Natalia Jaworska

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.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: Section 6. Special populations: Youth, women, and the elderly

Background: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. Methods: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. This section on “Special Populations” is the sixth of six guidelines articles. Results: Recent studies inform the treatment of MDD in children and adolescents, pregnant and breastfeeding women, women in perimenopause or menopause, and the elderly. Evidence for efficacy of treatments in these populations is more limited than for the general adult population, however, and risks of treatment in these groups are often poorly studied and reported. Conclusions: Despite the limited evidence base, extant data and clinical experience suggest that each of these special populations can benefit from the systematic application of treatment guidelines for treatment of MDD.

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.

Cortical thickness and emotion processing in young adults with mild to moderate depression: a preliminary study

BackgroundMajor depressive disorder (MDD) is a multifaceted illness involving cognitive, emotional, and structural brain changes; illness onset typically occurs in adolescence or young adulthood. Cortical thickness modulations may underlie, or accompany, functional brain activity changes in the prefrontal cortex (PFC) during emotional processing that tend to be observed in MDD.MethodsThirteen unmedicated young adults with mild to moderate MDD, aged 18–24, completed a facial expression Go/No Go task and underwent a magnetic resonance imaging (MRI) scan to assess cortical thickness. Cortical thickness and performance on the Go/No Go task was also assessed in age-matched healthy comparison subjects (HCs; N = 14).ResultsParticipants with depression had thicker left pars opercularis cortices than HCs. They also exhibited impaired response inhibition to neutral faces when responding only to sad faces, and a faster response time overall.ConclusionsThough our sample size is limited, this pilot study nevertheless provides evidence for cortical thickening in left frontal brain regions in a non-severely depressed, young adult group compared to healthy controls. There was also evidence of disturbances in emotion processing in this group.

The influence of 5-HTTLPR and Val66Met polymorphisms on cortical thickness and volume in limbic and paralimbic regions in depression: a preliminary study

BackgroundStructural brain abnormalities have been investigated in multi-genetic and complex disorders such as major depressive disorder (MDD). Among the various candidate genes implicated in MDD, the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and 5-HT transporter gene linked polymorphism (5-HTTLPR) have garnered the most attention due to their putative roles in neural plasticity and antidepressant response. However, relatively few studies have assessed the influence of these polymorphysims on cortical thickness or brain volume in para-limbic and limbic regions in MDD, which was the aim of this study.MethodsForty-three adults with MDD and 15 healthy controls (HC) underwent structural magnetic resonance imaging (MRI). Cortical thickness was assessed in frontal, cingulate and temporal regions. Volumetric measures were carried out in the thalamus, caudate, putamen, pallidum, hippocampus and amygdala. Participants were genotyped to determine their 5-HTTLPR (tri-allelic) and Val66Met polymorphisms.ResultsIn the combined sample (MDD + HC), smaller right pallidum volumes were found in LA/S (LA/S & LA/LG) heterozygotes compared to S/S (S/S, LG/S & LG/LG) homozygotes, though the effect was modest. In the MDD group, larger left thalamus and putamen volumes were observed in LA/LA homozygotes. No Val66Met or 5-HTTLPR genotype effects existed on cortical thickness and no main effects of the Val66Met polymorphism were observed.ConclusionOur preliminary results suggest that the 5-HTTLPR polymorphism is associated with morphometric changes in regions known to play an important role in emotional and reward processing in depression. A larger sample size is required to replicate these findings and to potentially reveal subtle morphometric changes.

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

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.

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.

