Kugaya A, Sanacora A. Beyond monoamines: Glutamatergic Function in Mood Disorders. CNS Spectrums 10: 808-818

Yale University, New Haven, Connecticut, United States
CNS spectrums (Impact Factor: 2.71). 11/2005; 10(10):808-19.
Source: PubMed


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.

  • Source
    • ", Ongür et al . , 1998 ; Kugaya and Sanacora , 2005 ; Ongür et al . , 2007 ; Valentine and Sanacora , 2009 ; Rajkowska and Stockmeier , 2013 ; Rajkowska et al . "

    Preview · Article · Jan 2016 · Frontiers in Integrative Neuroscience
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    No preview · Article · Feb 2015 · Schizophrenia Research
  • Source
    • "The hypothalamo-pituitary-adrenal (HPA)-axis, the monoamine systems and the autonomic nervous system are key regulating systems for stress responses and form major pathways for symptoms of depression [4,5]. Altered glutamatergic and reduced GABAergic and NO neurotransmission were observed in depression in a number of brain systems, which may significantly affect the neuronal activity involved in stress responses and mood regulation [1,2,6]. Changes in depression in the levels of these amino acids were found not only in different brain regions and cerebrospinal fluid (CSF), but also in blood and urine [7], which implies that they have the potential to serve as clinically relevant biomarkers or treatment efficacy monitors. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Amino acid neurotransmitters and nitric oxide (NO) are involved in the pathogenesis of major depressive disorder (MDD). Here we want to establish whether changes in their plasma levels may serve as biomarker for the melancholic subtype of this disorder. Plasma levels of glutamic acid (Glu), aspartic acid (Asp), glycine (Gly), gamma-aminobutyric acid (GABA), and NO were determined in 27 medicine-naive melancholic MDD patients and 30 matched controls. Seven of the MDD patients participated also in a follow-up study after 2 months' antidepressant treatment. The relationship between plasma and cerebral-spinal fluid (CSF) levels of these compounds was analyzed in an additional group of 10 non-depressed subjects. The plasma levels of Asp, Gly and GABA were significantly lower whereas the NO levels were significantly higher in melancholic MDD patients, also after 2 months of fluoxetine treatment. In the additional 10 non-depressed subjects, no significant correlation was observed between plasma and CSF levels of these compounds. These data give the first indication that decreased plasma levels of Asp, Gly and GABA and increased NO levels may serve as a clinical trait-marker for melancholic MDD. The specificity and selectivity of this putative trait-marker has to be investigated in follow-up studies.
    Full-text · Article · Apr 2014 · BMC Psychiatry
Show more