There was no significant difference in change from baseline to week 14 in the MADRS score for CP-610,927 versus placebo (least square mean difference [80% confidence interval], -1.30 [-3.32-0.71]). Post hoc analyses revealed that the drug-placebo difference in change from baseline (SE) to week 14 in MADRS score was greater in subjects with body mass index (BMI) less than or equal to 35 kg/m (-3.43 [1.87], P = 0.069) than those with BMI greater than 35 kg/m (3.37 [2.8], P = 0.230). Analysis of biomarkers associated with increased BMI suggests that baseline leptin had a significant effect on treatment outcome. P values for the effect of treatment on mean change in MADRS score for subjects with baseline leptin levels below and above the median were 0.055 and 0.0055, respectively. CP-601,927 was equivalent to placebo as an augmenting agent of antidepressants in major depressive disorder patients with insufficient response to SSRIs. However, post hoc analyses suggest that BMI, particularly elevated leptin levels, may have affected the response to CP-601,927; however, further study may be needed to confirm these results.

Study background: The atypical antipsychotic aripiprazole is commonly coadministered with antidepressant drugs as an adjunctive treatment for depression. The goal of the current study was to assess the potential for multiple-dose treatment with the antidepressant desvenlafaxine (administered as desvenlafaxine succinate) to modify the pharmacokinetics of aripiprazole. Methods: Healthy subjects received aripiprazole 5 mg alone and coadministered with desvenlafaxine 100 mg at steady-state in an open-label, 2-period, sequential, inpatient/outpatient study. Blood samples collected prior to aripiprazole administration and for 14 days after each aripiprazole dose were analyzed for plasma aripiprazole and dehydro-aripiprazole concentrations. Aripiprazole area under the plasma concentration curve (AUC) over infinite time (AUCinf) and peak plasma concentration (Cmax) were determined for aripiprazole administered alone and coadministered with desvenlafaxine. Lack of an interaction was concluded if the 90% confidence intervals (CIs) for the ratio of adjusted geometric means for AUCinf and Cmax fell wholly within a prespecified acceptance range of 80% to 125%. Safety and tolerability were also assessed. Results: Aripiprazole AUCinf in the presence of steady state desvenlafaxine was 1584 ng•h/mL, compared with 1494 ng•h/mL for aripiprazole alone. The ratio of adjusted geometric mean (90% CI) was 106.0%, with CIs (101.4%, 110.8%) falling wholly within the prespecified acceptance range. The geometric mean Cmax of aripiprazole was 24.7 ng/mL for aripiprazole administered alone or with desvenlafaxine (ratio of adjusted geometric means [90% CI], 101.1% [92.9% to 109.9%]). Coadministration of desvenlafaxine with aripiprazole did not alter dehydroaripiprazole AUCinf, or Cmax (ratio of adjusted geometric means [90% CI], 102.9% [94.2%, 112.5%], and 106.3% [101.0%, 111.9%], respectively). Conclusions: Median plasma aripiprazole concentration-time profiles for single-dose administration of aripiprazole 5 mg alone and with steady-state desvenlafaxine 100 mg/d were nearly superimposable indicating that coadministration of multiple-dose desvenlafaxine 100 mg does not significantly alter aripiprazole pharmacokinetics.

A series of 3 open-label, 2-period, sequential studies were conducted to assess the impact of desvenlafaxine on cytochrome P450 3A4 (CYP3A4) enzyme-mediated metabolism, and the effect of CYP3A4 inhibition on desvenlafaxine metabolism. Study 1 evaluated a single dose of desvenlafaxine 400 mg administered alone or with a CYP3A4 inhibitor (ketoconazole [400 mg/d for 8 days]). Studies 2 and 3 evaluated a single dose of CYP3A4 substrate (midazolam [4 mg]) administered alone or with multiple doses of desvenlafaxine 400 mg and 50 mg (the recommended therapeutic dose), respectively, to assess the potential inhibitory effect of desvenlafaxine. In study 1, desvenlafaxine peak plasma concentration (Cmax) and area under the plasma concentration-versus-time curve (AUC) geometric least-squares mean ratios (desvenlafaxine and ketoconazole vs. desvenlafaxine alone) were 108% (90% confidence interval [CI], 100% to 117%) and 143% (90% CI, 138% to 149%), respectively. Total oral clearance decreased by 29% with ketoconazole coadministration. In studies 2 and 3, Cmax and AUC geometric least-squares mean ratios (midazolam and desvenlafaxine vs. midazolam alone) were 84% (90% CI, 72% to 97%) and 69% (90% CI, 61% to 78%), respectively, for the desvenlafaxine 400-mg dose, and 86% (90% CI, 79% to 94%) and 71% (90% CI, 65% to 78%), respectively, for the desvenlafaxine 50-mg dose. No serious adverse events or safety-related discontinuations occurred. Desvenlafaxine is minimally metabolized by CYP3A4 and does not appear to inhibit CYP3A4.

OBJECTIVE Evaluate the 8-week efficacy and safety of desvenlafaxine at the recommended dose of 50 mg/d in perimenopausal and postmenopausal women with major depressive disorder (MDD) based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. METHOD This phase 4, multicenter, parallel-group, randomized, double-blind, placebo-controlled study was conducted from June 30, 2010, to June 8, 2011. Patients received placebo or desvenlafaxine 50 mg/d (1:1 ratio; n = 217 in each group). The primary outcome measure was the change at week 8 in the 17-item Hamilton Depression Rating Scale (HDRS17) total score. Secondary outcome measures included change in the Sheehan Disability Scale (SDS), the Clinical Global Impressions-Improvement scale (CGI-I), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Visual Analog Scale-Pain Intensity (VAS-PI). RESULTS At end point, compared to placebo, desvenlafaxine was associated with a significantly greater decrease in HDRS17 total scores (last-observation-carried-forward analysis; adjusted mean change from baseline -9.9 vs -8.1, respectively; P = .004) and significant improvements on the CGI-I (P < .001), MADRS (P = .002), SDS (P = .038), and VAS-PI (P < .001). Improvements on the SDS and VAS-PI reached significance by week 2. Desvenlafaxine was generally safe and well tolerated. CONCLUSIONS Short-term treatment with desvenlafaxine 50 mg/d was effective for the treatment of MDD in perimenopausal and postmenopausal women, with significant benefits on pain and functional outcomes evident as early as week 2. The safety and tolerability of desvenlafaxine were consistent with data in other populations. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01121484.