Relationship between neural activity and immunity in patients with undifferentiated somatoform disorder.

It has been suggested that somatoform disorders are related to both the brain and the immune system, and that immune functions may be influenced by cerebral asymmetry. However, few studies have examined the relationship between brain activity and immune function in somatoform disorders. Thirty-two patients with non-medicated undifferentiated somatoform disorder were enrolled in this study. Blastogenic responses to phytohemagglutinin (PHA) were used to measure immunity. Regional cerebral perfusion was measured by 99m-Tc-ethyl cysteinate dimer single photon emission computed tomography (SPECT). Significant hypoperfusion was found at the left inferior parietal lobule and the left supramarginal gyrus in the more immune-suppressed (MIS) subgroup compared with the less immune-suppressed (LIS) subgroup. However, no regions of significant hyperperfusion were found in the MIS subgroup compared with the LIS subgroup. Decreased cerebral blood flow in the left inferior parietal lobule and the left supramarginal gyrus in the patient group was also significantly associated with reduced blastogenic responses to PHA regardless of sex and age. These results suggest that the left inferior parietal lobule and the left supramarginal gyrus might play an immunomodulating role in patients with undifferentiated somatoform disorder. In addition, these results suggest the role of cerebral asymmetry in altered immunity in the patients.

Effects of high and low stress on proinflammatory and antiinflammatory cytokines.

The effects of stress, which varies throughout an academic year, on proinflammatory and antiinflammatory cytokines were examined in 44 medical students. This was tested by comparing stimulated cytokines during a baseline period, stress period, and poststress vacation period. During the stress period, compared with the baseline period, levels of IL-6 were reduced, while levels of IL-10 were elevated. During the poststress vacation period, compared with the stress period, levels of IL-6 and TNF-α were increased. However, the changes in stress-related psychological and physiological variables were not significantly associated with changes in levels of proinflammatory and antiinflammatory cytokines. These results suggest that vacation is more likely to have a counterstress effect on proinflammatory cytokines than on an antiinflammatory cytokine and that a stressor may affect changes in immune function independently of self-reported stress.

Effect of tryptophan hydroxylase gene polymorphism on aggression in major depressive disorder and undifferentiated somatoform disorder.

OBJECTIVE: Aggression and anger have been linked with depression, and anger suppression has been linked with somatic symptoms of somatoform disorders. However, the relationship between aggression or anger and genes in patients with depression and somatoform disorders has not been clearly elucidated. The objective of this study was to examine the effect of serotonin-related gene polymorphism on aggression in depressive disorders and somatoform disorders. METHOD: A serotonin-related polymorphic marker was assessed by using single nucleotide polymorphism (SNP) genotyping. 106 outpatients with major depressive disorder (MDD), 102 outpatients with undifferentiated somatoform disorder, and 133 healthy subjects were enrolled between October 2005 and May 2008. Diagnoses were made according to the Korean version of the Structured Clinical Interview Schedule for DSM-IV. The allele and genotype frequencies of tryptophan hydroxylase-1 (TPH1) A218C were compared between groups. The Hamilton Depression Rating Scale and the Aggression Questionnaire were used for psychological assessment. RESULTS: Each of the 2 disorder groups scored significantly higher on all the Aggression Questionnaire subscales and on the total Aggression Questionnaire score than the healthy subjects (P < .001). Patients with MDD had significantly higher frequencies of TPH1 C allele (P = .0002) and CC homozygote (P = .0003) than healthy subjects, regardless of sex and age. However, no significant differences were found in TPH1 C allele and CC homozygote frequencies between the undifferentiated somatoform disorder patients and the healthy subjects. TPH1 CC homozygote in the MDD group scored significantly higher in terms of verbal aggression (P = .03) and total Aggression Questionnaire score (P = .04) than A-carrier genotypes, regardless of sex and age. However, no significant differences were found in the scores of all the Aggression Questionnaire subscales and the total Aggression Questionnaire score between TPH1 CC homozygote and A-carrier genotypes in the undifferentiated somatoform disorder group and the control group, respectively. CONCLUSIONS: Aggression in MDD patients is more susceptible to an excess of TPH1 CC homozygote than in undifferentiated somatoform disorder patients, though the 2 disorders are high risk groups for aggression. In addition, TPH1 gene is most likely to have a shared effect on aggression and MDD.

