Antidepressant Effect of Ketamine During ECT

Ostroff, Robert; Gonzales, M Cervantes; Sanacora, Gerard

doi:10.1176/appi.ajp.162.7.1385

Cited by 81 publications

(39 citation statements)

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“…Beside the abovementioned report on D-cycloserine, slight antidepressant effects in humans have also been observed with the NMDA receptor antagonists amantadine 10,11 and ketamine. 12,13 Riluzole, an antiglutamatergic agent believed to increase the glutamatergic uptake into the astrocytes, is under intensive investigation for its antidepressant potential. 14 A recent series of openlabelled studies and case reports demonstrated its efficacy.…”

Section: Glutamate In Depressionmentioning

confidence: 99%

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

2007

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Beside the well-known deficiency in serotonergic neurotransmission as pathophysiological correlate of major depression (MD), recent evidence points to a pivotal role of increased glutamate receptor activation as well. However, cause and interaction of these neurotransmitter alterations are not understood. In this review, we present a hypothesis integrating current concepts of neurotransmission and hypothalamus-pituitary-adrenal (HPA) axis dysregulation with findings on immunological alterations and alterations in brain morphology in MD. An immune activation including increased production of proinflammatory cytokines has repeatedly been described in MD. Proinflammatory cytokines such as interleukin-2, interferon-c, or tumor necrosis factor-a activate the tryptophan-and serotonin-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Depressive states during inflammatory somatic disorders are also associated with increased proinflammatory cytokines and increased consumption of tryptophan via activation of IDO. An enhanced consumption of serotonin and its precursor tryptophan through IDO activation could well explain the reduced availability of serotonergic neurotransmission in MD. An increased activation of IDO and its subsequent enzyme kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to an enhanced production of quinolinic acid, a strong agonist of the glutamatergic N-methyl-D-aspartate receptor. In inflammatory states of the central nervous system, IDO is mainly activated in microglial cells, which preferentially metabolize tryptophan to the NMDA receptor agonist quinolinic acid, whereas astrocytes -counteracting this metabolism due to the lack of an enzyme of this metabolism -have been observed to be reduced in MD. Therefore the type 1/type 2 immune response imbalance, associated with an astrocyte/microglia imbalance, leads to serotonergic deficiency and glutamatergic overproduction. Astrocytes are further strongly involved in re-uptake and metabolic conversion of glutamate. The reduced number of astrocytes could contribute to both, a diminished counterregulation of IDO activity in microglia and an altered glutamatergic neurotransmission. Further search for antidepressant agents should take into account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors, might exert antidepressant effects by acting on serotonergic deficiency, glutamatergic hyperfunction and antagonizing neurotoxic effects of quinolinic acid. Molecular Psychiatry (2007) 12, 988-1000; doi:10.1038/sj.mp.4002006; published online 24 April 2007 Keywords: major depression; psychoneuroimmunology; IDO; glutamate; immune system; serotonin Glutamate in depressionGlutamatergic neurotransmission is involved in depression and interacts with the serotonergic and noradrenergic systems The common therapeutic mechanism of antidepressant drugs is the enhancement of serotonergic and/or noradrenergic neurotransmission. On the basis of this pharmacological profile of antidepressant drugs, neurochemical research on major depression ...

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Section: Glutamate In Depressionmentioning

confidence: 99%

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

2007

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“…Slight antidepressive effects have also been observed with amantadine (Huber et al 1999;Stryjer et al 2003). Moreover, preliminary data show antidepressant effects of the NMDA receptor antagonist ketamine (Kudoh et al 2002;Ostroff et al 2005) and riluzole, an antiglutamatergic agent believed to increase the glutamatergic uptake into the astrocytes, is under intensive investigation for its antidepressant efficacy (Frizzo et al 2004). A series of open-labelled studies and case reports demonstrated the efficacy of riluzole (Coric et al 2003;Sanacora et al 2004b;Zarate Jr et al 2004.…”

Section: Aspartate-receptor Function Are Disturbed In MDmentioning

confidence: 99%

Inflammatory Biomarkers and Depression

2010

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Antidepressants, predominantly serotonin- and/or noradrenaline reuptake inhibiting drugs have several shortcomings. The exact pathophysiological mechanisms leading to serotonergic-, noradrenergic- or dopaminergic dysfunction are still unclear. An inflammatory mechanism has been postulated and will be discussed here including possible therapeutic advantages of cyclooxygenase-2 (COX-2) inhibitors. Differences in the activation of the enzyme indoleamine 2,3-dioxygenase (IDO) and in the tryptophan-kynurenine metabolism resulting in an increased tryptophan and serotonin degradation and probably in an increased production of quinolinic acid might play a key role in major depression (MD). These differences are associated with an imbalance in the glutamatergic neurotransmission, which may contribute to an overweight of N-methyl-D: -aspartate agonism in MD. The immunological imbalance results in an increased prostaglandin E₂ production and probably also in an increased COX-2 expression. Although there is strong evidence for the view that the interactions of the immune system, IDO, the serotonergic system and the glutamatergic neurotransmission play a key role in MD, several gaps, e.g. the roles of genetics, disease course, sex, different psychopathological states, etc., have to be bridged by intense further research. There were already hints that anti-inflammatory therapy might have beneficial effects in MD. COX-2 inhibitors, however, have been tested in animal models and in preliminary clinical studies showing favourable effects compared to placebo in MD. The effects of COX-2 inhibition in the CNS as well as the different components of the inflammatory system, the kynurenine-metabolism and the glutamatergic neurotransmission, however, still need careful further scientific evaluation including clinical studies in bigger samples of patients.

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“…Recent observations in clinical settings suggest that at subanesthetic doses, ketamine produces therapeutic effects in depressed patients (Berman et al 2000;Ostroff et al 2005;Correll and Futter 2006;Zarate et al 2006;Goforth and Holsinger 2007). These antidepressant actions were characterized by a rapid (hours) onset of action (Berman et al 2000;Correll and Futter 2006), lasted for a significant time (1 week), appeared after a single dose, and were effective in treatment-resistant patients (Zarate et al 2006).…”

Section: Introductionmentioning

confidence: 99%