Byung Joo Ham

Neural correlates of affective processing in response to sad and angry facial stimuli in patients with major depressive disorder

Mood abnormalities related to major depressive disorder (MDD) seem to result from disturbances in pathways connecting the fronto-limbic and subcortical, both regions known to be involved in the processing of emotional information. Using functional magnetic resonance imaging (fMRI), we measured neural responses to viewing images of sad, angry and neutral faces in 21 patients with MDD and 15 healthy controls. When shown pictures of sad faces, patients with MDD relative controls showed decreased activations bilaterally in the dorsolateral prefrontal cortex, inferior orbitofrontal cortex (OFC), medial OFC, caudate, and hippocampus. We also found significant group differences under the angry face condition, bilaterally, in the inferior OFC and medial OFC areas. Our findings indicate that decreased activations in the fronto-limbic and subcortical regions in response to affectively negative stimuli may be associated with pathophysiology of MDD.

The neural substrates of affective processing toward positive and negative affective pictures in patients with major depressive disorder

Previous studies examining neural responses to emotional stimuli in individuals with major depressive disorder (MDD) have indicated increased responses within the left amygdala to sad faces, and increased activity within the visual cortex and striatum to expressions of happiness. Using functional magnetic resonance imaging (fMRI), the current study measured neural responses to neutral, positive and negative pictures of the International Affective Picture System in 15 healthy individuals and 15 patients with MDD. Depressed individuals demonstrated lower activity in the right hippocampus and the right insula to negative affective pictures, whereas they showed lower activity in the right anterior cingulate cortex and the left insula to positive pictures. However, within the MDD group, the severity of depression correlated with the activity of the left amygdala, bilateral inferior orbitofrontal areas, and the left insula to negative pictures, whereas there were no clear indications of association between specific cerebral regions and positive pictures. Our findings indicate that preferential decreases in the left amygdala in response to negative pictures might be involved in the processing of emotional stimuli in depressed individuals. Also, these findings suggest that the bilateral inferior orbitofrontal cortices and left amygdala may be preferentially recruited in MDD patients, but not in healthy individuals.

Association between major depressive disorder and the -1438A/G polymorphism of the serotonin 2A receptor gene

This study investigated the possible effect of the –1438A/G single-nucleotide polymorphism in the promoter region of the serotonin 2A receptor (5-HTR2A) gene on major depressive disorder (MDD) in a Korean population. This polymorphism was analyzed in 189 patients with MDD and in 148 unrelated healthy controls using a case-control design, which revealed a significant difference in the genotype distributions (χ2 = 10.78, d.f. = 2, p = 0.005). The frequency of the –1438G allele was also much higher in MDD patients than in normal controls (χ2 = 7.20, p = 0.007; OR = 1.52, 95% CI 1.12–2.06). We also found significantly more carriers of the G allele (GG+AG genotypes) in MDD patients than in normal controls (χ2 = 10.18, p = 0.001; OR = 2.46, 95% CI 1.40–4.32). Our results support the hypothesis that the –1438A/G polymorphism of the promoter region of the 5-HTR2A gene is associated with MDD patients in a Korean population.

Association between norepinephrine transporter gene polymorphism and major depression.

Noradrenergic and serotonergic abnormalities have long been implicated in patients with major depression. The novel selective norepinephrine reuptake inhibitor reboxetine has been shown to be at least as effective as imipramine, desipramine and fluoxetine in the treatment of major depression. It is suggested that the dysfunction of the norepinephrine transporter (NET) may be related to major depression. Although the transcriptional activity related to the NET gene expression is little known, it may be a good candidate gene for major depression. Therefore, we investigated whether the T-182C polymorphism of the NET gene is associated with major depression in a Korean sample of 112 major depression patients compared with 136 healthy controls. We found a significantly lower frequency in TT genotype in patients with major depression than in normal controls when the genotypes of T-182C polymorphism were classified into two groups: TT group versus TC + CC group (p = 0.019). This result suggests that the T-182C polymorphism in the NET gene might be associated with major depression.

Brain-derived neurotrophic factor gene polymorphisms and mirtazapine responses in Koreans with major depression

Brain-derived neurotrophic factor (BDNF) is a candidate molecule for influencing the clinical response to antidepressant treatment. The aims of this study were to determine the relationship between the Val66Met polymorphism in the BDNF gene and the response to mirtazapine in 243 Korean subjects with major depressive disorder (MDD). The reduction in the Hamilton Depression score over the 8-week treatment period was not influenced by BDNF V66M genotypes. A marginal effect of genotype on somatic anxiety score was observed at baseline (P = 0.047 in the dominant model). However, genotype–time interaction had no effect on somatic anxiety score after the 8-week a treatment period. Plasma BDNF levels tended to increase during mirtazapine treatment, although without statistical significance (P = 0.055). After 8 weeks of mirtazapine treatment, plasma BDNF levels were higher in Met allele homozygotes (1499.7 ± 370.6 ng/mL) than in Val allele carriers (649.7 ± 158.5 ng/mL, P = 0.049). Our results do not support the hypothesis that the Val66Met promoter polymorphism in the BDNF gene influences the therapeutic response to mirtazapine in Korean MDD patients. However, our data indicate that this polymorphism results in increased plasma BDNF after mirtazapine treatment.