The relation of serotonin-related gene and COMT gene polymorphisms with criminal behavior in schizophrenic disorder.

OBJECTIVE: It has been suggested that patients with schizophrenia might be involved in criminal behavior, such as homicidal and violent behavior. However, the relationship between criminal behavior and genes in patients with schizophrenia has not been clearly elucidated. The objective of this study was to examine the relation between criminal behavior and serotonin-related gene or catechol-O-methyltransferase (COMT) gene polymorphisms in patients with schizophrenia. METHOD: Serotonin-related and COMT polymorphic markers were assessed by using single nucleotide polymorphism (SNP) genotyping. Ninety-nine crime-related inpatients with schizophrenia (57 homicidal and 42 nonhomicidal violent) and 133 healthy subjects were enrolled between October 2005 and May 2008. Diagnoses were made according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. The genotype frequencies of tryptophan hydroxylase-1 (TPH1) A218C and COMT V158M were compared between groups. RESULTS: The TPH1 CC genotype had 2.7-fold higher odds of crime-related schizophrenia compared with A-carrier genotype after the analysis was controlled for sex and age (OR, 2.69; 95% CI, 1.22 - 5.91; P = .01). In addition, the TPH1 CC genotype had 3.4-fold higher odds of homicidal schizophrenia compared with A-carrier genotype after the analysis was controlled for sex and age (OR, 3.38; 95% CI, 1.40 - 8.18; P = .007). However, no significant differences were found in the frequencies of genotype of COMT polymorphism between criminal schizophrenics and healthy subjects, nor were any significant differences found between nonhomicidal schizophrenics and healthy subjects. CONCLUSIONS: These results indicate that the TPH1 CC recessive genotype is likely to be a genetic risk factor for criminal behavior, especially homicidal behavior in patients with schizophrenia. However, COMT gene polymorphisms were not associated with criminal behavior in schizophrenic patients.

Serotonin-related gene pathways associated with undifferentiated somatoform disorder.

It has been suggested that serotonergic hypofunction and serotonergic pathway genes underlie the somatic symptoms of somatoform disorders. We examined a variety of serotonin-related gene polymorphisms to determine whether undifferentiated somatoform disorder is associated with specific serotonin-related gene pathways. Serotonin-related polymorphic markers were assessed using single nucleotide polymorphism (SNP) genotyping. One hundred and two patients with undifferentiated somatoform disorder and 133 healthy subjects were enrolled. The genotype and allele frequencies of tryptophan hydroxylase (TPH)1 A218C, TPH2 rs1386494, serotonin receptor 2A-T102C (5-HTR 2A-T102C), 5-HTR 2A-G1438A and serotonin transporter (5HTTLPR) gene were compared between the groups. The Hamilton Rating Scale for Depression and the somatization subscale of the Symptom Checklist-90-Revised (SCL-90-R) were used for psychological assessment. Patients with undifferentiated somatoform disorder had higher frequencies of the TPH1 C allele than healthy controls (p=0.02) but the difference was not significant after Bonferroni correction. The frequency of TPH1 genotype also did not differ significantly between the patients and the healthy controls, nor did TPH2 rs1386494, 5-HTR 2A-T102C, 5-HTR 2A-G1438A or 5HTTLPR allele and genotype frequencies differ significantly between the two groups. These findings suggest that a variety of serotonin-related gene pathways are unlikely to be definite genetic risk factors for undifferentiated somatoform disorder. Therefore, the pathogenesis of the disorder may be related to epigenetic factors, including psychosocial and cultural factors. Nonetheless, future studies need to include a larger sample of subjects and polymorphisms of more serotonin-related gene variants.

Shared neural activity in panic disorder and undifferentiated somatoform disorder compared with healthy controls.

