Antidepressant effects of ketamine in depressed patients

Berman, R.; Cappiello, Angela; Anand, Amit; Oren, Dan A.; Heninger, George R.; Charney, Dennis S.; Krystal, John H.

doi:10.1016/s0006-3223(99)00230-9

Cited by 3,124 publications

(2,244 citation statements)

References 23 publications

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“…Consistent with the hypothesis that depression is associated with elevated glutamatergic transmission, NMDAR antagonists exhibit antidepressant-like potential in rodent antidepressant screening procedures (Moryl et al, 1993;Papp and Moryl, 1994). In addition, ketamine, an NMDAR antagonist, exhibits antidepressant activity in humans (Berman et al, 2000). If glutamatergic input to the LC is elevated in depression, the putative antidepressant properties of NMDAR antagonists may be mediated, at least in part, by blockade of excitatory input to the LC.…”

Section: Role Of Glutamatergic Signaling In Depressionmentioning

confidence: 71%

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Elevated Levels of the NR2C Subunit of the NMDA Receptor in the Locus Coeruleus in Depression

Karolewicz

Stockmeier

Ordway

2005

Neuropsychopharmacol

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Low levels of the intracellular mediator of glutamate receptor activation, neuronal nitric oxide synthase (nNOS) were previously observed in locus coeruleus (LC) from subjects diagnosed with major depression. This finding implicates abnormalities in glutamate signaling in depression. Receptors responding to glutamate in the LC include ionotropic N-methyl-D-aspartate receptors (NMDARs). The functional NMDAR is a hetero-oligomeric structure composed of NR1 and NR2 (A-D) subunits. Tissue containing the LC and a nonlimbic LC projection area (cerebellum) was obtained from 13 and 9 matched pairs, respectively, of depressed subjects and control subjects lacking major psychiatric diagnoses. NMDAR subunit composition in the LC was evaluated in a psychiatrically normal subject. NR1 and NR2C subunit immunoreactivities in LC homogenates showed prominent bands at 120 and 135 kDa, respectively. In contrast to NR1 and NR2C, very weak immunoreactivity of NR2A and NR2B subunits was observed in the LC. Possible changes in concentrations of NR1 and NR2C that might occur in depression were assessed in the LC and cerebellum. The overall amount of NR1 immunoreactivity was normal in the LC and cerebellum in depressed subjects. Amounts of NR2C protein were significantly higher ( þ 61%, p ¼ 0.003) in the LC and modestly, but not significantly, elevated in the cerebellum ( þ 35%) of depressives as compared to matched controls. Higher levels of NR2C subunit implicate altered glutamatergic input to the LC in depressive disorders.

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Section: Role Of Glutamatergic Signaling In Depressionmentioning

confidence: 71%

“…Moreover, recent studies have revealed that agonists of group III metabotropic glutamate receptors, known to inhibit glutamate release, exhibit antidepressant-like activity in animals (Palucha et al, 2004;Tatarczynska et al, 2002). Furthermore, ketamine, an NMDAR antagonist, exhibits antidepressant activity in humans (Berman et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Elevated Levels of the NR2C Subunit of the NMDA Receptor in the Locus Coeruleus in Depression

Karolewicz

Stockmeier

Ordway

2005

Neuropsychopharmacol

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“…More recently, NMDA receptors were directly implicated in a clinical study that demonstrated an improvement in depressive symptomatology after treatment with an NMDA receptor antagonist (Berman et al 2000). However, few studies have detailed abnormalities of glutamate physiology in MDD, and little is known regarding alterations in glutamate reuptake and metabolism in major depression (Auer et al 2000;Levine et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Striatal Excitatory Amino Acid Transporter Transcript Expression in Schizophrenia, Bipolar Disorder, and Major Depressive Disorder

