The positive effect on ketamine as a priming adjuvant in antidepressant treatment

Melo, Antonio Carlos de Paiva; Kokras, Nikolaos; Dalla, Christina; Ferreira, Clara; Ventura-Silva, Ana Paula; Sousa, Nuno; Pêgo, José M.

doi:10.1038/tp.2015.66

Cited by 43 publications

(34 citation statements)

References 43 publications

(49 reference statements)

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“…[10,15]). Moreover, rodent and human evidence show region-specific neuroplasticity effects of ketamine consistent with increased synaptic connectivity in the PFC and hippocampus, but decreased synaptic connectivity in the nucleus accumbens (NAc) [33,34]. The opposing changes in neuroplasticity were independently related to successful ketamine treatment [33].…”

Section: Discussionmentioning

confidence: 99%

Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin

Abdallah

Averill

Gueorguieva

et al. 2020

Neuropsychopharmacol.

146

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Twenty-four hours after administration, ketamine exerts rapid and robust antidepressant effects that are thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine. Twenty patients suffering a major depressive episode were randomized to pretreatment with oral rapamycin (6 mg) or placebo 2 h prior to the intravenous administration of ketamine 0.5 mg/kg in a double-blind cross-over design with treatment days separated by at least 2 weeks. Depression severity was assessed using Montgomery-Åsberg Depression Rating Scale (MADRS). Rapamycin pretreatment did not alter the antidepressant effects of ketamine at the 24-h timepoint. Over the subsequent 2-weeks, we found a significant treatment by time interaction (F (8,245) = 2.02, p = 0.04), suggesting a prolongation of the antidepressant effects of ketamine by rapamycin. Two weeks following ketamine administration, we found higher response (41%) and remission rates (29%) following rapamycin + ketamine compared to placebo + ketamine (13%, p = 0.04, and 7%, p = 0.003, respectively). In summary, single dose rapamycin pretreatment failed to block the antidepressant effects of ketamine, but it prolonged ketamine's antidepressant effects. This observation raises questions about the role of systemic vs. local blockade of mTORC1 in the antidepressant effects of ketamine, provides preliminary evidence that rapamycin may extend the benefits of ketamine, and thereby potentially sheds light on mechanisms that contribute to depression relapse after ketamine administration.Neuropsychopharmacology (2020) 45:990-997; https://doi.

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Section: Discussionmentioning

confidence: 99%

Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin

Abdallah

Averill

Gueorguieva

et al. 2020

Neuropsychopharmacol.

146

View full text Add to dashboard Cite

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“…A recent preclinical study has confirmed that chronic unpredictable stress induces an increase in dendritic length and spine density in the NAc. In addition, the study revealed that ketamine treatment reversed stress-induced neuroplasticity alterations in the NAc (Melo et al, 2015). The question is therefore raised whether these preclinical findings in the NAc would translate into tangible evidence in patients suffering from MDD.…”

Section: Introductionmentioning

confidence: 98%

The Nucleus Accumbens and Ketamine Treatment in Major Depressive Disorder

Abdallah

Jackowski

Salas

et al. 2017

Neuropsychopharmacol

111

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Animal models of depression repeatedly showed stress-induced nucleus accumbens (NAc) hypertrophy. Recently, ketamine was found to normalize this stress-induced NAc structural growth. Here, we investigated NAc structural abnormalities in major depressive disorder (MDD) in two cohorts. Cohort A included a cross-sectional sample of 34 MDD and 26 healthy control (HC) subjects, with high-resolution magnetic resonance imaging (MRI) to estimate NAc volumes. Proton MR spectroscopy (H MRS) was used to divide MDD subjects into two subgroups: glutamate-based depression (GBD) and non-GBD. A separate longitudinal sample (cohort B) included 16 MDD patients who underwent MRI at baseline then 24 h following intravenous infusion of ketamine (0.5 mg/kg). In cohort A, we found larger left NAc volume in MDD compared to controls (Cohen's d=1.05), but no significant enlargement in the right NAc (d=0.44). Follow-up analyses revealed significant subgrouping effects on the left (d⩾1.48) and right NAc (d⩾0.95) with larger bilateral NAc in non-GBD compared to GBD and HC. NAc volumes were not different between GBD and HC. In cohort B, ketamine treatment reduced left NAc, but increased left hippocampal, volumes in patients achieving remission. The cross-sectional data provided the first evidence of enlarged NAc in patients with MDD. These NAc abnormalities were limited to patients with non-GBD. The pilot longitudinal data revealed a pattern of normalization of left NAc and hippocampal volumes particularly in patients who achieved remission following ketamine treatment, an intriguing preliminary finding that awaits replication.

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“…Hippocampal tissue levels of glutamate were measured by HPLC, using a GBC LC1150 (GBC Inc, Braeside, Australia) pump coupled to a BAS LC4C electrochemical detector, after pre-column derivatization. Minor modifications of a previously-described method were used ( Kokras et al, 2009;Melo et al, 2015 ). Briefly, a glass-carbon working electrode (set at + 800 mV), an Ag/AgCl 2 reference electrode, and a Hypersil Gold aQ (150 mm × 2.1 mm, 5 μm, from Thermo Fisher Scientific) were used.…”

Section: Neurochemical Assaysmentioning

confidence: 99%

Neuroplasticity-related correlates of environmental enrichment combined with physical activity differ between the sexes

Kokras

Sotiropoulos

Besinis

et al. 2019

European Neuropsychopharmacology

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Environmental enrichment (EE), comprising positive physical (exercise) and cognitive stimuli, influences neuronal structure and usually improves brain function. The promise of EE as a preventative strategy against neuropsychiatric disease is especially high during early postnatal development when the brain is still amenable to reorganization. Despite the fact that male and female brains differ in terms of connectivity and function that may reflect early life experiences, knowledge of the neural substrates and mechanisms by which such changes arise remains limited. This study compared the impact of EE combined with physical activity on neuroplasticity and its functional consequences in adult male and female rats; EE was provided during the first 3 months of life and our analysis focused on the hippocampus, an area implicated in cognitive behavior as well as the neuroendocrine response to stress. Both male and female rats reared in EE displayed better object recognition memory than their control counterparts. Interestingly, sex differences were revealed in the effects of EE on time spent exploring the objects during this test. Independently of sex, EE increased hippocampal turnover rates of dopamine and serotonin and reduced expression of 5-HT 1A receptors; in addition, EE upregulated expression of synaptophysin, a presynaptic protein, in the hippocampus. As compared

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The positive effect on ketamine as a priming adjuvant in antidepressant treatment

Cited by 43 publications

References 43 publications

Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin

Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin

The Nucleus Accumbens and Ketamine Treatment in Major Depressive Disorder

Neuroplasticity-related correlates of environmental enrichment combined with physical activity differ between the sexes

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