OBJECTIVE: In previous studies, some brain areas, including parahippocampal gyrus, were suggested to be associated with panic disorder. Both panic disorder and somatoform disorders are associated with anxiety. This study sought to determine if there are shared neural activity underlying panic disorder and undifferentiated somatoform disorder. METHOD: Sixteen nonmedicated patients with panic disorder, 16 nonmedicated patients with undifferentiated somatoform disorder, and 10 healthy subjects were scanned between February 2005 and August 2006. Diagnoses were made according to the Korean version of the Structured Clinical Interview for DSM-IV Axis I Disorders, Research Version, Patient/Non-Patient Edition. Regional cerebral perfusion was measured by 99 m-Tc-ethyl cysteinate dimer single photon emission computed tomography (SPECT). Using statistical parametric mapping analysis, we compared the SPECT images between the groups. RESULTS: Significant hyperperfusion was found at the left superior temporal gyrus and the left supramarginal gyrus in the panic disorder patients when compared to the controls (family-wise error [FWE], P < .001). The somatoform disorder patients showed hyperperfusion in the left hemisphere at the superior temporal gyrus, inferior parietal lobule, middle occipital gyrus, precentral gyrus, postcentral gyrus, and, in the right hemisphere, at the superior temporal gyrus when compared to the controls (false discovery rate [FDR], P < .001). In contrast, significant hypoperfusion was found at the right parahippocampal gyrus in each of panic disorder (FWE, P = .001) and somatoform disorder (FWE, P < .001) groups compared to healthy controls. However, no significant differences were found in regional cerebral perfusion between the 2 disorder groups. CONCLUSIONS: Both panic disorder and undifferentiated somatoform disorder showed hyperperfusion in the left superior temporal gyrus and hypoperfusion in the right parahippocampal gyrus, which suggests that the 2 disorders are likely to share neural activity.

The relation between anger management style, mood and somatic symptoms in anxiety disorders and somatoform disorders.

The objective of this study was to examine the relationship between anger management style, depression, anxiety and somatic symptoms in anxiety disorder and somatoform disorder patients. The subjects comprised 71 patients with anxiety disorders and 47 with somatoform disorders. The level of anger expression or anger suppression was assessed by the Anger Expression Scale, the severity of anxiety and depression by the Symptom Checklist-90-Revised (SCL-90-R) anxiety and depression subscales, and the severity of somatic symptoms by the Somatization Rating Scale and the SCL-90-R somatization subscale. The results of path analyses showed that anger suppression had only an indirect effect on somatic symptoms through depression and anxiety in each of the disorders. In addition, only anxiety had a direct effect on somatic symptoms in anxiety disorder patients, whereas both anxiety and depression had direct effects on somatic symptoms in somatoform disorder patients. However, the anxiety disorder group showed a significant negative correlation between anger expression and anger suppression in the path from anger-out to anger-in to depression to anxiety to somatic symptoms, unlike the somatoform disorder group. The results suggest that anger suppression, but not anger expression, is associated with mood, i.e. depression and anxiety, and somatic symptoms characterize anxiety disorder and somatoform disorder patients. Anxiety is likely to be an important source of somatic symptoms in anxiety disorders, whereas both anxiety and depression are likely to be important sources of somatic symptoms in somatoform disorders. In addition, anger suppression preceded by inhibited anger expression is associated with anxiety and somatic symptoms in anxiety disorders.

Counter-stress effects of relaxation on proinflammatory and anti-inflammatory cytokines.

The counter-stress effects of relaxation on proinflammatory and anti-inflammatory cytokines were examined. From 36 medical students, 18 were randomly assigned to the relaxation group, and 18 were randomly assigned to the non-relaxation group. Relaxation lasted for four weeks. The levels of stimulated production of IL-6, TNF-alpha, and IL-10, and blood pressure were measured during the non-examination period (baseline period) and the pre-examination period (stress period). The levels of perceived stress were assessed by the Global Assessment of Recent Stress (GARS) scale, the Stress Response Inventory (SRI) and the Symptom Checklist-90-Revised (SCL-90-R) anxiety subscale. Repeat measure ANOVA revealed that the SRI total score, scores of the SCL-90-R anxiety subscale and diastolic blood pressure were significantly higher during the stress period than during the baseline period regardless of groups. The level of IL-6 production was significantly lower but the level of IL-10 production was significantly higher during the stress period than during the baseline period. Significant reduction in the delta (stress period value minus baseline period value) in the total GARS score, systolic and diastolic blood pressure, the levels of IL-6 and TNF-alpha production but significant enhancement in the delta in the level of the IL-10 production were found in the relaxation group compared with the non-relaxation group. These results suggest that relaxation is associated with reduction in stress-induced psychological or physiological responses and proinflammatory cytokine alterations but with enhancement in stress-induced anti-inflammatory cytokine alteration. Therefore, relaxation is more likely to have counter-stress effect on proinflammatory cytokines than on anti-inflammatory cytokine.

