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Although clinicians frequently add a second medication to an ineffective antidepressant, randomized trials comparing augmentation medications are lacking. In this study, adult outpatients with nonpsychotic major depressive disorder who had not had a remission during citalopram therapy were assigned to sustained-release bupropion or buspirone and had similar remission rates on the basis of clinician and self-reports. Several important secondary measures favored citalopram plus bupropion over citalopram plus buspirone. Adult outpatients with nonpsychotic major depressive disorder who had not had a remission during citalopram therapy were assigned to bupropion or buspirone and had similar remission rates. Several important secondary measures favored citalopram plus bupropion over citalopram plus buspirone. Numerous studies, 1 – 7 including one by Rush et al. 8 reported elsewhere in this issue of the Journal, have shown that major depressive disorder often requires more than one step of treatment to elicit a remission of symptoms. Frequently, a second medication is added to augment the first. 4 , 6 Augmentations of an initial selective serotonin-reuptake inhibitor (SSRI) with sustained-release bupropion, buspirone, mirtazapine, or dopamine agonists (e.g., pramipexole, dextroamphetamine, and methylphenidate) have been evaluated largely in open case series conducted in symptomatic volunteers with few psychiatric or general medical coexisting illnesses. 9 No randomized, controlled, prospective trials have directly compared two or more . . .

Duloxetine, a potent reuptake inhibitor of serotonin (5-HT) and norepinephrine, is effective for the treatment of major depressive disorder, diabetic neuropathic pain, stress urinary incontinence, generalized anxiety disorder and fibromyalgia. Duloxetine achieves a maximum plasma concentration (C max ) of approximately 47ng/mL (40 mg twice-daily dosing) to 110ng/mL (80 mg twice-daily dosing) approximately 6 hours after dosing. The elimination half-life of duloxetine is approximately 10–12 hours and the volume of distribution is approximately 1640 L. The goal of this paper is to provide a review of the literature on intrinsic and extrinsic factors that may impact the pharmacokinetics of duloxetine with a focus on concomitant medications and their clinical implications. Patient demographic characteristics found to influence the pharmacokinetics of duloxetine include sex, smoking status, age, ethnicity, cytochrome P450 (CYP) 2D6 genotype, hepatic function and renal function. Of these, only impaired hepatic function or severely impaired renal function warrant specific warnings or dose recommendations. Pharmacokinetic results from drug interaction studies show that activated charcoal decreases duloxetine exposure, and that CYP1A2 inhibition increases duloxetine exposure to a clinically significant degree. Specifically, following oral administration in the presence of fluvoxamine, the area under the plasma concentration-time curve and C max of duloxetine significantly increased by 460% (90% CI 359, 584) and 141% (90% CI 93, 200), respectively. In addition, smoking is associated with a 30% decrease in duloxetine concentration. The exposure of duloxetine with CYP2D6 inhibitors or in CYP2D6 poor metabolizers is increased to a lesser extent than that observed with CYP1A2 inhibition and does not require a dose adjustment. In addition, duloxetine increases the exposure of drugs that are metabolized by CYP2D6, but not CYP1A2. Pharmacodynamic study results indicate that duloxetine may enhance the effects of benzodiazepines, but not alcohol or warfarin. An increase in gastric pH produced by histamine H 2 -receptor antagonists or antacids did not impact the absorption of duloxetine. While duloxetine is generally well tolerated, it is important to be knowledgeable about the potential for pharmacokinetic interactions between duloxetine and drugs that inhibit CYP1A2 or drugs that are metabolized by CYP2D6 enzymes.

