Glutamate and the neural basis of the subjective effects of ketamine: a pharmaco-magnetic resonance imaging study (original) (raw)
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Psychological effects of ketamine in healthy volunteers
British Journal of Psychiatry, 2006
BackgroundThe psychosis-inducing effect of ketamine is important evidence supporting the glutamate hypothesis of schizophrenia. However, the symptoms the drug produces have not been described systematically.AimTo examine the effects of ketamine in healthy people using a structured psychiatric interview.MethodKetamine (200 ng/ml) or placebo was administered by continuous infusion to 15 healthy volunteers. Symptoms were rated using the Present State Examination, the Thought, Language and Communication Scale and the Scale for Assessment of Negative Symptoms.ResultsKetamine induced a range of perceptual distortions, but not hallucinations. Referential ideas were seen in nearly half the sample. There were only mild and infrequent ratings on the thought disorder scale. Affective flattening and alogia were seen in some volunteers.ConclusionsKetamine does not reproduce the full picture of schizophrenia. The main point of similarity concerns referential thinking. Phenomena resembling negativ...
ISMRM Annual Meeting, 2022
Background: The glutamate N-methyl-D-aspartate receptor antagonist ketamine has a rapid antidepressant effect in major depressive disorder (MDD) patients. Though, the ketamine's possible mechanism of action has been debated the main hypothesis was focused around glutamate. Methods: A proton short-echo MR Spectroscopy was utilised to examined three brain regions Anterior Cingulate Cortex, Hippocampus and Raphe nuclei before and 24-hours after treatment. 28 Selective Serotonin Reuptake Inhibitor resistant MDD patients were randomized to double blind monotherapy with 0.5 mg/kg ketamine or placebo infusion. Results: glutamate correlates with depression symptoms severity in ACC and HC in opposing ways in ketamine group.
Glutamate, N-acetyl aspartate and psychotic symptoms in chronic ketamine users
Psychopharmacology, 2014
Rationale Ketamine, a non-competitive NMDA receptor antagonist, induces acute effects resembling the positive, negative and cognitive symptoms of schizophrenia. Chronic use has been suggested to lead to persistent schizophrenia-like neurobiological changes. Objectives This study aims to test the hypothesis that chronic ketamine users have changes in brain neurochemistry and increased subthreshold psychotic symptoms compared to matched poly-drug users.
Neuroimaging markers of the delayed effects of ketamine
2020
Major Depressive Disorder is a chronic mood disorder, affecting approximately 320 million people worldwide. Rumination associated with biased AM recall and anhedonia linked to altered reward processing, are two of the most debilitating symptoms of depression that could persist in remission and are not successfully targeted by commonly prescribed antidepressants. Ketamine, a glutamate receptor antagonist, has emerged in the last two decades as a potent antidepressant with robust effects. The drug's fast acting (2h post drug administration) and relatively long-lived antidepressant action (24h-48h after a single ketamine infusion) also targets anhedonia and rumination. (Lehman et.,al 2016, Lally et al., 2014) However, the mechanism by which the drug exerts its antidepressant effects in the brain are not well understood. The aim of the present study was to identify brain areas that present with significantly altered activations 2h after the ketamine administration, when the antidepressant effects of the drug become detectable, and are important for reward processing and emotionally valenced AM (Autobiographical Memory) recall. For that purpose, we recruited remitted depressed volunteers who were scanned while performing an AM task (VAMP) and a reward processing task (MID). We hypothesized that ketamine, during the MID task would significantly increase striatal activations while during the VAMP task, the drug would modulate activations in the PCC, the sgACC and the amygdala, compared to placebo. These brain areas could serve as neuroimaging markers that could be linked to ketamine's antidepressant action. For this study we recruited 37 remitted-depressed, drug-naïve, male and female volunteers who took part in a double-bind, placebo-controlled, cross-over design. Ketamine (0.5mg/kg) and placebo ware administered intravenously over a 45min continuous infusion. Two hours after the drug administration, participants were scanned while performing the MID and the VAMP task. The MID is a reaction time task during which participants need to perform fast button presses, in response to a target stimulus, to win different monetary rewards (Knutson et al., 2001). A cue that is presented before the target signifies the value of the reward that they could win in each trail. The reward anticipation and feedback phases of this task were analysed at a whole brain level and activations were also examined at predefined ROIs associated with reward processing, namely the striatal regions, the VTA, the amygdala and the insula.