The relation between anger management style and organ system-related somatic symptoms in patients with depressive disorders and somatoform disorders.

PURPOSE: The objective of this study was to examine the relation between anger management style and organ system- related somatic symptoms in depressive disorder and somatoform disorder patients. MATERIALS AND METHODS: The subjects included 73 patients with depressive disorders and 47 with somatoform disorders. Anger management styles were assessed by the Anger Expression Scale, while the severity of organ system-related somatic symptoms was evaluated using the Somatic Stress Response Scale (SSRS). The severity of depression and hostility was assessed by the Symptom Checklist-90-Revised (SCL-90-R) depression and hostility subscales. RESULTS: The results of multiple regression analyses showed that, in depressive disorder patients, the level of anger expression was significantly associated with the severity of somatic symptoms related to neuromuscular, cardiorespiratory and gastrointestinal systems. However, in these patients, the level of anger suppression was not significantly associated with the severity of somatic symptoms related to any specific organ systems. In patients with somatoform disorders, there was no significant association between the level of anger suppression or anger expression and the severity of the somatic symptoms related to any specific organ systems. CONCLUSION: These results suggest that, in depressive disorder patients, anger expression is likely to be predominantly involved in the neuromuscular, cardiorespiratory and gastrointestinal organ systems. However, in each of depressive disorder and somatoform disorder patients, anger suppression is not likely to be associated with any specific organ systems.

Effect of coping on endocrinoimmune functions in different stress situations.

The objective of this study was to examine the effects of coping strategies on the endocrine and immune functions in different stress situations. Thirty-eight medical students were enrolled in this study. Cell-mediated immune function was measured using the lymphocyte proliferative response to phytohemagglutinin (PHA) and interleukin-2 (IL-2) production during the nonexamination period and during the preexamination period. Endocrine functions were assessed by measuring the plasma levels of norepinephrine, adrenocorticotropic hormone (ACTH) and cortisol. The Global Assessment of Recent Stress (GARS) scale, the Stress Response Inventory, the anxiety, depression, and somatization subscales of the Symptom Checklist-90-revised, the Way of Coping-revised, the Toronto Alexithymia Scale and the Anger Expression Scale were used as psychometric measures. The subjects with higher levels of total GARS scores showed significantly higher IL-2 production during the nonexam period than those with lower levels of total GARS scores. During the same period, IL-2 production in the less positive reappraisal group was significantly higher than in the more positive reappraisal group. Lymphocyte proliferation in the group seeking less social support was also significantly higher than in the group seeking more social support. However, no significant association was found between the coping strategies and each of the hormone levels. These results suggest that positive reappraisal and seeking social support can be associated with the alteration of immune function during a chronic stress period. In particular, positive reappraisal is likely to reverse the stress-induced immune responses. This study did not find that neuroendocrine function such as the sympathetic-adrenal medullary axis or the hypothalamic-pituitary-adrenal axis is playing a mediating role in the relationship between coping and immunity.

Development of the stress-induced cognition scale.

The objective of this study was to develop the stress- induced cognition scale (SCS). A preliminary survey was conducted on 109 healthy adults to obtain cognitive stress responses. Then, 215 healthy subjects completed a preliminary questionnaire. A comparison was made regarding cognitive stress responses among 73 patients with depressive disorders and 215 healthy subjects. Factor analysis of the SCS yielded 3 subscales: extreme thought, aggressive-hostile thought, and self-depreciative thought. The test-retest reliability for the 3 subscales and the total score was significantly high, ranging from 0.87 to 0.95. The Cronbach's alpha for the 3 subscales and total score ranged from 0.82 to 0.94. The convergent validity was calculated by correlating the 3 subscales and total score of the SCS with the total score of the global assessment of recent stress (GARS) scale, the perceived stress questionnaire (PSQ), and the Symptom Checklist-90-Revised (SCL-90-R). The correlations were all at significant levels. The depressive disorder group scored significantly higher than the healthy control group in all the subscale scores and total scores of the SCS. Female subjects were significantly higher than males in the total scores of the SCS. These results indicate that the SCS is highly reliable and valid, and that it can be utilized as an effective measure for research related to cognitive assessment.

