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The Effect of Food on the Single-Dose Bioavailability and Tolerability of the Highest Marketed Strength of Duloxetine.
Rizea-Savu, S, Duna, SN, Ghita, A, Iordachescu, A, Chirila, M
Clinical pharmacology in drug development. 2020;(7):797-804
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Abstract
Duloxetine is a combined serotonin and norepinephrine reuptake inhibitor indicated in adults for the treatment of major depressive disorder, diabetic peripheral neuropathic pain, and generalized anxiety disorder. The aim of these studies was to evaluate the effect of food on the pharmacokinetics and safety of duloxetine 60-mg gastroresistant hard capsules following single-dose administration. The data were obtained from 2 phase 1 bioequivalence studies, 1 in a fasting state and the other under fed conditions. Both studies have shown that, when administered as a single dose in the same prandial state, the test and reference duloxetine treatments were bioequivalent and exhibited similar safety profiles. The mean fed and fasting pharmacokinetic parameters and drug-related adverse events from the 2 studies were compared in order to assess the effect of food on the duloxetine bioavailability and respectively, tolerability. Administration of duloxetine in fed conditions increased peak plasma concentration by up to 30% and delayed mean time to peak concentration by an average of 1.15 hours while having an insignificant effect on extent of absorption (area under the plasma concentration-time curve in fed state within ±6% as compared with fasting conditions). Even though peak plasma levels were substantially higher in the fed state, there was no negative impact on the drug's safety profile. Actually, administration with food resulted in a lower average number of adverse events per single dose exposure. The negligible variation in overall systemic exposure suggests that efficacy remains unchanged irrespective of administration conditions; however, a better tolerability of the 60-mg dose is expected when the drug is taken with food.
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Randomized, Double-Blind, Placebo-Controlled Trial of the mGlu2/3 Negative Allosteric Modulator Decoglurant in Partially Refractory Major Depressive Disorder.
Umbricht, D, Niggli, M, Sanwald-Ducray, P, Deptula, D, Moore, R, Grünbauer, W, Boak, L, Fontoura, P
The Journal of clinical psychiatry. 2020;(4)
Abstract
OBJECTIVE To assess putative antidepressant and procognitive effects of decoglurant, a selective metabotropic glutamate receptor type 2/3 (mGlu2/3) negative allosteric modulator, as adjunctive treatment to selective serotonin reuptake inhibitors and/or serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs) in patients with partially refractory major depressive disorder (MDD), diagnosed using DSM-IV-TR criteria. METHODS This randomized, placebo-controlled, double-blind, multicenter phase 2 trial consisted of 4 weeks' screening, 6 weeks' treatment, and 8 weeks' follow-up between September 2011 and June 2014. Individuals with Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥ 25 and Clinical Global Impressions-Severity of Illness scale score ≥ 4, despite up to 2 adequate trials of an SSRI/SNRI and compliance confirmed by positive SSRI/SNRI blood levels, were randomized to decoglurant 5 mg (n = 101), 15 mg (n = 102), or 30 mg (n = 55) daily or placebo (n = 99) as adjunct to ongoing treatment with 1 SSRI/SNRI. An adaptive design was used with an interim analysis after 30 patients in each group had received 6 weeks' treatment. The primary outcome variable was change in MADRS total score from baseline to end of treatment. Primary assessments were performed by fully blinded centralized raters. RESULTS Of 357 participants, 310 completed 6 weeks' treatment. At 6 weeks, no significant differences between any active treatment arm and placebo in reducing MADRS total score or response or remission rates were observed. Decoglurant exerted no significant effects on Cambridge Neuropsychological Test Automated Battery cognitive accuracy and cognitive speed composite scores or on secondary measures of mood and functioning. A relatively high placebo response was observed, which may have constrained the ability to detect treatment effects. No deaths occurred; few patients reported serious adverse events. CONCLUSIONS Decoglurant was well tolerated overall but did not exert any antidepressant or procognitive effects. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01457677.
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Acetyl-l-carnitine deficiency in patients with major depressive disorder.
