Einstein schreef:Ik heb er bij mezelf op gelet, van psychedelica ervaar ik toch veel meer een antidepressieve werking dan van ketamine
Clinical studies consistently demonstrate that a single sub-psycho- mimetic dose of ketamine, an ionotropic glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depres- sive disorder, although the underlying mechanism is unclear1–3. Depressed patients report the alleviation of major depressive dis- order symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks1–3, unlike traditional antidepressants (serotonin re-uptake inhibitors), which take weeks to reach efficacy.
The ability of ketamine to produce rapidly acting, long-lasting anti- depressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. Here we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor.
Letter: NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses (2011)
Depression
Increased depression (assessed with the Beck Depression Inventory) in both daily users and ex-ketamine users was found over the course of 1 year in our longitudinal study [31] but not in current infrequent (>1 per month, <3 times per week) users. However, this elevated depression was not at clinical levels and the increase was not corre- lated with changes in ketamine use.
In contrast, a preliminary study of seven patients suggested that one dose of ketamine can have rapid and relatively prolonged antidepressant effects in depressed patients who did not respond to usual treatments [47]. Enthusiasm for this approach was rekindled by a larger study of 18 treatment-resistant patients administered 0.5 mg/kg ketamine over 40 minutes [48]. Twelve of the patients showed an immediate 50% reduction in mea- sures of depression compared with none of 14 patients given placebo. The antidepressant effects of one dose lasted 1–2 weeks in eight patients, but they all relapsed thereafter, leading to calls for repeated ketamine treat- ment of depression (e.g. [8]). In the first clinical trial, Aan het Rot et al. [49] gave depressed patients six infusions of ketamine (on days 0, 3, 5, 8, 10 and 12). Of the nine patients who received repeated infusions (dependent upon their response to the first infusion), eight relapsed within an estimated mean 30 days after the first infusion or 19 days after the sixth infusion. The rapid response to ketamine contrasts with the 3–4-week lag in response to mainstream antidepressants. However, the chronic effects of the drug should be monitored if repeated dosing is to be a strategy in the treatment of depression.
Ketamine use: a review (2011)
Another clinical use of ketamine is as part of the anesthetic procedures commonly used in electroconvulsive shock therapy (ECT) for the control of severe depression (e.g. Goforth and Holsinger, 2007).
Although ketamine has been an incidental part of ECT- related anesthesia for some time (e.g. Rasmussen et al., 1996), the possibility that it could have antidepressant effects by itself was only recently considered (Berman et al., 2000; Zarate et al., 2006; Ostroff et al., 2005; Correll et al., 2006). Most of these reports suggest that sub-anes- thetic doses of ketamine by themselves can have thera- peutic effects in depressed patients. Although these re- sults are counterintuitive (sub-anesthetic doses of CNS depressants typically exacerbate clinical depression), the antidepressant effects of ketamine seem replicable and have two properties that are clinically important. First, ket- amine’s antidepressant effect has been demonstrated in patients who were otherwise treatment-resistant (Zarate et al., 2006). Second, the antidepressant effect of ketamine emerged promptly, within a few hours or days of the initial treatment (Berman et al., 2000; Correll et al., 2006; Zarate et al., 2006), and persisted for up to a week post-injection (Zarate et al., 2006).
While the antidepressant effects of ketamine demon- strated in humans seem very promising, there have been few attempts to corroborate these findings in double blind, placebo-controlled clinical trials. Of the two double-blind placebo-controlled trials that do exist, the authors acknowl- edge that their experimental design may have been com- promised because of the well-know psychoactive effects of ketamine (Berman et al., 2000; Zarate et al., 2006). Both patients and clinicians were aware of these effects (e.g. the feeling of being “high”), and in this sense the trial was neither “blinded” nor “placebo” controlled. In addition, the i.v. route of administration used in these studies may have facilitated the rapid antidepressant-like effects of ketamine, since there are reports that “classic” antidepressant drugs (e.g. clomipramine) given intravenously also have rela- tively rapid antidepressant effects (Sallee et al., 1997).
Some of these issues can be addressed in experimental animal models which allow for the control and manipulation of many of these variables. However, studies of ketamine in animal models of depression have been sparse and have not systematically addressed issues such as dose, route of ad- ministration, and behavioral side effects. Both antidepres- sant-like and null effects have been reported in animal tests of the antidepressant effects of ketamine (Hayase et al., 2006; Mantovani et al., 2003; Rosa et al., 2003). Whether this variability is attributable to pharmacological factors such as dose, or to side-effects such as hyper-locomotion, needs to be systematically explored (Campos et al., 2006).
The receptor selectivity of the antidepressant-like ef- fect of ketamine is also an important issue, despite the widely held view that its effects are due to NMDA receptor blockade (e.g. Yilmaz et al., 2002). Ketamine binds to a number of neurotransmitter receptors in addition to NMDA, as well as to monoamine re-uptake transporters (e.g. DAT, SERT), with an affinity that is comparable to its affinity for the NMDA receptor (Kapur and Seeman, 2002). However, the involvement of non-NMDA receptor interactions in the antidepressant effects of ketamine has not been studied. The degree to which ketamine produces its antidepressant effects by blocking glutamatergic receptors or inhibiting monoaminergic transporters also has important implications for theories of antidepressant drug action.
In summary, although there is some reason to believe that ketamine has anxiolytic and antidepressant effects in humans and in animal models, the overall evidence for this belief is not entirely convincing.
ANXIOLYTIC- AND ANTIDEPRESSANT-LIKE PROPERTIES OF KETAMINE IN BEHAVIORAL AND NEUROPHYSIOLOGICAL ANIMAL MODELS (2009)
Het bovenstaande is de introductie van de paper, de rest van paper bekijkt de werking van ketamine binnen dier modellen waarbij er word vastgesteld dat ketamine een antidepressant-like effect heeft. De precieze onderliggende werking is hierbij niet bekend en vraagt om verdere studie.
Geplaatst: wo jul 13, 2011 12:08 pm
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