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ABSTRACT: Obsessive-compulsive disorder (OCD) has been associated with regional volumetric brain abnormalities, which provide promising intermediate phenotypes of the disorder. In this study, volumes of brain regions selected for a priori evidence of association with OCD (orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), thalamus, caudate, putamen, globus pallidus and pituitary) were measured using structural magnetic resonance imaging (MRI) in 20 psychotropic-naïve pediatric OCD patients. We examined the association between these regional brain volumes and a total of 519 single nucleotide polymorphisms (SNPs) from nine glutamatergic candidate genes (DLGAP1, DLGAP2, DLGAP3, GRIN2B, SLC1A1, GRIK2, GRIK3, SLITRK1 and SLITRK5). These genes were selected based on either previous reported association with OCD in humans or evidence from animal models of OCD. After correcting for multiple comparisons by permutation testing, no SNP remained significantly associated with volumetric changes. The strongest trend toward association was identified between two SNPs in DLGAP2 (rs6558484 and rs7014992) and OFC white matter volume (P=0.000565, P(adjusted)=0.3071). Our other top ranked association findings were with ACC, OFC and thalamus. These preliminary results suggest that sequence variants in glutamate candidate genes may be associated with structural neuroimaging phenotypes of OCD.
Psychiatry research. 11/2012;
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ABSTRACT: Obsessive-compulsive disorder (OCD) is a common and often debilitating neuropsychiatric condition characterized by persistent intrusive thoughts (obsessions), repetitive ritualistic behaviors (compulsions) and excessive anxiety. While the neurobiology and etiology of OCD has not been fully elucidated, there is growing evidence that disrupted neurotransmission of glutamate within corticalstriatal-thalamocortical (CSTC) circuitry plays a role in OCD pathogenesis. This review summarizes the findings from neuroimaging, animal model, candidate gene and treatment studies in the context of glutamate signaling dysfunction in OCD. First, studies using magnetic resonance spectroscopy are reviewed demonstrating altered glutamate concentrations in the caudate and anterior cingulate cortex of patients with OCD. Second, knockout mouse models, particularly the DLGAP3 and Sltrk5 knockout mouse models, display remarkably similar phenotypes of compulsive grooming behavior associated with glutamate signaling dysfunction. Third, candidate gene studies have identified associations between variants in glutamate system genes and OCD, particularly for SLC1A1 which has been shown to be associated with OCD in five independent studies. This converging evidence for a role of glutamate in OCD has led to the development of novel treatment strategies involving glutamatergic compounds, particularly riluzole and memantine. We conclude the review by outlining a glutamate hypothesis for OCD, which we hope will inform further research into etiology and treatment for this severe neuropsychiatric condition.
Pharmacology Biochemistry and Behavior 02/2012; 100(4):726-35. · 2.53 Impact Factor
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ABSTRACT: Objective: There is general consensus that second-generation antipsychotics are at least as effective as and more tolerable than first-generation antipsychotics. We address questions of safety and tolerability in both the short-term and long-term use of these medications by reviewing the existing literature in youth and adults.Data Sources: A MEDLINE search was conducted via PubMed using the following keywords (in various combinations): typical antipsychotics, atypical antipsychotics, children, adolescents, side effects, weight gain, diabetes, metformin, metabolic syndrome, and CATIE. Only English-language articles published from 2000-2010 were included. The bibliographies of papers identified through MEDLINE searches were also reviewed.Results: Six adult studies were analyzed in detail. A summary of the data suggests that there may be a lower association of weight gain and diabetes with ziprasidone, aripiprazole, and haloperidol, while olanzapine, clozapine, quetiapine, and risperidone appear to be more highly associated. There may be less difference than originally thought concerning frequency of extrapyramidal side effects among these medications. All of these antipsychotics, including perphenazine, are similarly efficacious in treating psychosis, with the exception of clozapine, which demonstrates significantly more effectiveness. Although the studies on youth tend to be small (few subjects with large age ranges of 4 to 19 years) and short term in comparison to the adult studies, the data reviewed from 5 studies suggest that, in youth, olanzapine may be associated with the greatest weight gain, extrapyramidal side effects and metabolic changes are quite prevalent, and the antipsychotics studied seem to be similarly effective.Conclusions: Considering effectiveness, safety, and tolerability, this literature review suggests that in adults there may be a lower association of weight gain and diabetes with ziprasidone, aripiprazole, and haloperidol as compared with olanzapine, clozapine, quetiapine, and risperidone. Youth may be particularly sensitive to weight gain, especially with olanzapine, as well as extrapyramidal side effects and metabolic changes. The literature suggests similar effectiveness among the antipsychotics, perhaps with the exception of clozapine having greater effectiveness, at least in adults.
