Platelet serotonin concentration and suicidal behavior in combat related posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a serious and global problem, a psychiatric disorder that frequently occurs with different comorbidities, and is associated with a high suicide rate. Pathophysiologically, both PTSD and suicidal behavior are related to disturbances in the central serotonergic system. Serotonin (5-hydroxytryptamine, 5-HT) controls emotional behavior, anxiety, impulsivity and aggression, and nearly all known antidepressants and antianxiety drugs affect 5-HT transmission. Platelet 5-HT can be used as a limited peripheral marker of the central serotonergic synaptosomes, since it is related to particular basic psychopathological characteristics of several psychiatric disorders. Platelet 5-HT concentration has been reported to be similar in PTSD subjects and healthy controls, but suicidal patients across different psychiatric diagnoses have reduced platelet 5-HT concentration. This study examined platelet 5-HT concentration by the spectrofluorimetric method in male subjects: 73 suicidal and 47 non-suicidal veterans with current and chronic combat related PTSD, 45 suicidal and 30 non-suicidal comparative non-PTSD subjects and 147 healthy men. The presence of suicidal behavior (score=0, non-suicidal; scores > or =1, suicidal) was assessed with the Hamilton Depression Rating Scale-17 (HDRS). Platelet 5-HT concentration was significantly lower in suicidal PTSD and non-PTSD patients compared to non-suicidal patients or healthy controls. Since the majority of patients scored very low on item 3 of HDRS, no significant correlation between suicidal scores and platelet 5-HT concentration was found. These results show that reduced platelet 5-HT concentration is related to suicidal behavior in PTSD, and suggest that platelet 5-HT concentration might be used as a peripheral marker to predict suicidal behavior across psychiatric diagnoses.     

Serum brain-derived neurotrophic factor predicts responses to escitalopram in chronic posttraumatic stress disorder

Introduction

Some studies have found that antidepressants increase serum brain-derived neurotrophic factor (BDNF) levels in patients with major depression and the expression of BDNF mRNA in limbic structures of rats.

Objectives

This study addressed whether the SSRI escitalopram increases serum BDNF levels in subjects with PTSD and whether BDNF levels are associated with treatment response.

Methods

Medically healthy male subjects (N = 16) with chronic PTSD completed a 12 week open-label trial of flexible dose (5–20 mg/day) escitalopram monotherapy. BDNF levels were obtained at baseline, and at weeks 4, 8 and 12.

Results

PTSD symptoms significantly declined over the course of the 12 week escitalopram treatment. Despite a substantial improvement in PTSD symptoms, there was virtually no change in BDNF levels over time. Nevertheless, mean BDNF levels across the trial were strongly correlated with the slope of PTSD symptoms over the 12 weeks (r = 0.58, p = 0.018). Lower mean BDNF was associated with a greater decrease in PTSD symptoms over the course of the trial.

Conclusions

PTSD subjects with low BDNF levels demonstrated the largest treatment response from an agent with putative neurotrophic effects.     

Natural killer cell cytotoxicity and lymphocyte perforin expression in veterans with posttraumatic stress disorder

Objective

To examine the effect of posttraumatic stress disorder (PTSD) on the measures of immune function and the hypothalamic–pituitary–adrenal axis components, and to determine whether additional life stressors affect measured variables.

Methods

We simultaneously examined the natural killer cell cytotoxicity (NKCC), perforin and glucocorticoid receptor (GCR) expression in natural killer (NK) and cytotoxic T (CD8) cells, as well as serum cortisol concentration in a group of Croatian war veterans with chronic, combat-related PTSD (n = 29) and a group of healthy, age-matched men (n = 13). PTSD patients were divided into two subgroups: compensation-seeking (n = 15) and retired or compensation non-seeking (n = 14) subjects. The former includes those involved in the process of getting disability-based army retirement as an additional life stressor.