Substantial concerns have been raised about the neuropsychiatric safety of the smoking cessation medications varenicline and bupropion. Their efficacy relative to nicotine patch largely relies on indirect comparisons, and there is limited information on safety and efficacy in smokers with psychiatric disorders. We compared the relative neuropsychiatric safety risk and efficacy of varenicline and bupropion with nicotine patch and placebo in smokers with and without psychiatric disorders. We did a randomised, double-blind, triple-dummy, placebo-controlled and active-controlled (nicotine patch; 21 mg per day with taper) trial of varenicline (1 mg twice a day) and bupropion (150 mg twice a day) for 12 weeks with 12-week non-treatment follow-up done at 140 centres (clinical trial centres, academic centres, and outpatient clinics) in 16 countries between Nov 30, 2011, and Jan 13, 2015. Participants were motivated-to-quit smokers with and without psychiatric disorders who received brief cessation counselling at each visit. Randomisation was computer generated (1:1:1:1 ratio). Participants, investigators, and research personnel were masked to treatment assignments. The primary endpoint was the incidence of a composite measure of moderate and severe neuropsychiatric adverse events. The main efficacy endpoint was biochemically confirmed continuous abstinence for weeks 9–12. All participants randomly assigned were included in the efficacy analysis and those who received treatment were included in the safety analysis. The trial is registered at ClinicalTrials.gov (number NCT01456936) and is now closed. 8144 participants were randomly assigned, 4116 to the psychiatric cohort (4074 included in the safety analysis) and 4028 to the non-psychiatric cohort (3984 included in the safety analysis). In the non-psychiatric cohort, 13 (1·3%) of 990 participants reported moderate and severe neuropsychiatric adverse events in the varenicline group, 22 (2·2%) of 989 in the bupropion group, 25 (2·5%) of 1006 in the nicotine patch group, and 24 (2·4%) of 999 in the placebo group. The varenicline–placebo and bupropion–placebo risk differences (RDs) for moderate and severe neuropsychiatric adverse events were −1·28 (95% CI −2·40 to −0·15) and −0·08 (−1·37 to 1·21), respectively; the RDs for comparisons with nicotine patch were −1·07 (−2·21 to 0·08) and 0·13 (−1·19 to 1·45), respectively. In the psychiatric cohort, moderate and severe neuropsychiatric adverse events were reported in 67 (6·5%) of 1026 participants in the varenicline group, 68 (6·7%) of 1017 in the bupropion group, 53 (5·2%) of 1016 in the nicotine patch group, and 50 (4·9%) of 1015 in the placebo group. The varenicline–placebo and bupropion–placebo RDs were 1·59 (95% CI −0·42 to 3·59) and 1·78 (−0·24 to 3·81), respectively; the RDs versus nicotine patch were 1·22 (−0·81 to 3·25) and 1·42 (−0·63 to 3·46), respectively. Varenicline-treated participants achieved higher abstinence rates than those on placebo (odds ratio [OR] 3·61, 95% CI 3·07 to 4·24), nicotine patch (1·68, 1·46 to 1·93), and bupropion (1·75, 1·52 to 2·01). Those on bupropion and nicotine patch achieved higher abstinence rates than those on placebo (OR 2·07 [1·75 to 2·45] and 2·15 [1·82 to 2·54], respectively). Across cohorts, the most frequent adverse events by treatment group were nausea (varenicline, 25% [511 of 2016 participants]), insomnia (bupropion, 12% [245 of 2006 participants]), abnormal dreams (nicotine patch, 12% [251 of 2022 participants]), and headache (placebo, 10% [199 of 2014 participants]). Efficacy treatment comparison did not differ by cohort. The study did not show a significant increase in neuropsychiatric adverse events attributable to varenicline or bupropion relative to nicotine patch or placebo. Varenicline was more effective than placebo, nicotine patch, and bupropion in helping smokers achieve abstinence, whereas bupropion and nicotine patch were more effective than placebo. Pfizer and GlaxoSmithKline.

Duloxetine is a serotonin and norepinephrine reuptake inhibitor that possesses antidepressant and pain-relieving properties. Compared with other antidepressants, it has a high affinity for both norepinephrine and serotonin reuptake transporters, which are relatively balanced. Analgesic onset has been observed within the first week of administration in randomized controlled trials and is likely obtained by enhancing the tone of the descending pain inhibition pathways of the central nervous system. Randomized trials have documented significant analgesic effects for managing chronic pain associated with fibromyalgia and diabetic peripheral neuropathic pain. Studies have also suggested that pain associated with major depressive disorder can be reduced with this medication. Modest effects for headache, osteoarthritic pain, and pain secondary to Parkinson disease have also been documented, but data are obtained from single-blinded or open-label trials that require further corroboration with larger randomized studies. Duloxetine has not yet been directly compared with other antidepressants or anticonvulsants for the treatment of pain syndromes.