The primary care companion to CNS disorders. 01/2012; 14(3).
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ABSTRACT: Cortical abnormalities have been noted in previous studies of major depressive disorder (MDD).
To hypothesize differences in regional cortical thickness among children with MDD, children with obsessive-compulsive disorder (OCD), and healthy controls.
Cross-sectional study of groups.
Children's Hospital of Michigan in Detroit.
A total of 24 psychotropic drug-naive pediatric patients with MDD (9 boys and 15 girls), 24 psychotropic drug-naive pediatric outpatients with OCD (8 boys and 16 girls), and 30 healthy controls (10 boys and 20 girls).
Magnetic resonance imaging.
Cortical thickness.
In the right hemisphere of the brain, the pericalcarine gyrus was thinner in patients with MDD than in outpatients with OCD (P = .002) or healthy controls (P = .04), the postcentral gyrus was thinner in patients with MDD than in outpatients with OCD (P = .002) or healthy controls (P = .02), and the superior parietal gyrus was thinner in patients with MDD than in outpatients with OCD (P = .008) or healthy controls (P = .03). The outpatients with OCD and the healthy controls did not differ in these regions of the brain. The temporal pole was thicker in patients with MDD than in outpatients with OCD (P < .001) or healthy controls (P = .01), both of which groups did not differ in temporal pole thickness. The cuneus was thinner in patients with MDD than in outpatients with OCD (P = .008), but it did not differ from that in healthy controls. In the left hemisphere, the supramarginal gyrus was thinner in both patients with MDD (P = .04) and outpatients with OCD (P = .01) than in healthy controls, and the temporal pole was thicker in patients with MDD than in both healthy controls and outpatients with OCD (P < .001).
To our knowledge, this is the first study to explore cortical thickness in pediatric patients with MDD. Although differences in some regions of the brain would be expected given neurobiological models of MDD, our study highlights some unexpected regions (ie, supramarginal and superior parietal gyri) that merit further investigation. These results underscore the need to expand exploration beyond the frontal-limbic circuit.
Archives of general psychiatry 05/2011; 68(5):527-33. · 12.26 Impact Factor
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Psychopharm Review. 04/2010; 45(5):33–39.
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Journal of the American Academy of Child and Adolescent Psychiatry 01/2010; 49(1):7-10. · 4.98 Impact Factor
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Paul Daniel Arnold,
Frank P Macmaster,
Margaret A Richter,
Gregory L Hanna,
Tricia Sicard,
Eliza Burroughs,
Yousha Mirza,
Phillip C Easter,
Michelle Rose,
James L Kennedy, David R Rosenberg
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ABSTRACT: In this preliminary study, 16 psychotropic-naïve pediatric patients with obsessive-compulsive disorder (OCD) were studied using magnetic resonance spectroscopy (MRS) and genotyped for six candidate polymorphisms in two glutamate system genes. A significant association was identified between the rs1019385 polymorphism of the glutamate receptor, ionotropic, N-methyl-d-aspartate 2B (GRIN2B) and decreased anterior cingulate cortex (ACC) glutamatergic concentration (Glx) but not with occipital Glx. These results suggest that GRIN2B may be associated with Glx in the ACC, a region consistently implicated in OCD.