Results

NKCC was decreased in both PTSD groups when compared to controls. Impairment of NKCC could not be attributed to the perforin expression as perforin was not decreased in comparison to controls. Moreover, the increased level of perforin was recorded in NK cells of retired PTSD subjects. Both PTSD groups shared an increased relative quantity of GCR in lymphocytes, whereas no difference between the groups in the baseline levels of serum cortisol was observed.

Conclusions

Diminished NKCC was not accompanied by perforin insufficiency in PTSD subjects, and other causes should be examined. An additional life stressor does not contribute considerably to either immune or endocrine system related changes.     

Source imaging of P300 auditory evoked potentials and clinical correlations in patients with posttraumatic stress disorder

Objective

Posttraumatic stress disorder (PTSD) is associated with abnormal information processing. The P300 component of event-related potentials (ERPs) is known to be a useful marker of information processing. The purposes of this study were to determine the P300 current source density in PTSD patients, and its relationship with symptom severity.

Methods

ERPs were recorded in 30 PTSD patients and 33 healthy controls while participants were performing the auditory oddball task. We compared P300 current source density data - obtained by standardized low-resolution brain electromagnetic tomography (sLORETA) - between the two groups. The correlation between P300 current source density and clinical symptoms (as evaluated using the Korean version of the Structured Interview for PTSD — K-SIPS and Davidson Trauma Scale — K-DTS) was conducted.

Results

In PTSD patients, the current source density of P300 is significantly reduced in the inferior frontal gyrus, precentral gyrus, insula, and anterior cingulate compared to healthy controls. Total K-DTS scores were correlated with the P300 current source density in the posterior cingulate gyrus. The K-SIP B items (re-experiencing) and K-SIB D items (increased arousal) were positively correlated with P300 current source densities in several brain regions located in the frontal, parietal, and temporal lobe (p < 0.05). Conversely, the K-SIP C items (avoidance and numbing) were negatively correlated with P300 current source densities in the superior and middle frontal gyri in the frontal lobes (p < 0.05).

Conclusion

The P300 current source densities reflected the pathophysiology of PTSD patients. PTSD symptoms were related to different neural activities, depending on their symptom characteristics.     

Hippocampus and amygdalar volumes in patients with refractory obsessive-compulsive disorder

Functional and structural neuroimaging studies have implicated the hippocampus-amygdala complex in the pathophysiology of obsessive-compulsive disorder (OCD), although no consensus has been established. These brain regions have not been investigated in refractory OCD patients. Volumes of the hippocampus, and amygdala were measured by magnetic resonance imaging (MRI) in a sample of 14 refractory OCD patients and 14 healthy comparison subjects. The mean left and right hippocampal and amygdala volumes of the patients were smaller than those of the healthy controls. OCD severity was not correlated with amygdala volumes but was related to the left hippocampus. Duration of illness was correlated with both hippocampus and left amygdala. Our findings suggest that hippocampus and amygdalar abnormalities can be considered in refractoriness to OCD.     

Pro-inflammatory cytokines and treatment response to escitalopram in major depressive disorder

Alterations in the immune system may have importance for the pathophysiology of depression. Several studies have linked increased production of pro-inflammatory cytokines to depression and depressive symptoms. There is growing evidence that antidepressive treatment may influence the production of pro-and anti-inflammatory cytokines. In the present study we aimed to find associations between the levels of soluble interleukin-2 receptor (sIL-2R), interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-alpha) and the response to antidepressant treatment in patients with major depression. Our study group consisted of 100 patients (35 males and 65 females) who were treated with escitalopram 10-20 mg/day for 12 weeks. Responders and non-responders were identified according to Montgomery-Asberg's Depression Rating Scale (MADRS) scores. The levels of cytokines were measured at baseline and at 4th and 12th week of the treatment and compared to cytokine concentrations in healthy volunteers (n=45; 19 males and 26 females). Our data indicated that a higher level of TNF-alpha might predict a non-response to treatment with escitalopram and that changes in concentrations of sIL-2R during the treatment were different in responders and non-responders.     

