Emerging drugs for major depressive disorder.
ABSTRACT INTRODUCTION: Major depressive disorder (MDD) remains a major public health concern, and one that continues to suffer an incompletely-met need for effective and acceptable treatments. The development of antidepressants, to date, has focused primarily on increasing monoamine neurotransmission with increasing efficacy while minimizing adverse effects. Medications currently recommended as 'first-line' are far more tolerable than the older medications they replaced, but as many as 70% of patients continue to suffer significant depressive symptoms after treatment with one of these agents, and as many as 50% will discontinue a trial due to issues with acceptability. This review will summarize antidepressants that have recently entered the market as well as those still in development to help characterize the current state of antidepressant development. AREAS COVERED: Currently available first-line antidepressants are reviewed with respect to efficacy and tolerability, and their weaknesses are discussed as targets for future development. The background, clinical trial data and potential significance of the three most recently introduced antidepressants (trazodone-ER, desvenlafaxine and vilazodone) and the most recently approved augmentation agents (aripiprazole and quetiapine) are discussed. Following a review of the current market, all medications currently in Phase II or later clinical trials are listed and discussed, based on a thorough review of the US National Institutes of Health clinicaltrials.gov index for trials using medications to treat MDD and a search of the Informa Pharmaprojects database for medications currently being developed for a depression indication. Compounds thus identified were then used as search terms in a PubMed search of each medication. Based on pharmacologic properties, medications in development were grouped into those acting on: i) monoamine neurotransmission; ii) cholinergic neurotransmission; iii) glutamatergic neurotransmission; iv) opioid receptors; v) sigma receptors; vi) neurokinin receptors; vii) corticotrophin-releasing factor receptors and viii) other mechanisms. In the discussion of each, a brief review of the pharmacology and physiology of the related system is provided. Potential issues for the future of antidepressant development and an expert opinion are discussed. EXPERT OPINION: The past decade has not yielded a large number of new antidepressants and, with the possible exception of agomelatine, none of the newer medications that have been introduced have decisively addressed the several unmet needs in this area of therapeutics. Among the various novel strategies that are being evaluated, results of several small studies of ketamine suggest that drugs that modulate glutamatergic neurotransmission may hold the greatest promise for exerting rapid and large antidepressant effects in patients who have not responded to SSRIs or SNRIs.
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ABSTRACT: This study assessed prevention of relapse in patients with treatment-resistant depression (TRD) taking olanzapine/fluoxetine combination (OFC). Patients with major depressive disorder (MDD) who failed to satisfactorily respond to ⩾2 different antidepressants for ⩾6 weeks within the current MDD episode were acutely treated for 6-8 weeks, followed by stabilization (12 weeks) on OFC. Those who remained stable were randomized to OFC or fluoxetine for up to 27 weeks. Time-to-relapse was the primary efficacy outcome defined as 50% increase in Montgomery-Åsberg Depression Rating Scale score with Clinical Global Impressions-Severity of Depression score of ⩾4; hospitalization for depression or suicidality; or discontinuation for lack of efficacy or worsening of depression or suicidality. A total of 444 patients were randomized 1:1 to OFC (N=221) or fluoxetine (N=223). Time-to-relapse was significantly longer in OFC-treated patients compared with fluoxetine-treated patients (p<0.001). Treatment-emergent weight gain and some mean and categorical fasting metabolic changes were significantly greater in OFC-treated patients. Clinically significant weight gain (⩾7%) was observed in 55.7% of patients who remained on OFC throughout the study, including the relapse-prevention phase (up to 47 weeks). There were no significant differences between patients treated with OFC and fluoxetine in extrapyramidal symptoms or serious adverse events. We believe this is the first controlled relapse-prevention study in subjects with TRD that supports continued use of a second-generation antipsychotic beyond stabilization. A thorough assessment of benefits and risks (in particular metabolic changes) associated with continuing treatment with OFC or fluoxetine must be done based on individual patient needs.Neuropsychopharmacology accepted article preview online, 07 May 2014; doi:10.1038/npp.2014.101.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 05/2014; · 8.68 Impact Factor
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ABSTRACT: The study assessed the consumption of antidepressants in Italy between 2000 and 2011 and identified trends in use.Psychiatric services (Washington, D.C.) 07/2014; · 2.81 Impact Factor
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ABSTRACT: Major depression is a highly prevalent disorder and is predicted to be the second leading cause of disease burden by 2020. Although many antidepressant drugs are currently available, they are far from optimal. Approximately 50% of patients do not respond to initial first line antidepressant treatment, while approximately one third fail to achieve remission following several pharmacological interventions. Furthermore, several weeks or months of treatment are often required before clinical improvement, if any, is reported. Moreover, most of the commonly used antidepressants have been primarily designed to increase synaptic availability of serotonin and/or noradrenaline and although they are of therapeutic benefit to many patients, it is clear that other therapeutic targets are required if we are going to improve the response and remission rates. It is clear that more effective, rapid-acting antidepressants with novel mechanisms of action are required. The purpose of this review is to outline the current strategies that are being taken in both preclinical and clinical settings for identifying superior antidepressant drugs. The realisation that ketamine has rapid antidepressant-like effects in treatment resistant patients has reenergised the field. Further, developing an understanding of the mechanisms underlying the rapid antidepressant effects in treatment-resistant patients by drugs such as ketamine may uncover novel therapeutic targets that can be exploited to meet the Olympian challenge of developing faster, better and stronger antidepressant drugs.European Journal of Pharmacology 08/2014; · 2.68 Impact Factor