Psychiatry Research 06/2009; 172(2):136-9. · 2.52 Impact Factor
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Paul Daniel Arnold,
Frank P Macmaster,
Gregory L Hanna,
Margaret A Richter,
Tricia Sicard,
Eliza Burroughs,
Yousha Mirza,
Phillip C Easter,
Michelle Rose,
James L Kennedy, David R Rosenberg
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ABSTRACT: This pilot study was undertaken to determine if there was a significant association between specific glutamate system genes and regional volumes of interest implicated in the pathogenesis of obsessive-compulsive disorder (OCD). Volumetric magnetic resonance imaging (MRI) and genotyping of 7 polymorphisms in two genes, glutamate receptor, ionotropic, N-methyl-d-aspartate 2B (GRIN2B) and solute linked carrier, family 1, member 1 (SLC1A1) were conducted in 31 psychotropic-naïve pediatric OCD patients. The rs1805476 variant of GRIN2B was associated with left but not right orbital frontal cortex (OFC) (p=0.04) and right but not left anterior cingulate cortex (ACC) volume (p=0.02). The SLC1A1 rs3056 variant was associated with increased total (p=0.01), left (p=0.02) and right (p=0.02) thalamic volume. These results suggest that GRIN2B and SLC1A1 may be associated with regional volumetric alterations in OFC, ACC, and thalamus in children with OCD.
Brain Imaging and Behavior 03/2009; 3(1):64-76. · 1.66 Impact Factor
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ABSTRACT: Adults with major depressive disorder (MDD) are reported to have reduced orbitofrontal cortex (OFC) volumes, which could be related to decreased neuronal density. We conducted a study on medication naïve children with MDD to determine whether abnormalities of OFC are present early in the illness course.
Twenty seven medication naïve pediatric Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition (DSM-IV) MDD patients (mean age +/- SD = 14.4 +/- 2.2 years; 10 males) and 26 healthy controls (mean age +/- SD = 14.4 +/- 2.4 years; 12 males) underwent a 1.5T magnetic resonance imaging (MRI) with 3D spoiled gradient recalled acquisition. The OFC volumes were compared using analysis of covariance with age, gender, and total brain volume as covariates.
There was no significant difference in either total OFC volume or total gray matter OFC volume between MDD patients and healthy controls. Exploratory analysis revealed that patients had unexpectedly larger total right lateral (F = 4.2, df = 1, 48, p = 0.05) and right lateral gray matter (F = 4.6, df = 1, 48, p = 0.04) OFC volumes compared to healthy controls, but this finding was not significant following statistical correction for multiple comparisons. No other OFC subregions showed a significant difference.
The lack of OFC volume abnormalities in pediatric MDD patients suggests the abnormalities previously reported for adults may develop later in life as a result of neural cell loss.
Journal of child and adolescent psychopharmacology 01/2009; 18(6):551-6. · 2.59 Impact Factor
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ABSTRACT: The medial temporal cortex (MTC) has been implicated in the pathogenesis of pediatric major depressive disorder (MDD). Eleven MDD case-control pairs underwent proton magnetic resonance spectroscopic imaging. N-acetyl-aspartate was lower in the left MTC (27%) in MDD patients versus controls. Lower N-acetyl-aspartate concentrations in MDD patients may reflect reduced neuronal viability.
Psychiatry Research 09/2008; 164(1):86-9. · 2.52 Impact Factor
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ABSTRACT: The striatum, including the putamen and caudate, plays an important role in executive and emotional processing and may be involved in the pathophysiology of mood disorders. Few studies have examined structural abnormalities of the striatum in pediatric major depressive disorder (MDD) patients. We report striatal volume abnormalities in medication-naïve pediatric MDD compared to healthy comparison subjects.