Longitudinal volume changes of the pituitary gland in patients with schizotypal disorder and first-episode schizophrenia

An enlarged volume of the pituitary gland has been reported in the schizophrenia spectrum, possibly reflecting the hypothalamic-pituitary-adrenal (HPA) hyperactivity. However, it remains largely unknown whether the pituitary size longitudinally changes in the course of the spectrum disorders. In the present study, longitudinal magnetic resonance imaging (MRI) data were obtained from 18 patients with first-episode schizophrenia, 13 patients with schizotypal disorder, and 20 healthy controls. The pituitary volume was measured at baseline and follow-up (mean, 2.7 years) scans and was compared across groups. The pituitary volume was larger in the schizophrenia patients than controls at baseline, and both patient groups had significantly larger pituitary volume than controls at follow-up. In a longitudinal comparison, both schizophrenia (3.6%/year) and schizotypal (2.7%/year) patients showed significant pituitary enlargement compared with controls (− 1.8%/year). In the schizophrenia patients, greater pituitary enlargement over time was associated with less improvement of delusions and higher scores for thought disorders at the follow-up. These findings suggest that the pituitary gland exhibits ongoing volume changes during the early course of the schizophrenia spectrum as a possible marker of state-related impairments.     

Hippocampus and amygdalar volumes in patients with somatization disorder

In regard to somatization disorder which covers an important section of our patient population, there is no systematic structural magnetic resonance imaging (MRI) study in the literature. Therefore, we aimed to use structural MRI to evaluate the hippocampus amygdalar complex which is associated with both stress and regulation of emotion that are main basis clinical presentation of somatization disorder in the patients with somatization disorder. Totally 40 subjects (20 patients with somatization disorder and 20 healthy controls) were enrolled. Intracranial volume (ICV), whole brain volume, gray and white matter volumes, and hippocampus and amygdalar volumes of the subjects were measured. In regard to unadjusted mean volumes of measured structures, the patients had significantly smaller mean volumes of the left and right amygdala. However, two groups did not differ significantly in terms of whole brain, total gray and white matter or hippocampus volumes. The repeated measures ANCOVA predicting left and right amygdala volumes demonstrated a significant main effect of diagnostic group. In conclusion, the findings of the present study revealed that the patients with somatization disorder had significantly smaller mean volumes of the left and right amygdala without any differences in regard to whole brain, total gray and white matter or hippocampus volumes. On the basis of the current findings, it seems reasonable to evaluate that abnormalities in connectivity and/or metabolism dimensions and to examine the effects of drugs or psychotherapeutic approaches could be especially informative.     

Brain-derived neurotrophic factor plasma levels in patients suffering from post-traumatic stress disorder

In both animals and humans, stress has been demonstrated to reduce the expression of the Brain-Derived Neurotrophic Factor (BDNF), a neurotrophin (NT) which promotes the proliferation, survival and differentiation of neurons. Although traumatic events have been found to be associated with lower BDNF plasma levels in affective disorders, no study has explored this parameter in patients with post-traumatic stress disorder (PTSD). We, therefore, measured BDNF plasma level in 18 patients with PTSD and in 18 healthy control subjects. Diagnoses were assessed by the Structured Clinical Interview for DSM-IV, while the specific symptoms were examined in the patients by means of the Impact of Event Scale for PTSD and the traumas experienced were assessed by using the Life Events Checklist. BDNF plasma levels were evaluated by means of a standardized Elisa method. The results, while showing significantly lower BDNF levels in PTSD patients, as compared with those of healthy subjects (p = 0.001), although obtained in a small sample size, would suggest that this NT may be involved in the pathophysiology of PTSD.     

