Amino Acid Neurotransmitters Assessed by Proton Magnetic Resonance Spectroscopy: Relationship to Treatment Resistance in Major Depressive Disorder

Price, Rebecca B.; Shungu, Dikoma C.; Mao, Xiangling; Nestadt, Paul S.; Kelly, Catherine; Collins, Katherine A.; Murrough, James W.; Charney, Dennis S.; Mathew, Sanjay J.

doi:10.1016/j.biopsych.2008.10.025

Cited by 235 publications

(189 citation statements)

References 39 publications

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“…Prior MRS studies revealed GABA reductions in depressed individuals compared with healthy controls, 11,28 with more pronounced MPFC reductions in a treatment-refractory subgroup. 15 Further, and also in support of the GABAdeficit hypothesis of depression, a variety of different antidepressants seem to function, in part, by elevating GABA. These include SSRIs, 12 the monoamine-oxidase inhibitor phenelzine, 29 the GABA-reuptake inhibitor tiagabine 30 and ECT.…”

Section: Discussionmentioning

confidence: 91%

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Elevated prefrontal cortex GABA in patients with major depressive disorder after TMS treatment measured with proton magnetic resonance spectroscopy

Dubin

Mao

Banerjee

et al. 2016

jpn

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122

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IntroductionTranscranial magnetic stimulation (TMS) is an effective treatment for major depressive disorder (MDD), particularly in individuals resistant to first-line antidepressants.1-3 Effect sizes of TMS from recent meta-analyses range from 0.39 to 0.55. 4,5 Less is known about the neurobiological mechanisms of antidepressant response to TMS. Emerging evidence suggests that in addition to its effects on the dorsolateral prefrontal cortex (DLPFC), TMS also affects structures to which the DLPFC projects, including the medial prefrontal cortex (MPFC). 6 The MPFC is overactive in individuals with MDD,7 and functional connectivity between the DLPFC and MPFC predicts response to TMS. [8][9][10] Little is known about how connectivity between the DLPFC and MPFC gives rise to the antidepressant effect of TMS.Other antidepressants appear to act in part by modulating the excitability of cortical circuits. Levels of γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain, which are generally decreased in depressed individuals, 11 have been reported to increase after treatment with selective serotonin reuptake inhibitors (SSRIs) 12 and electroconvulsive therapy (ECT).13 Although TMS affects the balance of excitation and inhibition in cortical circuits, 14 it is unknown whether changes in excitation-inhibition balance mediate antidepressant response.In this naturalistic study, we tested whether TMS alters the levels of GABA and those of the combined resonance of glutamate and glutamine (Glx) in patients with MDD. Specifically, the standard J-edited spin echo difference proton magnetic resonance spectroscopy ( 1 H MRS) technique was implemented at 3 T to measure levels of MPFC GABA and Background: GABAergic and glutamatergic neurotransmitter systems are central to the pathophysiology of depression and are potential targets of repetitive transcranial magnetic stimulation (rTMS). We assessed the effect of 10-Hz rTMS over the left dorsolateral prefrontal cortex (DLPFC) of patients with major depressive disorder on the levels of medial prefrontal cortex (MPFC) γ-aminobutyric acid (GABA) and the combined resonance of glutamate and glutamine (Glx) as assessed in vivo with proton magnetic resonance spectroscopy ( 1 H MRS). Methods: Currently depressed individuals between the ages of 23 and 68 years participated in a 5-week naturalistic, open-label treatment study of rTMS, with 1 H MRS measurements of MPFC GABA and Glx levels at baseline and following 5 weeks of the rTMS intervention. We applied rTMS pulses over the left DLPFC at 10 Hz and 80%-120% of motor threshold for 25 daily sessions, with each session consisting of 3000 pulses. We assessed therapeutic response using the 24-item Hamilton Rating Scale for Depression (HAMD24). The GABA and Glx levels are expressed as ratios of peak areas relative to the area of the synchronously acquired and similarly fitted unsuppressed voxel water signal (W). Results: Twenty-three currently depressed individuals (7 men) participated in the study. GABA/W in the MPFC i...

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Section: Discussionmentioning

confidence: 91%

“…Based on the majority of reports in patients with MDD on the neurochemical response to antidepressant therapy, 11,12,15 we hypothesized that TMS would selectively increase MPFC GABA levels while minimally affecting those of Glx.…”

Section: J Psychiatry Neurosci 2016;41(3)mentioning

confidence: 99%

Elevated prefrontal cortex GABA in patients with major depressive disorder after TMS treatment measured with proton magnetic resonance spectroscopy

Dubin

Mao

Banerjee

et al. 2016

jpn

Self Cite

122

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“…Thus, weak inhibition, as may be found in depression, can prevent cortical plasticity (Fagiolini et al, 2004). In depression, in vivo magnetic resonance spectroscopy studies have found reduced cortical g-aminobutyric acid (GABA) concentrations (Sanacora et al, 1999;Price et al, 2009) with deficits in GABA receptor-mediated inhibition (Levinson et al, 2010). Further, there is evidence that the rate-limiting enzyme for GABA synthesis (GAD67) is reduced in the cortex of individuals with bipolar disorder (Thompson et al, 2009) and hippocampus of depressed individuals (Thompson et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Neuroplasticity in Depressed Individuals Compared with Healthy Controls