Monoamine oxidase A-uVNTR genotype affects limbic brain activity in response to affective facial stimuli.

Monoamine oxidase A (MAOA) enzymatically degrades biogenic amines such as norepinephrine, dopamine, and serotonin, and plays a key role in the regulation of their neurotransmission. Allelic variations at the MAOA locus have been implicated in the neurobiology of aggression and impulsivity. We investigated the possible relationship between the MAOA–upstream variable number of tandem repeats (uVNTR) polymorphism and brain responses to negative facial stimuli, using functional magnetic resonance imaging (fMRI). We found a significant association between a low activity allele of MAOA–uVNTR and neural activation to negative facial stimuli. In the sad condition, participants with the low activity allele showed greater brain activity in the left amygdala. In the angry condition, participants with the low activity allele showed greater brain activity in the right anterior cingulate cortex and hippocampus. Our results suggest that MAOA–uVNTR polymorphism can affect activation of limbic regions, elicited by negative emotional stimuli.

Association between the 5-HT6 receptor C267T polymorphism and response to antidepressant treatment in major depressive disorder

Abstract  The purpose of the present study was to determine if a 5‐HT6 receptor polymorphism is associated with antidepressant treatment response in major depressive disorder (MDD). Ninety‐one patients with MDD, compared with 127 normal control subjects, were evaluated after an 8‐week treatment period. An association analysis revealed no differences in genotype and allele distribution between patients with MDD and normal control subjects. However, there were significant differences in the treatment response in some Hamilton Depression Rating Scale (HAM‐D) scores (sleep, activity, somatic anxiety, and total) between genotypes. Moreover, the heterozygote group (CT genotype) had significantly better treatment response than the homozygote group (CC + TT genotypes), especially in the somatic‐anxiety subcategory and the total score of HAM‐D. These findings imply that a 5‐HT6 receptor polymorphism (C267T) is associated with treatment response in MDD.

Decreased GABA levels in anterior cingulate and basal ganglia in medicated subjects with panic disorder: a proton magnetic resonance spectroscopy (1H-MRS) study.

The purpose of this study was to investigate the brain gamma-aminobutyric acid (GABA) concentration and its relationship with clinical variables in patients with panic disorder (PD). Single voxel proton magnetic resonance spectroscopy ((1)H-MRS) scan was performed on 22 medicated subjects with PD and 25 age and sex-matched healthy comparison subjects. GABA and other metabolite levels were measured in the anterior cingulate cortex (ACC) and basal ganglia. GABA levels were significantly lower in the ACC and basal ganglia of PD patients relative to comparison subjects. Lactate and choline concentrations in the ACC in PD patients were also higher than in the comparison subjects. Our data suggested in part that alterations of the GABA function and the energy metabolism in ACC and basal ganglia may play an important role in the pathophysiology of panic disorder.

Association between the tryptophan hydroxylase-1 gene A218C polymorphism and citalopram antidepressant response in a Korean population

Tryptophan hydroxylase-1 (TPH1) is the rate-limiting enzyme in serotonin biosynthesis, and selective serotonin reuptake inhibitors (SSRIs) exert their activity enhancing the general serotonergic tone. Citalopram is the most selective SSRI, with little or no affinity for a variety of receptor types. The goal of this study was to investigate whether the A218C polymorphism of the TPH1 gene is associated with the citalopram antidepressant response in subjects with major depressive disorder (MDD). All of the patients were evaluated using the 21-item Hamilton Depression Rating Scale before beginning and after 8 weeks of citalopram treatment. Genotyping was performed with the polymerase chain reaction. The remission rate to citalopram treatment was worse in MDD subjects with the TPH1 A/A and A/C genotypes than in those with the TPH1 C/C genotype. Our results suggest that the A218C polymorphism of the TPH1 gene serves as a modulator of antidepressant activity, especially in terms of treatment remission.

Serotonergic genes and personality traits in the Korean population

Serotonergic genes have been implicated in mood disorders, alcoholism and certain personality traits. The goal of this study was to investigate the relationship between personality traits and several important genes in the serotonin system. The participants included 146 healthy adults with no history of psychiatric disorders or other physical illness during the last 6 months. All participants were tested by the Temperament and Character Inventory (TCI) and genotyped serotonin transporter, serotonin receptors (5-HT(2A) and 5-HT(6)) and tryptophan hydroxylase gene polymorphisms. Genotyping was analyzed with polymerase chain reaction. Differences in TCI dimensions and sub-scales among three groups were examined with ANOVA. Our result suggested that 5-HT(2A) receptor gene polymorphism (A-1438G) appears to be associated with self-determinism and self-transcendence (ST). Our result also indicated a significant relationship between 5-HT(6) receptor gene polymorphism (C267T) and ST. Further studies of polymorphisms of other genes and their interactions may clarify the complex relationship between personality and genes.