Elevated noise power in gamma band related to negative symptoms and memory deficit in schizophrenia

Patients with schizophrenia have low extraversion and high neuroticism. These personality traits affect the everyday life of patients with schizophrenia, making it important to investigate neurobiological basis of personality traits. In healthy people, extraversion is associated with hemodynamic responses in the amygdala and electrophysiological brain activity such as event-related potential and event-related desynchronization during emotional face processing. Patients with schizophrenia show abnormal neural activity during emotional face processing, such as an N170 amplitude reduction. However, few studies to date have reported an association between personality traits and neural activity during emotional face processing in schizophrenia. In the present study, we examined N170 during emotional face processing, and association with personality traits in patients with schizophrenia. Fifteen male patients with chronic schizophrenia and 15 healthy male subjects participated in this study. Patients with schizophrenia had reduced N170 amplitudes (p=0.007). While healthy subjects had increased N170 amplitudes in response to emotional faces compared with neutral faces (p=0.003), patients with schizophrenia showed no difference in N170 amplitudes between emotional and neutral faces (p=0.60). Reduced N170 amplitude in response to neutral faces was correlated with low extraversion scores in patients with schizophrenia (r(s)=-0.69, p=0.005). The abnormal N170 and its association with extraversion in schizophrenia were found at the right rather than the left posterior temporal electrode. An abnormal N170 in schizophrenia may reflect impairments in the structural encoding of emotional faces, and indiscrimination between emotional and neutral faces at this stage of information processing. The association between abnormal N170 amplitudes and extraversion suggests that abnormal neural activity in the early stages of emotional face processing may underlie low extraversion characteristic of schizophrenia.     

Sunshine-exposure variation of human striatal dopamine D2/D3 receptor availability in healthy volunteers

Background

In addition to the serotonergic system, the central dopaminergic system has been reported to be correlated with seasonality. The aim of this study was to explore the difference in striatal dopamine D₂/D₃ receptor availability between healthy volunteers who had a high-sunshine exposure and those who had a low exposure.

Methods

Sixty-eight participants were enrolled, and those in the upper and lower quartiles in terms of sunshine exposure were categorized into high- (n = 17) and low-sunshine-exposure (n = 18) subgroups. Single photon emission computed tomography with [¹²³I] iodo-benzamide was used to measure striatal dopamine D₂/D₃ receptor availability.

Results

Striatal dopamine D₂/D₃ receptor availability was significantly greater in the subjects with high-sunshine exposure than in those with low-sunshine exposure (F = 7.97, p = 0.01) after controlling for age, sex, and smoking status.

Limitations

Different subjects were examined at different time points in our study. In addition, the sex and tobacco use distributions differed between groups.

Conclusion

The central dopaminergic system may play a role in the neurobiological characteristics of sunshine-exposure variation.     

Gustatory and olfactory function in patients with unipolar and bipolar depression

Although the crucial distinction between unipolar depressive disorder and bipolar disorder is the presence of mania (or hypomania) in the course of the latter, significant differences between unipolar and bipolar depression have also been found in clinical studies. The primary aim of the present investigation was to assess pleasantness/unpleasantness ratings of chemosensory stimuli in depressed patients, including subjects with unipolar and bipolar depression. Sensory aspects (thresholds and identification abilities) of gustatory and olfactory function were also assessed. There were no major differences between a depression group, as a whole, and healthy controls in terms of gustatory and olfactory thresholds and identification abilities. Similarly, pleasantness ratings of various gustatory and olfactory stimuli did not differ between the control and depression group. Gustatory and olfactory thresholds and identification abilities did not differ between individuals with unipolar and bipolar depression. Bipolar patients tended to rate less gustatory stimuli as unpleasant and more olfactory stimuli as pleasant compared to unipolar patients. The present results suggest that: i) depression is not associated with any major deficit in sensory aspects of gustatory and olfactory function or altered hedonic ratings of chemosensory stimuli; ii) hedonic responses to chemosensory stimuli tend to be increased in bipolar as compared to unipolar depressed patients.     

