Current Status of Ketamine and Related Compounds for Depression

Experimental Therapeutics and Pathophysiology, National Institute of Mental Health (NIMH), 베서스다, Maryland, United States
The Journal of Clinical Psychiatry (Impact Factor: 5.5). 05/2013; 74(5):516-7. DOI: 10.4088/JCP.13ac08382
Source: PubMed
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    • "In this study we have used a translational rodent assay of affective bias (Stuart et al, 2013) to investigate whether temporal differences in onset of clinical efficacy seen with delayed-onset (eg, noradrenaline and serotonin reuptake inhibitor venlafaxine) vs rapid-onset antidepressant treatments (eg, NMDA antagonist ketamine) (Zarate et al, 2006; Mathews and Zarate, 2013) could involve differential modification of these affective biases. The rodent affective bias test (ABT) has shown that experience-dependent learning is biased by affective state or pharmacological treatments, and it exhibits both translational and predictive validity "
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    ABSTRACT: The biochemical targets for antidepressants are relatively well established, but we lack a clear understanding of how actions at these proteins translate to clinical benefits. This study used a novel rodent assay to investigate how different antidepressant drugs act to modify affective biases, which have been implicated in depression. In this bowl-digging task, rats encounter two equal value learning experiences on separate days (one during an affective manipulation, one during control conditions). This induces an affective bias which is quantified using a preference test in which both digging substrates are presented together and the individual rats' choices recorded. The assay can be used to measure affective biases associated with learning (when the treatment is given at the time of the experience) or, examine the modification of previously acquired biases (when the treatment is administered before the preference test). The rapid onset antidepressant ketamine, but not the delayed onset antidepressant, venlafaxine, attenuated the previously acquired FG7142-induced negative bias following systemic administration. Venlafaxine but not ketamine induced a positive bias when administered before learning. We then used local drug infusions and excitotoxic lesions to localise the effects of ketamine to the medial prefrontal cortex and venlafaxine to the amygdala. Using a modified protocol we also showed that positive and negative biases amplified further when the number of substrate-reinforcer associations are increased. We propose that this pattern of results could explain the delayed onset of action of venlafaxine and the rapid onset of action but lack of long term efficacy seen with ketamine.Neuropsychopharmacology accepted article preview online, 05 March 2015. doi:10.1038/npp.2015.59.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 03/2015; 40(9). DOI:10.1038/npp.2015.59 · 7.05 Impact Factor
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    ABSTRACT: While stressful experiences are a part of everyone's life, they can also exact a major toll on health. Stressful life experiences are associated with increased substance abuse, and there exists significant co-morbidity between mental illness and substance use disorders [N.D. Volkow & T.K. Li (2004) Nat. Rev. Neurosci., 5, 963–970; G. Koob & M.J. Kreek (2007) Am. J. Psych., 164, 1149–1159; R. Sinha (2008) Annals N.Y. Acad. Sci., 1141, 105–130]. The risk for development of mood or anxiety disorders after stress is positively associated with the risk for substance use disorders [R. Sinha (2008) Annals N.Y. Acad. Sci., 1141, 105–130], suggesting that there are common substrates for vulnerability to addictive and affective disorders. Understanding the molecular and physiological substrates of stress may lead to improved therapeutic interventions for the treatment of substance use disorders and mental illnesses.
    European Journal of Neuroscience 04/2014; 39(7). DOI:10.1111/ejn.12490 · 3.18 Impact Factor
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    ABSTRACT: Summary Bipolar depression remains a major challenge for psychiatric therapeutics. It is associated with disability and excess mortality, and accounts for three-quarters of the time spent in morbid states by treated patients with bipolar disorder. Major limitations of research on the treatment of depression in bipolar disorder include a paucity of short-term and lack of long-term trials, probably reflecting concern about inducing mania. In addition, polytherapy with multiple drugs appears to be widespread, but it is virtually untested for efficacy and safety. Here, we summarise the evidence concerning efficacy of treatment of bipolar depression with antidepressants, moodstabilising anticonvulsants, lithium and secondgeneration antipsychotics. Learning objectives • Gain critical appreciation of the paucity of research on the treatment of bipolar depression. • Rationally balance the benefits and risks of using antidepressants in patients with bipolar disorder. • Assess the evidence supporting a range of research-based treatment options for bipolar depression. Declaration of interest None.
    Advances in Psychiatric Treatment 04/2014; 20(20):193-201. DOI:10.1192/apt.bp.113.011460
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