Player

Taylor

Weickert

et al. 2013

Neuropsychopharmacol

106

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Several lines of evidence suggest that neuroplasticity is impaired in depression. This study aimed to compare neuroplasticity in 23 subjects with DSM-IV major depressive episode and 23 age-and gender-matched healthy controls, using an objective test that is independent of subject effort and motivation. Neuroplasticity was assessed in the motor cortex using a brain stimulation paradigm known as paired associative stimulation (PAS), which induces transient changes in motor cortical function. Motor cortical excitability was assessed before and after PAS using single-pulse transcranial magnetic stimulation (TMS) to induce motor evoked potentials (MEPs) in a hand muscle. After PAS, MEP amplitudes significantly increased in healthy controls compared with depressed subjects (P ¼ 0.002). The functional significance of motor cortical changes was assessed using a motor learning task-a computerized version of the rotor pursuit task. Healthy controls also performed better on motor learning (P ¼ 0.02). BDNF blood levels and genotype were assayed to determine any relationship with motor cortical plasticity. However, PAS results did not correlate with motor learning, nor appear to be related to BDNF measures. The significance of these findings is that it provides one of the first direct demonstrations of reduced neuroplasticity in depressed subjects, using an objective test.

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“…Proton magnetic resonance spectroscopy ( 1 H-MRS) is a safe, noninvasive method for repeated measure of brain GABA and glutamate in human subjects that does not require radioactive tracers or dyes. 1 H-MRS has been applied to the study of GABA and/or glutamate in seizure disorders (Petroff et al, 1995(Petroff et al, , 1996a, major depression (Price et al, 2009;Hasler et al, 2007;Sanacora et al, 1999Sanacora et al, , 2004Auer et al, 2000), anxiety disorders (Hasler et al, 2009;Goddard et al, 2001), premenstrual dysphoric disorder (Epperson et al, 2002), schizophrenia (Kegeles et al, 2012;Marsman et al, 2011), bipolar disorder (Benedetti et al, 2009), nicotine, alcohol, and cocaine addiction (Epperson et al, 2006;Gomez et al, 2011;Licata and Renshaw, 2010) and neurodegenerative diseases such as Parkinson's Disease and Alzheimer's Disease (Griffith et al, 2008). The majority of published in vivo human 1 H-MRS studies have been conducted at fields of 4 Tesla or less and have not included within day or between day reproducibility data for either GABA or glutamate.…”

Section: Introductionmentioning

confidence: 99%

The Impact of Gabapentin Administration on Brain GABA and Glutamate Concentrations: A 7T 1H-MRS Study

Cai

Nanga

Lamprou

et al. 2012

Neuropsychopharmacol

129

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Gamma-aminobutyric acid (GABA) and glutamate are implicated in numerous neuropsychiatric and substance abuse conditions, but their spectral overlap with other resonances makes them a challenge to quantify in humans. Gabapentin, marketed for the treatment of seizures and neuropathic pain, has been shown to increase in vivo GABA concentration in the brain of both rodents and humans. Gabapentin effects on glutamate are not known. We conducted a gabapentin (900 mg) challenge in healthy human subjects to confirm and explore its effects on GABA and glutamate concentrations, respectively, and to test the ability of single voxel localized proton magnetic resonance spectroscopy ( 1 H-MRS) to reliably measure GABA and glutamate in the visual cortex at the ultra-high magnetic field of 7 Tesla. Reproducibility of GABA and glutamate measurements was determined in a comparison group without drug twice within day and 2 weeks apart. Although GABA concentration changes were small both within day (average 5.6%) and between day (average 4.8%), gabapentin administration was associated with an average increase in GABA concentration of 55.7% (6.9-91.0%). Importantly, druginduced change in GABA levels was inversely correlated to the individual's baseline GABA level (R 2 ¼ 0.72). Mean glutamate concentrations did not change significantly with or without drug administration. In conclusion, localized 1 H-MRS at 7 Tesla can be successfully applied to the measurement of GABA concentration and is sensitive to acute drug-induced changes in cortical GABA. Whether baseline GABA concentrations predict clinical efficacy of gabapentin is an area worthy of exploration.

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Amino Acid Neurotransmitters Assessed by Proton Magnetic Resonance Spectroscopy: Relationship to Treatment Resistance in Major Depressive Disorder

Cited by 235 publications

References 39 publications

Elevated prefrontal cortex GABA in patients with major depressive disorder after TMS treatment measured with proton magnetic resonance spectroscopy

Elevated prefrontal cortex GABA in patients with major depressive disorder after TMS treatment measured with proton magnetic resonance spectroscopy

Neuroplasticity in Depressed Individuals Compared with Healthy Controls

The Impact of Gabapentin Administration on Brain GABA and Glutamate Concentrations: A 7T 1H-MRS Study

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