ILAR Journal, 2011
Ketamine was developed in the early 1960s as an anesthetic and has been used for medical and veterinary procedures since then. Its unique profi le of effects has led to its use at subanesthetic doses for a variety of other purposes: it is an effective analgesic and can prevent certain types of pathological pain; it produces schizophrenia-like effects and so is used in both clinical studies and preclinical animal models to better understand this disorder; it has rapid-acting and longlasting antidepressant effects; and it is popular as a drug of abuse both among young people at dance parties and raves and among spiritual seekers. In this article we summarize recent research that provides insight into the myriad uses of ketamine. Clinical research is discussed, but the focus is on preclinical animal research, including recent fi ndings from our own laboratory. Of particular note, although ketamine is normally considered a locomotor stimulant at subanesthetic doses, we have found locomotor depressant effects at very low subanesthetic doses. Thus, rather than a monotonic dosedependent increase in activity, ketamine produces a more complex dose response. Additional work explores the mechanism of action of ketamine, ketamine-induced neuroadaptations, and ketamine reward. The fi ndings described will inform future research on ketamine and lead to a better understanding of both its clinical uses and its abuse.
Frontiers in Psychiatry, 2023
While ketamine has emerged as a promising therapeutic for treatment-resistant depression (TRD) and psychiatric emergencies, including suicidality occurring in the course of major depressive disorder (MDD), several issues pertaining to clinical efficacy remain not fully elucidated. These issues include the role of ketamine-assisted psychotherapy (KAP) in enhancing or prolonging antidepressant effects; the therapeutic value of the so-called psychedelic protocols that value the state-altering properties of ketamine; the therapeutic potential of ketamine as a first-line treatment for MDD, other mood diseases, and potentially other psychiatric diagnoses; and the safety and efficacy of home treatment with self-administered ketamine.
Behavioural Brain Research, 2020
Ketamine, a dissociative anesthetic and psychedelic compound, has revolutionized the field of psychopharmacology by showing robust, and rapid-acting antidepressant activity in patients suffering from major depressive disorder (MDD), suicidal tendencies, and treatment-resistant depression (TRD). Ketamine's efficacy, however, is transient, and patients must return to the clinic for repeated treatment as they experience relapse. This is cause for concern because ketamine is known for its abuse liability, and repeated exposure to drugs of abuse often leads to drug abuse/ dependence. Though the mechanism(s) underlying its antidepressant activity is an area of current intense research, both clinical and preclinical evidence shows that ketamine's effects are mediated, at least in part, by molecular adaptations resulting in long-lasting synaptic changes in mesolimbic brain regions known to regulate natural and drug reward. This review outlines our limited knowledge of ketamine's neurobiological and biochemical underpinnings mediating its antidepressant effects and correlates them to its abuse potential. Depression and addiction share overlapping neural circuitry and molecular mechanisms, and though speculative, repeated use of ketamine for the treatment of depression could lead to the development of substance use disorder/ addiction, and thus should be tempered with caution. There is much that remains to be known about the long-term effects of ketamine, and our lack of understanding of neurobiological mechanisms underlying its antidepressant effects is a clear limiting factor that needs to be addressed systematically before using repeated ketamine in the treatment of depressed patients.
2014
The burden of depressive disorders and the frequent inadequacy of their current pharmacological treatments are well established. The anaesthetic and hallucinogenic drug ketamine has provoked much interest over the past decade or so as an extremely rapidly acting antidepressant that does not modify 'classical' monoaminergic receptors. Current evidence has shown several ways through which it might exert therapeutic antidepressant actions: blockade of glutamatergic NMDA receptors and relative upregulation of α-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtypes may alter cortical connectivity patterns; through intracellular changes in protein expression, including the proteins mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF); and alteration of intracellular signalling cascades. The clinical evidence demonstrates rapid improvements in mood and suicidal thinking in most participants, although study numbers have generally been small and many trials are unblinded and methodologically weak. There is a small body of work to suggest ketamine might also augment electroconvulsive therapy and potentially have a role as a surgical anaesthetic in depressed patients. A major problem is that the effects of ketamine appear temporary, disappearing after days to weeks (although longer benefits have been sustained in some), and attempts to circumvent this through pharmacological augmentation have been disappointing thus far. These exciting data are providing new insights into neurobiological models of depression, and potentially opening up a new class of antidepressants, but there are significant practical and ethical issues about any future mainstream clinical role it might have.
Antidepressant Effects of Ketamine In Depressed Patients
Biological …, 2000
Background: A growing body of preclinical research suggests that brain glutamate systems may be involved in the pathophysiology of major depression and the mechanism of action of antidepressants. This is the first placebo-controlled, double-blinded trial to assess the ...