Beyond monoamines: Glutamatergic function in mood disorders

Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
CNS spectrums (Impact Factor: 1.3). 11/2005; 10(10):808-19.
Source: PubMed

ABSTRACT The monoamine theory has implicated abnormalities in serotonin and norepinephrine in the pathophysiology of major depression and bipolar illness and contributed greatly to our understanding of mood disorders and their treatment. Nevertheless, some limitations of this model still exist that require researchers and clinicians to seek further explanation and develop novel interventions that reach beyond the confines of the monoaminergic systems. Recent studies have provided strong evidence that glutamate and other amino acid neurotransmitters are involved in the pathophysiology and treatment of mood disorders. Studies employing in vivo magnetic resonance spectroscopy have revealed altered cortical glutamate levels in depressed subjects. Consistent with a model of excessive glutamate-induced excitation in mood disorders, several antiglutamatergic agents, such as riluzole and lamotrigine, have demonstrated potential antidepressant efficacy. Glial cell abnormalities commonly associated with mood disorders may at least partly account for the impairment in glutamate action since glial cells play a primary role in synaptic glutamate removal. A hypothetical model of altered glutamatergic function in mood disorders is proposed in conjunction with potential antidepressant mechanisms of antiglutamatergic agents. Further studies elucidating the role of the glutamatergic system in the pathophysiology of mood and anxiety disorders and studies exploring the efficacy and mechanism of action of antiglutamatergic agents in these disorders, are likely to provide new targets for the development of novel antidepressant agents.