Reduced cortical thickness in non-medicated patients with obsessive-compulsive disorder

Increasing evidence suggests the presence of grey matter volume abnormalities in patients with obsessive-compulsive disorder (OCD) and the mediation of the expression of different OCD symptoms by discrete neural systems of the brain. However, limited studies have investigated the abnormalities of cortical thickness, and their results are comparatively inconsistent, possibly owing to the inclusion of medicated patients. Therefore, this study investigated cortical thickness abnormalities using surface-based analysis to identify distinct neural correlates of each symptom dimension in non-medicated patients with OCD. Thirty non-medicated patients with OCD and 30 age- and gender-matched healthy controls underwent magnetic resonance imaging. Group comparison of cortical thickness was performed using surface-based analysis. We also conducted correlation analysis between cortical thickness and each symptom dimension score. Compared to the healthy controls, the OCD patients had statistically significant reduction in cortical thickness in the cluster that contained the left superior temporal gyrus and posterior insular cortex (p<.05, corrected); no areas of the brain had significantly greater cortical thickness. Negative correlation was also found between cortical thickness and "cleaning" dimension scores in the left postcentral and right superior parietal gyri. The present results suggest that cortical thinning in the region that contains the left superior temporal gyrus and posterior insula may underlie pathophysiology of OCD and that discrete neural systems may mediate the "cleaning" symptom dimension.     

Volumetric MRI study of key brain regions implicated in obsessive-compulsive disorder

Neuroanatomic abnormalities have been implicated in the pathophysiology of obsessive-compulsive disorder (OCD). To date, no study has measured the orbito-frontal cortex (OFC), anterior cingulate, caudate nucleus, and thalamus concurrently in first-episode patients. Thus, we performed a volumetric MRI study in patients who were treatment-naive and healthy controls focusing on the in vivo neuroanatomy of the whole brain, total gray and white matter volume, thalamus, caudate nucleus, anterior cingulate cortex, and OFC concurrently. The volumes of thalamus, caudate nucleus, anterior cingulate cortex, and OFC were measured in 12 OCD patients who were treatment-naive and 12 healthy control subjects. Anterior cingulate and OFC volumes included both white and gray matters. Volumetric measurements were made with T1-weighted coronal MRI images, with 1.5-mm-thick slices, at 1.5 T. The patients had increased white matter volume than healthy controls. The patient group had significantly smaller left and right OFC volumes and significantly greater left and right thalamus volumes compared with healthy controls. Anterior cingulate exhibited a near-significant difference between the patients and healthy controls on left side. Significant correlations were found between Y-BOCS scores and left OFC, and right OFC, and between Y-BOCS and left thalamus volumes in the patient group. In conclusion, our findings suggest that abnormalities in these areas may play an important role in the pathophysiology of OCD.     

Patterns of cardiorespiratory coordination in young women with recurrent major depressive disorder treated with escitalopram or venlafaxine

Evidence from previous studies suggests autonomic dysregulation in patients with major depressive disorder (MDD). Antidepressant treatment may also affect central autonomic function. We investigated whether the type of antidepressant might be associated with the pattern of cardiorespiratory coordination in non-depressed women with recurrent MDD. Resting electrocardiograms and respiratory signals were simultaneously recorded from 38 euthymic women with recurrent MDD who were treated with either escitalopram (n=19) or venlafaxine (n=19) monotherapy and from 38 healthy women. Linear measures of heart rate variability were extracted to assess cardiac autonomic control. Sample entropy (SampEn) was computed to assess the complexity of heart rate and respiratory signals, and cross-SampEn was calculated to measure the nonlinear interaction of both signals. Significant decreases in the cardiovagal tone and cardiorespiratory coupling of women with recurrent MDD receiving venlafaxine, and tendencies toward lower cardiovagal tone and cardiorespiratory coupling in women with recurrent MDD receiving escitalopram were observed when compared with healthy controls. Effect sizes for these differences were large between women receiving venlafaxine and healthy controls. We found a positive association between cardiorespiratory decoupling and venlafaxine dose. Norepinephrine-enhancement, within a therapeutic dose range, seems to be closely associated with decreased vagal tone and reduced nonlinear coupling between heart rate and respiration in euthymic women with recurrent MDD. However, the effects of serotonin enhancement on cardiovagal tone should be considered. Our results suggest that the pharmacodynamic properties of antidepressants may affect autonomic regulation of women with recurrent MDD even in euthymic state.     