Twenty seven medication-naïve pediatric Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) MDD and 26 healthy comparison subjects underwent volumetric magnetic resonance imaging (MRI). The putamen and caudate volumes were traced manually by a blinded rater, and the patient and control groups were compared using analysis of covariance adjusting for age, sex, intelligence quotient, and total brain volumes.
MDD patients had significantly smaller right striatum (6.0% smaller) and right caudate volumes (7.4% smaller) compared to the healthy subjects. Left caudate volumes were inversely correlated with severity of depression in MDD subjects. Age was inversely correlated with left and right putamen volumes in MDD patients but not in the healthy subjects.
These findings provide fresh evidence for abnormalities in the striatum of medication-naïve pediatric MDD patients and suggest the possible involvement of the striatum in the pathophysiology of MDD.
Journal of Child and Adolescent Psychopharmacology 05/2008; 18(2):121-31. · 2.88 Impact Factor
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ABSTRACT: Although several magnetic resonance imaging (MRI) studies have been conducted in adults with obsessive-compulsive disorder (OCD), few studies have used voxel-based morphometry to examine brain structure, especially in psychotropic drug-naive pediatric patients.
MRI examinations of 37 psychotropic drug-naive pediatric OCD patients and 26 age- and sex-matched healthy volunteers were acquired on a 1.5 T MRI system, normalized to a customized template, and segmented with optimized voxel-based morphometry.
Pediatric OCD patients had significantly more gray matter in regions predicted to differ a priori between groups, including the right and left putamen and orbital frontal cortex. Among patients, more gray matter in the left putamen and right lateral orbital frontal cortex correlated significantly with greater OCD symptom severity, but not with anxiety or depression. Manual region-of-interest measurements confirmed more gray matter in the orbital frontal cortex and putamen in patients compared to healthy volunteers. More anterior cingulate gray matter was evident among patients compared to healthy volunteers with regional volumetry but not with voxel-based morphometry. Regions of significantly less gray matter in OCD were confined to the occipital cortex and were not predicted a priori.
Our results suggest that OCD is characterized by more gray matter in brain regions comprising cortical-striatal-thalamic-cortical circuits. These findings are consistent with functional neuroimaging studies reporting hypermetabolism and increased regional cerebral blood flow in striatal, anterior cingulate, and orbital frontal regions among OCD patients while in a resting state.
American Journal of Psychiatry 05/2008; 165(10):1299-307. · 12.54 Impact Factor
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ABSTRACT: Neuroimaging studies have identified alterations in frontostriatal circuitry in obsessive-compulsive disorder (OCD). Voxel-based morphometry (VBM) allows for the assessment of differences in gray matter density across the whole brain. VBM has not previously been used to examine regional gray matter density in pediatric OCD patients and the siblings of pediatric OCD patients. Volumetric magnetic resonance imaging (MRI) studies were conducted in 10 psychotropic naïve pediatric patients with OCD, 10 unaffected siblings of pediatric patients with OCD, and 10 healthy controls. VBM analysis was conducted using SPM2. Statistical comparisons were performed with the general linear model, implementing small volume random field corrections for a priori regions of interest (anterior cingulate cortex or ACC, striatum and thalamus). VBM analysis revealed significantly lower gray matter density in OCD patients compared to healthy in the left ACC and bilateral medial superior frontal gyrus (SFG). Furthermore, a small volume correction was used to identify a significantly greater gray matter density in the right putamen in OCD patients as compared to unaffected siblings of OCD patients. These findings in patients, siblings, and healthy controls, although preliminary, suggest the presence of gray matter structural differences between affected subjects and healthy controls as well as between affected subjects and individuals at risk for OCD.
Neuroscience Letters 05/2008; 435(1):45-50. · 2.11 Impact Factor
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Pediatric Radiology 04/2008; 38(3):270. · 1.67 Impact Factor
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ABSTRACT: Abnormalities in the amygdala and hippocampus have been implicated in the pathogenesis of major depressive disorder (MDD). To our knowledge, no prior study has examined amygdala-hippocampus anatomy in pediatric patients with familial MDD (at least one first degree relative with MDD).