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    • "Res. (2014), brain regions such as the anterior cingulate cortex (Goff and Coyle, 2001; Clinton and Meador-Woodruff, 2004; Kugaya and Sanacora, 2005; Javitt et al., 2012). Specifically, schizophrenia patients have exhibited increased concentrations of glutamatergic metabolites if the patients were in a first-episode and conversely, decreased concentrations if the patients had a chronic disease (Ohrmann et al., 2005; Ohrmann et al., 2008; Marsman et al., 2013; Schwerk et al., 2014). "
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    ABSTRACT: Background: Superior temporal cortices include brain regions dedicated to auditory processing and several lines of evidence suggest structural and functional abnormalities in both schizophrenia and bipolar disorder within this brain region. However, possible glutamatergic dysfunction within this region has not been investigated in adult patients. Methods: Thirty patients with schizophrenia (38.67 ± 12.46 years of age), 28 euthymic patients with bipolar I disorder (35.32 ± 9.12 years of age), and 30 age-, gender- and education- matched healthy controls were enrolled. Proton Magnetic Resonance Spectroscopy data were acquired using a 3.0T Siemens MAGNETOM TIM Trio MR system and single voxel Point Resolved Spectroscopy Sequence (PRESS) in order to quantify brain metabolites within the left and right Heschl Gyrus and Planum Temporale of superior temporal cortices. Results: There were significant abnormalities in Glutamate (Glu) (F(2,78)=8.52, p<0.0001), n- Acetyl Aspartate (tNAA) (F(2,81)=5.73, p=0.005), Creatine (tCr) (F(2,83)=5.91, p=0.004) and Inositol (Ins) (F(2,82)=8.49, p<0.0001) concentrations in the left superior temporal cortex. In general, metabolite levels were lower for bipolar disorder patients when compared to healthy participants. Moreover, patients with bipolar disorder exhibited significantly lower tCr and Ins concentrations when compared to schizophrenia patients. In addition, we have found significant correlations between the superior temporal cortex metabolites and clinical measures. Conclusion: As the left auditory cortices are associated with language and speech, left hemisphere specific abnormalities may have clinical significance. Our findings are suggestive of shared glutamatergic abnormalities in schizophrenia and bipolar disorder.
    Schizophrenia Research 02/2015; 161(2-3). DOI:10.1016/j.schres.2014.11.012 · 4.43 Impact Factor
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    • "The data gathered during recent years suggests that abnormalities within glutamatergic transmission, especially NMDA (N-methyl- D-aspartate) receptor overactivation, are associated with more generalized mechanisms of brain dysfunction that may underlie various psychiatric disorders, including major depressive disorder. The accumulated evidence demonstrated that the functional and structural pathology of excitatory neurotransmitters have been observed in animal models of depression and clinical trials (Hansen et al., 1983; Kugaya and Sanacora 2005; Petrie et al., 2000; Sanacora et al., 2003; Zarate et al., 2002; Hashimoto, 2009; Pilc et al., 2013). Furthermore, there is evidence that NMDA receptor ligands (functional antagonists ) interacting with different components of the NMDA receptor– ionophore complex produced antidepressant-like effects (Lopes et al., 1997; Panconi et al., 1993; Poleszak et al., 2007; Przegalinski et al., 1998; Trullas and Skolnick, 1990; Szewczyk et al., 2012). "
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    ABSTRACT: There is evidence for an association between suicidal behavior and depression. Accumulating data suggests that depression is related to a dysfunction of the brain's glutamatergic system, and that the N-methyl-d-aspartate (NMDA) receptor plays an important role in antidepressant activity. Zinc and magnesium, the potent antagonists of the NMDA receptor complex, are involved in the pathophysiology of depression and exhibit antidepressant activity. The present study investigated the potency of Zn(2+) and Mg(2+) to [(3)H] MK-801, which binds to the NMDA receptor channel in the hippocampus of suicide victims (n=17) and sudden death controls (n=6). Moreover, the concentrations of zinc and magnesium (by flame atomic absorption spectrometry) and levels of NMDA subunits (NR2A and NR2B) and PSD-95 protein (by Western blotting) were determined. Our results revealed that there was a statistically significant decrease (by 29% and 40%) in the potency of zinc and magnesium (respectively) to inhibit [(3)H] MK-801 binding to NMDA receptors in the hippocampus in suicide tissue relative to the controls. These alterations were associated with increased NR2A (+68%) and decreases in both the NR2B (-46%) and PSD-95 (-35%) levels. Furthermore, lower concentrations (-9%) of magnesium (although not of zinc) were demonstrated in suicide tissue. Our findings indicate that alterations in the zinc, magnesium and NMDA receptor complex in the hippocampus are potentially involved in the pathophysiology of suicide-related disorders (depression), which may lead to functional NMDA receptor hyperactivity.
    Journal of Affective Disorders 08/2013; 151(3). DOI:10.1016/j.jad.2013.08.009 · 3.71 Impact Factor
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    • "In particular, their effect on glutamate clearance may be relevant for the pathogenesis of MDD, because an excess of this neurotransmitter potentially exerts neurotoxic effects (Hynd et al., 2004; Mattson, 2007). Therefore, ADs may act both on astrocytes and neurons to re-establish a properly functional astrocyte–neuronal network, thereby restoring physiological glutamate homeostasis (Kugaya and Sanacora, 2005; Sanacora et al., 2012). "
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    ABSTRACT: The onset of action of antidepressants (ADs) usually takes several weeks, but first molecular responses to these drugs may appear already after acute administration. The ERK/MAPK signalling pathway is a target of antidepressants and an important pathway involved in cellular plasticity. In major depressive disorder (MDD), especially the prefrontal cortex and hippocampus are most likely affected in depressive patients and recent work revealed a hyperactivated ERK signalling in the rat prefrontal cortex after chronic stress, a precipitating factor for MDD. Strong evidences support that not only neurons but also astrocytes participate in neuronal activity and may therefore additionally be substrate of antidepressant action. In this study, we show by Western blot that neither fluoxetine nor desipramine preferentially affects the activation of one of the two ERK isoforms, ERK1 and ERK2, in respect to the other. Further immunohistochemical analysis in the prefrontal cortex revealed that basal levels of phospho-activated ERK (pERK) are mostly found in neurons in contrast to very few astrocytes. Both ADs can inhibit neuronal pERK as early as 15 minutes after drug administration with peculiar regional and layer specificities. Contrarily, at this time point none of the two ADs shows a clear modulation of astrocytic pERK. We propose that this mechanism of action of ADs may be protective against an exacerbated cortical ERK activity that may exert detrimental effects on susceptible neuronal populations. Our findings on acute effects of AD treatment in the adult mouse prefrontal cortex encourage to examine further how this treatment might influence pERK in animal models of depression to identify early targets of AD action.
    Neuroscience 12/2012; 232. DOI:10.1016/j.neuroscience.2012.11.061 · 3.33 Impact Factor
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