A possible association between missense polymorphism of the breakpoint cluster region gene and lithium prophylaxis in bipolar disorder

Lithium is one of the most commonly used drugs for the treatment of bipolar disorder. To prescribe lithium appropriately to patients, predictors of response to this drug were explored, and several genetic markers are considered to be good candidates. We previously reported a significant association between genetic variations in the breakpoint cluster region (BCR) gene and bipolar disorder. In this study, we examined a possible relationship between response to maintenance treatment of lithium and Asn796Ser single-nucleotide polymorphism in the BCR gene. Genotyping was performed in 161 bipolar patients who had been taking lithium for at least 1 year, and they were classified into responders for lithium mono-therapy and non-responders. We found that the allele frequency of Ser796 was significantly higher in non-responders than in responders. Further investigation is warranted to confirm our findings.     

Pituitary volume in patients with panic disorder

Panic patients have many functional deficiencies in the hypothalamic-pituitary-adrenal (HPA) axis. Previous studies have shown changed pituitary gland volume in some psychiatric disorders that have functional deficiencies in the HPA axis. However, to date no study has evaluated the pituitary gland volume in patients with panic disorder (PD). We investigated the pituitary gland volume in patients with PD (n = 27) and age- and sex-matched healthy controls (n = 27), using 1.5-T magnetic resonance imaging in this study. Analysis showed that patients with PD had significantly smaller pituitary volume compared to healthy subjects. Patients with agoraphobia especially had a significantly smaller pituitary volume than patients without agoraphobia. There was a significant relationship between the pituitary volume and both the severity of symptoms and the illness duration in the patient group. The results show that patients with PD have reduced pituitary volume, which may reflect the functional abnormalities seen in this disorder. These findings may help us better understand the pathology of PD.     

Brain GABA levels in patients with bipolar disorder

Purpose

A growing body of research supports an important role for GABA in the pathophysiology of bipolar and other mood disorders. The purpose of the current study was to directly examine brain GABA levels in a clinical sample of bipolar patients.

General methods

We used magnetic resonance spectroscopy (MRS) to examine whole brain and regional GABA, glutamate and glutamine in 13 patients with bipolar disorder compared to a matched group of 11 healthy controls.

Findings

There were no significant differences in GABA, glutamate or glutamine between patients and controls.

Conclusions

Further research is needed to better characterize the GABAergic and glutamatergic effects of pharmacotherapy, anxiety comorbidity and clinical state in bipolar disorder.     

Anterior insular volume is larger in patients with obsessive-compulsive disorder

There has been increasing evidence indicating gray matter abnormalities in patients with obsessive-compulsive disorder (OCD). Several voxel-based morphometry (VBM) studies have reported volume changes in the insular cortex. Although there are distinct differences in the connectivity and functions in the anterior and posterior insular cortices, these two regions have never been distinguished in previous VBM studies. In this study, we adopted a region of interest (ROI) method to measure insular volume separately. We investigated insular volume in 32 drug-free patients with OCD and in 34 healthy controls using magnetic resonance imaging (MRI). Repeated measures multivariate analysis of covariance (MANCOVA) was conducted to examine the difference between the patients and the controls. Compared with the healthy controls, the patients had a significantly larger gray matter volume in the anterior insular cortex bilaterally (post hoc test, p = 0.036; left, p = 0.047; right). This is the first volumetric MRI study to separately investigate the anterior and posterior insular cortex volumes in non-medicated patients with OCD. The results suggest that the anterior insular cortex may be related to the pathophysiology of OCD.