Thirty-two psychotropic-naive patients with familial MDD, aged 8-21 years (12 males and 20 females), and 35 group-matched healthy participants (13 males and 22 females) underwent volumetric magnetic resonance imaging in order to evaluate hippocampal and amygdala volumes.
Patients with familial MDD had significantly smaller left hippocampal (p = .007, effect size [d] = .44) and right hippocampal volumes (p = .025, d = .33) than controls. No differences were noted in amygdala volumes between groups (right: p > .05, left: p > .05). No correlations between hippocampal or amygdala volumes and demographic or clinical variables were noted.
Reduced hippocampal volume may be suggestive of a risk factor for developing MDD.
Biological psychiatry 03/2008; 63(4):385-90. · 8.93 Impact Factor
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ABSTRACT: Few studies have examined pituitary gland size in mood disorders, particularly in adolescents. We hypothesized increase in the pituitary gland size in early-onset mood disorders.
Thirty subjects between the ages of 13 and 20 years participated in the study. Three groups (control, bipolar I depression and unipolar depression) of 10 subjects each (4 male, 6 female) underwent volumetric magnetic resonance imaging at 1.5 T.
Analysis of covariance (covarying for age, sex and intracranial volume) revealed a significant difference in pituitary gland volume amongst the groups [F(2,24) = 7.092, p = 0.014]. Post hoc analysis revealed that controls had a significantly smaller pituitary gland volume than both bipolar patients (p = 0.019) and depressed patients (p = 0.049). Bipolar and depressed subjects did not differ significantly from each other with regard to pituitary gland volume (p = 0.653). Control females had larger pituitary glands than control males [F(1,8) = 10.523, p = 0.012], but no sex differences were noted in the mood disorder groups.
Pituitary glands are enlarged in adolescents with mood disorders compared to controls. Healthy young females have larger pituitary glands than males, but such a difference is not evident in individuals with unipolar depression or bipolar disorder. These findings provide new evidence of abnormalities of the pituitary in early onset mood disorders, and are consistent with neuroendocrine dysfunction in early stages of such illnesses.
Bipolar Disorders 03/2008; 10(1):101-4. · 5.29 Impact Factor
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ABSTRACT: The objective of this study was to examine the effect of antipsychotics on pituitary volume in schizophrenic subjects. Pituitary volumes were measured in 16 patients with schizophrenia at baseline and 12 months after treatment with an antipsychotic medication using magnetic resonance imaging (MRI). A group of 12 healthy controls was evaluated at baseline and after 12 months. Pituitary volume significantly increased in the schizophrenic subjects after treatment (12% increase). This appeared to be specific to the prolactin-elevating drugs. In controls, pituitary volume did not change significantly (3% decrease). Pituitary volume may be a useful biomarker for treatments that affect neuroendocrine function.
Schizophrenia Research 06/2007; 92(1-3):207-10. · 4.75 Impact Factor
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ABSTRACT: To address a rising trend of emergency department (ED) visits for mental disorders (VMD), our ED implemented a child guidance model for their efficient evaluation and disposition.
The main objective of our study was to evaluate the impact of the child guidance model on the ED length of stay (LOS) and ED costs on children with VMD.
We conducted a retrospective chart analysis on 1031 VMD visits made to an inner-city tertiary care pediatric ED in 2002 (1.4% of the total 2002 ED visits). We collected demographic and LOS information on all VMD visits. The child guidance model was implemented June 2002, after which we divided the VMD cases into 2 groups based on the presence or absence of the model. We performed a cost analysis to assess the impact of the model on LOS and determined the opportunity costs of prolonged LOS of the VMD visits as compared with 500 non-VMD visits.