Examining relations between alpha power as well as anterior cingulate cortex-localized theta activity and response to single or dual antidepressant pharmacotherapies

Electrocortical indices may be useful in predicting antidepressant response. Greater pretreatment alpha power and high rostral anterior cingulate cortex (rACC) theta activity tend to index a favorable outcome. The predictive utility of alpha power asymmetry has been under-explored. Baseline alpha2 (10.5–13.0 Hz) power/asymmetry, rACC theta2 (6.0–8.0 Hz) activity and early (one week) changes in these measures were assessed in relation to antidepressant response by week 12 to three treatment regimens (escitalopram (ESC) + bupropion (BUP), ESC or BUP) in patients with major depressive disorder (N=51). No treatment differences in response existed at week 12. Overall, treatment responders exhibited high, and non-responders low, frontal baseline alpha2 power. Frontal alpha2 power weakly discriminated responders/non-responders overall while posterior alpha2 power and BA25-localized theta2 activity strongly discriminated ESC responders/non-responders. No associations with alpha2 asymmetry and response emerged. BUP responders exhibited high, and BUP non-responders low, baseline rACC theta2 activity. Greater early decreases in rACC theta2 activity existed in ESC+BUP non-responders versus ESC+BUP responders. BUP responders exhibited greater rACC theta2 activity decreases than ESC responders. These preliminary results indicate that baseline and early changes in alpha2 and rACC theta2 activity associate with response and have implications for tailoring antidepressant treatments.

Mental Health Services for Students at Postsecondary Institutions: A National Survey:

Objective: Although the high prevalence of mental health issues among postsecondary students is well documented, comparatively little is known about the adequacy, accessibility, and adherence to best practices of mental health services (MHSs)/initiatives on postsecondary campuses. We evaluated existing mental health promotion, identification, and intervention initiatives at postsecondary institutions across Canada, expanding on our previous work in one Canadian province. Methods: A 54-question online survey was sent to potential respondents (mainly front-line workers dealing directly with students [e.g., psychologists/counsellors, medical professionals]) at Canada’s publicly funded postsecondary institutions. Data were analyzed overall and according to institutional size (small [<2000 students], medium [2000–10 000 students], large [>10 000 students]). Results: In total, 168 out of 180 institutions were represented, and the response rate was high (96%; 274 respondents). Most institutions have some form of mental health promotion and outreach programs, although most respondents felt that these were not a good use of resources. Various social supports exist at most institutions, with large ones offering the greatest variety. Most institutions do not require incoming students to disclose mental health issues. While counselling services are typically available, staff do not reliably have a diverse complement (e.g., gender or race diversity). Counselling sessions are generally limited, and follow-up procedures are uncommon. Complete diagnostic assessments and the use of standardized diagnostic systems are rare. Conclusions: While integral MHSs are offered at most Canadian postsecondary institutions, the range and depth of available services are variable. These data can guide policy makers and stakeholders in developing comprehensive campus mental health strategies.

Effects of nicotine on electroencephalography and affect in adolescent females with major depressive disorder: a pilot study.

Background:Given that smoking is typically initiated during adolescence, and that this period in brain development seems to be uniquely sensitive to nicotine, depressed youth may be most susceptible to the neuromodulatory and mood-altering effects of nicotine. Electroencephalographic (EEG) studies suggest that individuals with major depressive disorder (MDD) exhibit left frontal lobe hypoactivation (indexed by increased EEG alpha), a region implicated in positive affect regulation, as well as right parietal hypoactivation. Smoking/nicotine abstinence has been associated with increased left frontal and right parietal alpha activity (reduced activation), which has been correlated with increased depression ratings; nicotine administration seems to normalize this depression-associated asymmetry. Objectives:This pilot study investigated whether acute nicotine administration in adolescent female smokers with MDD would alter resting EEG activity and affect. Methods:Subjective mood ratings and EEG recordings were acquired before and 2 hours after administering a transdermal placebo or nicotine (21 mg) patch to 8 adolescent female smokers with MDD. Results:Nicotine induced a modest increase in alpha1 amplitude in the right hemisphere and simultaneously decreased left-favoring alpha1 amplitude asymmetry. It also attenuated left alpha1 and alpha2 amplitude in the central region. Consistent with nicotines stimulatory action, nicotine decreased theta amplitude in the right parietal region. No accompanying mood alterations were found, although smoking withdrawal and craving as well as physical symptom scores were reduced with nicotine. Conclusions:The results of this pilot study, the first to examine the electrocortical effects of nicotine in depressed adolescents, indicate that nicotine modulates EEG asymmetry measures, laying the stage for further research regarding the role of nicotine on affective neurocircuitry in this population.