Development of the somatic stress response scale and its application in clinical practice.

The objective of this study was to develop the Somatic Stress Response Scale (SSRS), and then to use the scale in clinical practice. A preliminary survey was conducted using 109 healthy adults to obtain somatic stress responses. Then, 215 healthy subjects completed a preliminary questionnaire. A comparison was made regarding the somatic stress responses among 191 patients (71 with anxiety disorders, 73 with depressive disorders and 47 with somatoform disorders) and 215 healthy subjects. Factor analysis of the SSRS yielded five subscales: the cardiorespiratory response, somatic sensitivity, gastrointestinal response, general somatic response and genitourinary response subscales. The test-retest reliability for the five subscales and the total score was significantly high, ranging from .86 to .94. The Cronbach's afor the five subscales ranged from .72 to .92, and was .95 for the total score. By correlating the five subscales and the total score of the SSRS with the somatization subscale scores of the Symptom Checklist-90-Revised (SCL-90-R), convergent validity was calculated. The correlations were all at significant levels. Each of the disorder groups was significantly higher in scores of the cardiorespiratory response, gastrointestinal response, general somatic response and genitourinary response subscale, and in the total SSRS score than the healthy group. Only the depressive disorder group scored significantly higher on the somatic sensitivity subscale than the healthy group, and they also scored significantly higher on the genitourinary response subscale than the anxiety disorder group did. These results suggest that the SSRS is highly reliable and valid, and that it can be effectively utilized as a measure for research of the somatic symptoms related to stress. It also implies that somatic sensitivity and genitourinary responses are associated with depressive disorders.

The relation between anger expression, depression, and somatic symptoms in depressive disorders and somatoform disorders.

BACKGROUND: In previous studies, the relationship between either anger suppression and depression or anger suppression and somatic symptoms was examined. However, the relationship between anger expression, depression, and somatic symptoms was not examined in depressive disorders and somatoform disorders. METHOD: The DSM-IV-diagnosed subjects included 73 patients with depressive disorders and 47 patients with somatoform disorders. The Anger Expression Scale was used to assess the level of anger expression or suppression. The severity of depression was assessed using the Symptom Checklist-90-Revised (SCL-90-R). The Somatization Rating Scale and the SCL-90-R somatization subscale were used to assess the severity of somatic symptoms. Data were collected from March 2000 to March 2001. RESULTS: The results of the path analyses showed that in depressive disorder patients, anger expression had a stronger effect on somatic symptoms through depression than did anger suppression, although both anger expression and anger suppression had a significant indirect effect on somatic symptoms. The depressive disorder group also showed a significant but negative direct effect of anger suppression on anger expression in the path from anger suppression to anger expression to depression to somatic symptoms. However, only anger suppression had an indirect effect on somatic symptoms through depression in somatoform disorder patients. CONCLUSIONS: The results suggest that anger expression might play a more predominant role in depression and somatic symptoms of depressive disorder patients than anger suppression, but only anger suppression might be associated with depression and somatic symptoms of somatoform disorder patients. In addition, incomplete anger suppression followed by anger expression is likely to be associated with depression and somatic symptoms in depressive disorders.

Reduced anxiety level by therapeutic interventions and cell-mediated immunity in panic disorder patients.

OBJECTIVE: This study examined the relationship between reduced anxiety level by therapeutic interventions and cell-mediated immunity (CMI) in patients with panic disorder. METHODS: The subjects consisted of 42 patients with panic disorder and 42 normal gender- and age-matched controls. Among the patients, 21 were randomly assigned to a combined treatment of cognitive-behavioral therapy and the benzodiazepine antianxiety agent ethyl loflazepate (2 mg daily), and 21 were assigned to the antianxiety agent only. The treatment lasted for 6 weeks. Cell-mediated immune function was measured by the lymphocyte proliferative response to phytohemagglutinin (PHA) and interleukin-2 (IL-2) production. The anxiety level was assessed by the Hamilton Rating Scale for Anxiety and the anxiety subscale of the Symptom Checklist-90 Revised. RESULTS: Prior to treatment, the panic disorder patients had significantly lower IL-2 production and blastogenic response to PHA than the normal controls. However, no significant differences in CMI were found between the pretreatment and posttreatment period in either the patient group receiving medication only or the combined treatment group, though after treatment, patients were significantly less anxious than before treatment in both intervention groups. The delta change (posttreatment value minus pretreatment value) in the self-reported anxiety level was significantly associated with the delta change in the blastogenic response in the combined treatment group. CONCLUSION: These findings suggest that panic disorder may be associated with decreased CMI, and the reduced level of self-reported anxiety in the patients who underwent combined therapeutic intervention is likely to increase the blastogenic response. Further studies are needed to evaluate the long-term effects of treatment on immune function.