From recent developments on how roots affect soil organic carbon (SOC) an apparent paradox has emerged where roots drive SOC stabilization causing SOC accrual, but also SOC destabilization causing SOC loss. We synthesize current results and propose the new Rhizo-Engine framework consisting of two linked components: microbial turnover and the soil physicochemical matrix. The Rhizo-Engine is driven by rhizodeposition, root turnover, and plant uptake of nutrients and water, thereby accelerating SOC turnover through both stabilization and destabilization mechanisms. This Rhizo-Engine framework emphasizes the need for a more holistic approach to study root-driven SOC dynamics. This framework would provide better understanding of plant root effects on soil carbon sequestration and the sensitivity of SOC stocks to climate and land-use changes.

The classic model of nitrogen (N) flux into roots is as a Michaelis–Menten (MM) function of soil-N concentration at root surfaces. Furthermore, soil-N transport processes that determine soil-N concentration at root surfaces are seen as a bottleneck for plant nutrition. Yet, neither the MM relationship nor soil-N transport mechanisms are represented in current terrestrial biosphere models. Processes governing N supply to roots – diffusion, mass flow, N immobilization by soil microbes – are incorporated in a model of root-N uptake. We highlight a seldom considered interaction between these processes: nutrient traverses the rhizosphere more quickly in the presence of mass flow, reducing the probability of its immobilization before reaching the root surface. Root-N uptake is sensitive to the rate of mass flow for widely spaced roots with high N uptake capacity, but not for closely spaced roots or roots with low uptake capacity. The results point to a benefit of root switching from high- to low-affinity N transport systems in the presence of mass flow. Simulations indicate a strong impact of soil water uptake on N delivery to widely spaced roots through transpirationally driven mass flow. Furthermore, a given rate of N uptake per unit soil volume may be achieved by lower root biomass in the presence of mass flow.

Background Chemotherapy-induced peripheral neuropathy (CIPN) is a troublesome chronic symptom that has no proven pharmacologic treatment. The purpose of this double-blind randomized placebo-controlled trial was to evaluate a novel compounded topical gel for this problem. Methods Patients with CIPN were randomized to baclofen 10 mg, amitriptyline HCL 40 mg, and ketamine 20 mg in a pluronic lecithin organogel (BAK-PLO) versus placebo (PLO) to determine its effect on numbness, tingling, pain, and function. The primary endpoint was the baseline-adjusted sensory subscale of the EORTC QLQ-CIPN20, at 4 weeks. Results Data in 208 patients reveal a trend for improvement that is greater in the BAK-PLO arm over placebo in both the sensory ( p  = 0.053) and motor subscales ( p  = 0.021). The greatest improvements were related to the symptoms of tingling, cramping, and shooting/burning pain in the hands as well as difficulty in holding a pen. There were no undesirable toxicities associated with the BAK-PLO and no evidence of systemic toxicity. Conclusion Topical treatment with BAK-PLO appears to somewhat improve symptoms of CIPN. This topical gel was well tolerated, without evident systemic toxicity. Further research is needed with increased doses to better clarify the clinical role of this treatment in CIPN.

Objectives To reanalyse SmithKline Beecham’s Study 329 (published by Keller and colleagues in 2001), the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression. The reanalysis under the restoring invisible and abandoned trials (RIAT) initiative was done to see whether access to and reanalysis of a full dataset from a randomised controlled trial would have clinically relevant implications for evidence based medicine. Design Double blind randomised placebo controlled trial. Setting 12 North American academic psychiatry centres, from 20 April 1994 to 15 February 1998. Participants 275 adolescents with major depression of at least eight weeks in duration. Exclusion criteria included a range of comorbid psychiatric and medical disorders and suicidality. Interventions Participants were randomised to eight weeks double blind treatment with paroxetine (20-40 mg), imipramine (200-300 mg), or placebo. Main outcome measures The prespecified primary efficacy variables were change from baseline to the end of the eight week acute treatment phase in total Hamilton depression scale (HAM-D) score and the proportion of responders (HAM-D score ≤8 or ≥50% reduction in baseline HAM-D) at acute endpoint. Prespecified secondary outcomes were changes from baseline to endpoint in depression items in K-SADS-L, clinical global impression, autonomous functioning checklist, self-perception profile, and sickness impact scale; predictors of response; and number of patients who relapse during the maintenance phase. Adverse experiences were to be compared primarily by using descriptive statistics. No coding dictionary was prespecified. Results The efficacy of paroxetine and imipramine was not statistically or clinically significantly different from placebo for any prespecified primary or secondary efficacy outcome. HAM-D scores decreased by 10.7 (least squares mean) (95% confidence interval 9.1 to 12.3), 9.0 (7.4 to 10.5), and 9.1 (7.5 to 10.7) points, respectively, for the paroxetine, imipramine and placebo groups (P=0.20). There were clinically significant increases in harms, including suicidal ideation and behaviour and other serious adverse events in the paroxetine group and cardiovascular problems in the imipramine group. Conclusions Neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs. Access to primary data from trials has important implications for both clinical practice and research, including that published conclusions about efficacy and safety should not be read as authoritative. The reanalysis of Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base.