The average LOS of VMD visits was longer than that of the 500 non-VMD visits (236.04 minutes +/- 162.82 vs. 134.69 minutes +/- 95.19; mean difference, 101.34 minutes; P = 0.001). The LOS was significantly reduced after the model was implemented (259.49 minutes +/- 171.12 vs. 216.39 +/- 152.95 minutes, P = 0.00). The lost revenue due to extended VMD LOS was calculated as opportunity costs of $201,173.30, whereas the cost savings during the study period due to reduced LOS after the model was implemented was $10,651.
This study suggests that children with VMD visits contribute a substantial resource burden in the ED, and focused interventions such as the child guidance model in the ED can significantly decrease LOS and reduce ED costs.
Pediatric emergency care 05/2007; 23(4):212-7. · 0.92 Impact Factor
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Frank P MacMaster,
Matcheri Keshavan,
Yousha Mirza,
Normand Carrey,
Ameet R Upadhyaya,
Rhonda El-Sheikh,
Christian J Buhagiar,
S Preeya Taormina,
Courtney Boyd,
Michelle Lynch,
Michelle Rose,
Jennifer Ivey,
Gregory J Moore, David R Rosenberg
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ABSTRACT: The pituitary gland plays a central role in sexual development and brain function. Therefore, we examined the effect of age and gender on pituitary volume in a large sample of healthy children and adults. Volumetric magnetic resonance imaging (MRI) was conducted in one hundred and fifty four (77 males and 77 females) healthy participants. Males were between the ages of 7 to 35 years (16.91+/-5.89 years) and females were 7 to 35 years of age (16.75+/-5.75 years). Subjects were divided into subgroups of age (7 to 9, 10 to 13, 14 to 17, 18 to 21, 22 and older) and sex (male/female). Pituitary gland volume differed between sexes when comparing the age groups (F=3.55, df=2, 143, p=0.03). Females demonstrated larger pituitary glands than males in the age 14 to 17 year old groups (p=0.04). Young (19 years and under) and old (20 years and older) females demonstrated a correlation between pituitary volume and age. Males did not show this relationship. These findings provide additional evidence for gender differences in the normative anatomy of the pituitary and may have relevance for the study of various childhood onset neuropsychiatric disorders in which pituitary dysfunction has been implicated.
Life Sciences 03/2007; 80(10):940-4. · 2.53 Impact Factor
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Frank P MacMaster,
Aileen Russell,
Yousha Mirza,
Matcheri S Keshavan,
S Preeya Taormina,
Rashmi Bhandari,
Courtney Boyd,
Michelle Lynch,
Michelle Rose,
Jennifer Ivey,
Gregory J Moore, David R Rosenberg
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ABSTRACT: Prior pilot investigation identified a larger pituitary gland volume (PGV) in pediatric patients with major depressive disorder (MDD) compared with healthy pediatric control subjects that was most prominent in boys with MDD. In this independent sample, we focus on gender differences in pituitary volume in a larger sample of pediatric patients with MDD.
Volumetric magnetic resonance imaging studies were conducted in 35 psychotropic drug-naïve children (15 boys, 20 girls), ages 8-17 years, and 35 case-matched healthy control subjects.
The MDD boys had larger PGV (19%) compared with male control subjects. No significant diagnostic group differences in pituitary volume were observed in girls. Healthy boys had significantly smaller PGV (27%) than healthy girls, whereas MDD boys did not differ from girls with MDD. Nonfamilial (without a family history of mood disorder) boys with MDD had significantly larger PGV (35%) than male healthy control subjects and tended to have a larger PGV (27%) than familial (at least one first-degree relative with MDD) boys with MDD. Boys with familial MDD did not differ from control subjects.
These findings provide new evidence of increased pituitary volume in psychotropic-naïve pediatric patients with MDD that seems to be more prominent in male patients with nonfamilial MDD.
Biological Psychiatry 11/2006; 60(8):862-6. · 8.28 Impact Factor
