Some of them have appreciable affinities at other sites (mainly DAT and sigma receptors), a 10-fold selectivity isn't really considered very selective.On a side note, I am also curious about Sodium Acetate Tri-Hydrate as a catalyst instead of Sulfuric/ Phosphoric acid.
To sum up briefly: the effectiveness of ketamine as an antidepressant stems not from its action as an antagonist of NMDA receptors, as was previously thought, but rather those of one of its metabolites (blocking the metabolic step blocked the beneficial effects of ketamine). The metabolite is non-psychoactive, and turns out to act on AMPA receptors (it activates them, and preventing their activation blocks the antidepressant effects). Quite a turn up for the books!NMDAR inhibition-independent antidepressant actions of ketamine metabolites
Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist (R,S)-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2R,6R)-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of (R,S)-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants.
Stimulants don't effect people with ADD any differently than others
Stimulants such as methylphenidate and amphetamine are currently the most common treatment for attention deficit hyperactivity disorder (ADHD). For years, it was assumed that stimulants had paradoxical calming effects in ADHD patients, whereas stimulating ?€˜normal?€™ individuals and producing locomotor activation in rats. It is now known that low doses of stimulants focus attention and improve executive function in both normal and ADHD subjects. Furthermore, the seminal work of Kuczenski and Segal showed that low, oral doses of methylphenidate reduce locomotor activity in rats as well.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32802-7/fulltextWe identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2.13 (95% credible interval [CrI] 1.89-2.41) for amitriptyline and 1.37 (1.16-1.63) for reboxetine. For acceptability, only agomelatine (OR 0.84, 95% CrI 0.72-0.97) and fluoxetine (0.88, 0.80-0.96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1.30, 1.01-1.6. When all trials were considered, differences in ORs between antidepressants ranged from 1.15 to 1.55 for efficacy and from 0.64 to 0.83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1.19-1.96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0.51-0.84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0.43-0.77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1.30-2.32). 46 (9 of 522 trials were rated as high risk of bias, 380 (73 trials as moderate, and 96 (18 as low; and the certainty of evidence was moderate to very low.
All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants.