A pilot study of hippocampal N-acetyl-aspartate in youth with treatment resistant major depression.

BACKGROUND: Smaller hippocampal volumes, as assessed by magnetic resonance imaging (MRI), and proton magnetic resonance spectroscopy (1H-MRS) indexed alterations in brain metabolites have been identified in adults with major depressive disorder (MDD). Our group has found similar effects in MDD youth. However, this has not been studied in youth with treatment resistant MDD (TRD), nor has the interaction between regional N-acetyl-aspartate and volume deficits. N-acetyl-aspartate is an amino acid in the synthesis pathway of glutamate, and serves a marker of neuronal viability/number. METHODS: Fifteen typically developing youth (16-22 years of age; 7 males, 8 females) and eighteen youth with TRD (14-22 years of age; 8 males, 10 females) underwent 1H-MRS and MRI on a 3T scanner. A short echo PRESS protocol was used with voxels in the right and left hippocampi (6mL each). Hippocampal volume was evaluated using FreeSurfer. RESULTS: Compared with the typically developing group, youth with TRD had lower concentrations of N-acetyl-aspartate in the left hippocampus (p=0.004), and a trend for smaller left hippocampal volume (p=0.067). In TRD subjects, hippocampal N-acetyl-aspartate was inversely correlated with left (r=-0.68, p=0.003) but not right hippocampal volume. Right hippocampal glutamate+glutamine was greater in TRD youth compared to typically developing controls (p=0.007). CONCLUSIONS: These results suggest a neurochemical and structural deficit in the hippocampi of youth with TRD. These findings fit with the role of N-acetyl-aspartate in glutamate neurotransmission and the effect of glutamate on brain morphology.

The psychiatry resident research experience.

BACKGROUND: Research activity is especially critical in the field of psychiatry as it is evolving rapidly thanks to advances in neuroscience. RESULTS: We administered a 34-item survey regarding research experiences targeted at psychiatry residents and postgraduate residency program directors in Canada. One hundred and nineteen participants answered the survey (16 program directors, 103 residents) allowing for a margin of error of 8.4% at a 95% confidence interval. Research was rated as important in informing clinical practice (87.0% yes, 13.0% no), but only 28.7% of respondents reported that it was taught well at their home institution (33.0% no, 38.3% neutral). Only a small proportion was enthusiastic or very enthusiastic about participating in research (21.7%). CONCLUSIONS: While the importance of research is recognized, there is little consensus with respect to whether a standardized research practicum component is included in the resident curriculum.

Proton spectroscopy study of the dorsolateral prefrontal cortex in youth with familial depression.

AIM: Structural, functional, and metabolic changes in the dorsolateral prefrontal cortex (DLPFC) are implicated in the pathogenesis of major depressive disorder (MDD). We used proton magnetic resonance spectroscopy ((1) H-MRS) to examine the metabolite choline (glycerophosphocholine plus phosphocholine), which is used as an index of membrane integrity in the left DLPFC, in adolescents and young adults with MDD who were treatment-resistant and had a positive family history compared to healthy controls. Differences in the choline resonance indicate an imbalance between synthesis and degradation activity of neuronal and glia membrane phospholipids. METHODS: Seventeen adolescents with MDD and 11 healthy controls underwent (1) H-MRS. A short echo point-resolved spectroscopy (echo time = 30 ms, repetition time = 2000 ms) protocol was used with a voxel (4.5cm(3) , 128 averages) placed within the left DLPFC. RESULTS: There were significantly increased choline (P = 0.04) and creatine concentrations (P = 0.005) in the left DLPFC of the MDD group compared to controls. In MDD participants, choline concentration correlated with scores on the Beck Depression Inventory (r = 0.41, P = 0.03). CONCLUSION: Increased left DLPFC choline and creatine levels in depressed adolescents may be biomarkers for the disorder. The increased choline levels may indicate abnormalities in neuronal membrane integrity, and the increased creatine could be reflective of altered energy demands and metabolism.

Subgenual anterior cingulate cortex and hippocampal volumes in depressed youth: The role of comorbidity and age.

OBJECTIVES: Many studies have reported that adults with recurrent major depressive disorder (MDD) have smaller hippocampal volumes than control participants. The data are more variable in youth with MDD, where findings have been inconsistent and the effects of factors such as age and co-morbidity have not been systematically examined. This study therefore assessed hippocampus and subgenual anterior cingulate (sgACC) morphometry in 168 youth, aged 12-25, with or without MDD and comorbid anxiety. METHODS: Structural magnetic resonance imaging (MRI) scans and clinical assessments were obtained from 80 participants with MDD (36 with comorbid anxiety disorder) and 88 age-matched control participants. RESULTS: Participants with MDD had smaller right hippocampi than controls (p=.013). Older depressed participants (20.1-25 years) had smaller hippocampal volumes than younger ones (<20.1 years; p=.05); this age effect was not apparent in controls (p=.46). Depression scores, indexed by the HAMD17, correlated with hippocampal volumes in older depressed youth. Depressed participants with comorbid anxiety had smaller sgACC, but not hippocampal, volumes than those without anxiety (p=.042). LIMITATIONS: Longitudinal, versus cross-sectional, studies can most optimally assess the influence of depression on neurodevelopmental profiles. Though our participants were largely treatment-naïve or in their first week of pharmacotherapy, a handful had extensive treatment histories; thus, treatment history may have influenced brain morphometry. CONCLUSIONS: Age effects were apparent when hippocampal volumes of older and younger participants with MDD were compared; such differences were not apparent in healthy participants. Comorbid anxiety was associated with decreased sgACC volumes suggesting delayed or altered neurodevelopment in a key emotion regulation region.

Corpus callosal morphology in youth with bipolar depression.

OBJECTIVES: Recent evidence has demonstrated that corpus callosum maturation follows a similar developmental timeline to cognitive processes. Bipolar disorder (BD) has been associated with disruptions in error processing, response inhibition, and motor functioning, which are mediated by underlying white matter structures, including the corpus callosum. Disruptions in white matter integrity have been demonstrated in BD. However, it is unknown whether alterations in the developmental trajectory of the corpus callosum may contribute to cognitive impairments in the disorder. METHODS: We assessed the area of the corpus callosum and its subregions (the genu, rostral body, anterior and posterior bodies, isthmus, and splenium) in 14 treatment-naïve adolescents with BD (<21 years of age and in the depressed phase) and 18 healthy adolescent controls. RESULTS: In comparison with healthy controls, participants with BD demonstrated a significantly reduced overall corpus callosum area. We also noted smaller areas in the anterior and posterior mid-body of the corpus callosum in adolescents with BD. CONCLUSIONS: Our results suggest that commissural fibers of the corpus callosum are disrupted in early-onset BD. Specific decreases in the anterior and posterior mid-body callosal aspects may contribute to motor organization and inhibition deficits seen in BD. These findings are consistent with the involvement of inter-hemispheric tracts in early-onset BD, which may reflect an early deviation in white matter development.

Glutamate alterations associated with transcranial magnetic stimulation in youth depression: a case series.

OBJECTIVE: We hypothesized an increase in dorsolateral prefrontal cortex (DLPFC) glutamate levels would occur after 3 weeks of repetitive transcranial magnetic stimulation (rTMS) treatment and a decrease in major depressive disorder (MDD) symptoms. METHODS: We report 6 patients (4 females) 15 to 21 years of age with treatment-resistant MDD. Participants had a mean (SD) age of 18.7 (1.95) years and a mean (SD) IQ of 102.3 (3.39). Short echo proton magnetic resonance spectroscopy (¹H-MRS) was used to quantify glutamate levels in the left DLPFC (4.5 cc) before and after rTMS treatment. Repetitive transcranial magnetic stimulation was localized to the left DLPFC and applied for 15 consecutive weekdays (120% resting motor threshold; 40 pulses over 4 seconds [10 Hz]; intertrain interval, 26 seconds; 75 trains; 3000 pulses). Treatment response was defined as a greater than 50% reduction in Hamilton Depression Rating Scale scores. Short echo proton magnetic resonance spectroscopy data were analyzed with LCModel to determine glutamate concentration. RESULTS: After rTMS, treatment responders (n = 4) showed an increase (relative to baseline) in left DLPFC glutamate levels (11%), which corresponded to an improvement in depressive symptom severity (68% Hamilton Depression Rating Scale score reduction). Treatment nonresponders (n = 2) had elevated baseline glutamate levels compared to responders in that same region, which decreased with rTMS (-10%). Procedures were generally well tolerated with no adverse events. CONCLUSIONS: Repetitive transcranial magnetic stimulation is feasible and possibly efficacious in adolescents with MDD. In responders, rTMS may act by induced elevations in elevating DFPLC glutamate levels in the left DLPFC, thereby leading to symptom improvement.