The relationship of anger expression and alexithymia with coronary artery stenosis in patients with coronary artery diseases.

This study examined the relationship between anger expression or alexithymia and coronary artery stenosis in patients with coronary artery diseases. 143 patients with coronary artery diseases (104 males and 39 females) were enrolled in this study. The severity of their coronary artery stenosis was measured by angiography. The Anger Expression Scale and the Toronto Alexithymia Scale were used to assess the level of anger expression and alexithymia. The more stenotic group (occluded by 75% or more) exhibited a significantly higher level of alexithymia than the less stenotic group (occluded by less than 25%). Multiple regression analysis on the extent of stenosis also revealed that regardless of gender and age, the coronary artery disease patients with higher alexithymia were likely to show a greater level of stenosis. However, no significant differences were found on either the anger-in or anger-out subscale scores between the two groups. These results suggest that alexithymia is associated with the severity of coronary artery stenosis in patients with coronary artery disease. However, both anger expression and anger suppression were not shown to be associated with the severity of coronary artery stenosis.

Anger and coronary calcification in individuals with and without risk factors of coronary artery disease.

The authors investigated the relationship between anger and the calcification of the coronary artery in individuals with and without risk factors for coronary artery disease in Korea. Sixty-one subjects with risk factors of coronary artery disease and 31 subjects without risk factors were enrolled in this study. Electron Beam Computed Tomography was used to measure the calcium level of coronary artery. The anger expression scale was used to measure the anger levels. The anxiety, depression, hostility, and somatization subscales of the symptom checklist-90-revised (SCL-90-R) and the global assessment of recent stress (GARS) scale were used to assess the psychopathology and perceived stress. The logistic regression analysis results showed that only the anger-total score was significantly associated with the coronary calcification regardless of the risk factors. These results suggest that anger plays an important role in the calcification of the coronary artery.

Predominance of anger in depressive disorders compared with anxiety disorders and somatoform disorders.

OBJECTIVE: The object of this study was to make a comparison regarding various dimensions of anger between depressive disorder and anxiety disorder or somatoform disorder. METHOD: The subjects included 73 patients with depressive disorders, 67 patients with anxiety disorders, 47 patients with somatoform disorders, and 215 healthy controls (diagnoses made according to DSM-IV criteria). Anger measures--the Anger Expression Scale, the hostility subscale of the Symptom Checklist-90-Revised (SCL-90-R), and the anger and aggression subscales of the Stress Response Inventory--were used to assess the anger levels. The severity of depression, anxiety, phobia, and somatization was assessed using the SCL-90-R. RESULTS: The depressive disorder group showed significantly higher levels of anger on the Stress Response Inventory than the anxiety disorder, somatoform disorder, and control groups (p < .05). The depressive disorder group scored significantly higher on the anger-out and anger-total subscales of the Anger Expression Scale than the somatoform disorder group (p < .05). On the SCL-90-R hostility subscale, the depressive disorder group also scored significantly higher than the anxiety disorder group (p < .05). Within the depressive disorder group, the severity of depression was significantly positively correlated with the anger-out score (r = 0.49, p < .001), whereas, in the somatoform and anxiety disorder groups, the severity of depression was significantly positively correlated with the anger-in score (somatoform disorder: r = 0.51, p < .001; anxiety disorder: r = 0.57, p < .001). CONCLUSION: These results suggest that depressive disorder patients are more likely to have anger than anxiety disorder or somatoform disorder patients and that depressive disorder may be more relevant to anger expression than somatoform disorder.