IntroductionProgressive supranuclear palsy (PSP) is a devastating neurodegenerative disease characterised by cognitive, behavioural and motor problems. Motor symptoms are highly disabling, while cognitive and behavioural changes have a major impact on carer burden, quality of life and prognosis. Apathy and impulsivity are very common, often coexistent in PSP, and negatively predict survival. In preclinical models and other diseases, apathy and impulsivity are associated with noradrenergic deficits, which can be severe in PSP.Methods and analysisNoradrenaline for Progressive Supranuclear Palsy Syndromes trial is a randomised, double-blind, placebo-controlled, crossover design, Phase IIb clinical trial to evaluate the efficacy and safety of oral atomoxetine for the treatment of cognitive and behavioural changes in PSP. Participants receive atomoxetine 40 mg (10 mg/mL oral solution) once daily or a matched placebo solution, in random order, each for 8 weeks. An ‘informant’, who knows the patient with PSP well, is co-recruited to complete some of the trial outcome measures. Participants remain in the trial for 22 weeks after randomisation. The primary objectives are to assess (1) safety and tolerability and (2) efficacy versus placebo on challenging behaviours as reported in a subscale of the Cambridge Behavioural Inventory. Secondary and exploratory measures relate to cognition, the PSP Rating Scale, mood and potential baseline predictors of individual response to atomoxetine computed from imaging, genetic and cognitive measures at baseline.Ethics and disseminationThe trial was approved by the South Central-Oxford B Research Ethics Committee (REC) and the Medicines and Healthcare products Regulatory Agency (REC reference: 20/SC/0416). Dissemination will include publication in peer-reviewed journals, presentations at academic and public conferences and engagement with patients, the public, policymakers and practitioners.Trial registration numberISRCTN99462035; DOI: https://doi.org/10.1186/ISRCTN99462035; EudraCT (European Union Drug Regulating Authorities Clinical Trials Database)/CTIS (Clinical Trial Information System) number: 2019-004472-19; IRAS (Integrated Research Application System) number: 272063; Secondary identifying numbers: CPMS (Central Portfolio Management System) 44441.

Mineral phosphorus (P) fertilizers support high crop yields and contribute to feeding the teeming global population. However, complex edaphic processes cause P to be immobilized in soil, hampering its timely and sufficient availability for uptake by plants. The resultant low use efficiency of current water-soluble P fertilizers creates significant environmental and human health problems. Current practices to increase P use efficiency have been inadequate to curtail these problems. We advocate for the understanding of plant physiological processes, such as physiological P requirement, storage of excess P as phytate, and plant uptake mechanisms, to identify novel ways of designing and delivering P fertilizers to plants for improved uptake. We note the importance and implications of the contrasting role of micronutrients such as zinc and iron in stimulating P availability under low soil P content, while inhibiting P uptake under high P fertilization; this could provide an avenue for managing P for plant use under different P fertilization regimes. We argue that the improvement of the nutritional value of crops, especially cereals, through reduced phytic acid and increased zinc and iron contents should be among the most important drivers toward the development of innovative fertilizer products and fertilization technologies. In this paper, we present various pathways in support of this argument. Retuning P fertilizer products and application strategies will contribute to fighting hunger and micronutrient deficiencies in humans. Moreover, direct soil P losses will be reduced as a result of improved P absorption by plants.