Nasca, C, Bigio, B, Lee, FS, Young, SP, Kautz, MM, Albright, A, Beasley, J, Millington, DS, Mathé, AA, Kocsis, JH, et al
Proceedings of the National Academy of Sciences of the United States of America. 2018;(34):8627-8632
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Abstract
The lack of biomarkers to identify target populations greatly limits the promise of precision medicine for major depressive disorder (MDD), a primary cause of ill health and disability. The endogenously produced molecule acetyl-l-carnitine (LAC) is critical for hippocampal function and several behavioral domains. In rodents with depressive-like traits, LAC levels are markedly decreased and signal abnormal hippocampal glutamatergic function and dendritic plasticity. LAC supplementation induces rapid and lasting antidepressant-like effects via epigenetic mechanisms of histone acetylation. This mechanistic model led us to evaluate LAC levels in humans. We found that LAC levels, and not those of free carnitine, were decreased in patients with MDD compared with age- and sex-matched healthy controls in two independent study centers. Secondary exploratory analyses showed that the degree of LAC deficiency reflected both the severity and age of onset of MDD. Moreover, these analyses showed that the decrease in LAC was larger in patients with a history of treatment-resistant depression (TRD), among whom childhood trauma and, specifically, a history of emotional neglect and being female, predicted the decreased LAC. These findings suggest that LAC may serve as a candidate biomarker to help diagnose a clinical endophenotype of MDD characterized by decreased LAC, greater severity, and earlier onset as well as a history of childhood trauma in patients with TRD. Together with studies in rodents, these translational findings support further exploration of LAC as a therapeutic target that may help to define individualized treatments in biologically based depression subtype consistent with the spirit of precision medicine.
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Clinical predictors of ketamine response in treatment-resistant major depression.
Niciu, MJ, Luckenbaugh, DA, Ionescu, DF, Guevara, S, Machado-Vieira, R, Richards, EM, Brutsche, NE, Nolan, NM, Zarate, CA
The Journal of clinical psychiatry. 2014;(5):e417-23
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Abstract
OBJECTIVE The N-methyl-D-aspartate receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD) and bipolar depression. Clinical predictors may identify those more likely to benefit from ketamine within clinically heterogeneous populations. METHOD Data were analyzed from 4 studies of treatment-resistant inpatients with DSM-IV-TR-diagnosed MDD or bipolar I or II depression. Patients who were currently experiencing a moderate-to-severe major depressive episode were enrolled between November 2004 and March 2013. All subjects received a single subanesthetic (0.5 mg/kg) ketamine infusion over 40 minutes. Patients were analyzed at the 230-minute postinfusion time point (n = 108), at day 1 (n = 82), and at day 7 (n = 71). Univariate Pearson correlations were performed for each variable with percent change from baseline in the 17-item Hamilton Depression Rating Scale (HDRS). Multivariate linear regression was then conducted for statistically significant predictors (P ≤ .05, 2-tailed). RESULTS Higher body mass index correlated with greater HDRS improvement at 230 minutes (standardized β = -0.30, P = .004) and at day 1 (standardized β = -0.37, P = .001), but not at day 7 (standardized β = -0.18, P = .10). Family history of an alcohol use disorder in a first-degree relative was associated with greater HDRS improvement at day 1 (standardized β = -0.27, P = .014) and day 7 (standardized β = -0.41, P < .001). No prior history of suicide attempt(s) was associated with greater improvement only at day 7 (standardized β = 0.28, P = .01). The overall statistical model explained 13%, 23%, and 36% of HDRS percent change variance at 230 minutes, day 1, and day 7, respectively. CONCLUSIONS Despite its post hoc nature, this study identified several clinical correlates of ketamine's rapid and durable antidepressant effects. Further investigation of these relationships is critical for individualized treatment of depression.
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Depression, self-care, and medication adherence in type 2 diabetes: relationships across the full range of symptom severity.
Gonzalez, JS, Safren, SA, Cagliero, E, Wexler, DJ, Delahanty, L, Wittenberg, E, Blais, MA, Meigs, JB, Grant, RW
Diabetes care. 2007;(9):2222-7
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Abstract
OBJECTIVE We examined the association between depression, measured as either a continuous symptom severity score or a clinical disorder variable, with self-care behaviors in type 2 diabetes. RESEARCH DESIGN AND METHODS We surveyed 879 type 2 diabetic patients from two primary care clinics using the Harvard Department of Psychiatry/National Depression Screening Day Scale (HANDS), the Summary of Diabetes Self-Care Activities, and self-reported medication adherence. RESULTS Of the patients, 19% met the criteria for probable major depression (HANDS score >or=9), and an additional 66.5% reported at least some depressive symptoms. After controlling for covariates, patients with probable major depression reported significantly fewer days' adherent to diet, exercise, and glucose self-monitoring regimens (P < 0.01) and 2.3-fold increased odds of missing medication doses in the previous week (95% CI 1.5-3.6, P < 0.001) compared with all other respondents. Continuous depressive symptom severity scores were better predictors of nonadherence to diet, exercise, and medications than categorically defined probable major depression. Major depression was a better predictor of glucose monitoring. Among the two-thirds of patients not meeting the criteria for major depression (HANDS score <9, n = 709), increasing HANDS scores were incrementally associated with poorer self-care behaviors (P < 0.01). CONCLUSIONS These findings challenge the conceptualization of depression as a categorical risk factor for nonadherence and suggest that even low levels of depressive symptomatology are associated with nonadherence to important aspects of diabetes self-care. Interventions aimed at alleviating depressive symptoms, which are quite common, could result in significant improvements in diabetes self-care.