McCullumsmith

Meador‐Woodruff

2002

Neuropsychopharmacology

175

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Because abnormalities of glutamatergic neurotransmission in psychiatric illness are likely not limited to glutamate receptor expression, we investigated expression of excitatory amino acid transporters (EAATs) in the striatum. The EAATs, normally expressed in both glia (EAAT1 and EAAT2) and neurons (EAAT3 and EAAT4), have previously been implicated in Huntington's disease, amyotrophic lateral sclerosis, and schizophrenia. In A growing literature suggests abnormal expression of ionotropic glutamate receptors in the brain in schizophrenia. The preponderance of these studies has detected complex and regionally specific alterations in ␣ -amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainate, and N-methyl-D-aspartate (NMDA) receptor expression, especially in cingulate cortex and medial temporal lobe structures (Akbarian et al. 1996;Aparicio-Legarza et al. 1998;Deakin et al. 1989;Eastwood et al. 1997aEastwood et al. , 1997bEastwood et al. , 1995Grimwood et al. 1999;Harrison et al. 1991;Healy et al. 1998;Humphries et al. 1996;Ibrahim et al. 2000;Kerwin et al. 1988Kerwin et al. , 1990Kornhuber et al. 1989; MeadorWoodruff and Healy 2000;Nishikawa et al. 1983;Noga et al. 1997;Ohnuma et al. 1998;Porter et al. 1997;Sokolov 1998). Recently, such studies have been extended to other brain regions associated with limbic circuitry felt to be disturbed in psychiatric illnesses, including the striatum. Increased NMDA receptor binding at both the glycine/D-serine coagonist site and the intrachannel MK801 site was detected in the putamen, and increased CNQX (an AMPA/kainate antagonist) binding was detected in the caudate in schizophrenia (Aparicio-Legarza et al. (Arriza et al. 1993;Utsunomiya-Tate et al. 1996). The transporters have specific patterns of cellular localization: EAAT1 and EAAT2 have been localized to astroglia, whereas EAAT3 and EAAT4 are localized to neurons (Bar-Peled et al. 1997;Chaudhry et al. 1995;Furuta et al. 1997;Lehre et al. 1995;Milton et al. 1997;Rothstein et al. 1994;Sims and Robinson 1999;Yamada et al. 1996Yamada et al. , 1997. The best studied of the glutamate transporters, EAAT2 (called GLT-1 in the rat) accounts for ‫ف‬ 90% of forebrain glutamate reuptake in the rodent (Rothstein et al. 1996;Tanaka et al. 1997). The predominately glial expression of EAAT2 mRNA and protein, observed throughout the human brain, is highest in the forebrain (Bar-Peled et al. 1997;Milton et al. 1997). Similar to EAAT2, EAAT3 (called EAAC1 in the rat) protein expression in the human brain is detected in the frontal cortex and the hippocampus (Bar-Peled et al. 1997). EAAT3 is localized to both post-and presynaptic neuronal soma and is associated with ‫ف‬ 40% of rodent hippocampal glutamate transport (Rothstein et al. 1994). In contrast, levels of EAAT1 (called GLAST in the rat) and EAAT4 protein expression in the rodent central nervous system (CNS) are highest in the cerebellum in the Bergmann glia and Purkinje cell types, respectively, whereas human studies of EAAT1 protein expression indicate high levels in the f...

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“…Ketamine is a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist that has attracted widespread attention for its rapid-onset antidepressant effects, especially in individuals with treatment-resistant depression and suicidal ideation [1][2][3]. Compared with the traditional antidepressants that take weeks, if not months, to benefit patients and are associated with a high rate of relapse, ketamine exerts its antidepressant effects within several hours.…”

mentioning

confidence: 99%

“…Compared with the traditional antidepressants that take weeks, if not months, to benefit patients and are associated with a high rate of relapse, ketamine exerts its antidepressant effects within several hours. These clinical benefits can last for 2 weeks after a single injection [1,2,4]. However, ketamine still has limited clinical application, mainly because of its psychotomimetic side-effects and liability of abuse.…”

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confidence: 99%