Neurochemistry of the hippocampus in patients with obsessive-compulsive disorder.

AIM: To date, despite possible neuroanatomical importance, no magnetic resonance spectroscopy (MRS) study on hippocampus has been performed in obsessive-compulsive disorder (OCD). The purpose of the present study was therefore to compare hippocampal chemicals in patients with OCD with those in healthy subjects with no psychopathology. METHODS: Eighteen patients meeting DSM-IV criteria for OCD and 18 healthy controls were studied. The patients and controls underwent proton magnetic resonance spectroscopy ((1)H-MRS), and measures of N-acetyl-l-aspartate (NAA), choline (CHO), and creatine (CRE) in hippocampal regions were obtained. RESULTS: Both NAA/CRE and NAA/CHO ratios in the hippocampus in patients with OCD were reduced relative to healthy controls. The anova showed a near-significant effect of diagnosis for NAA/CRE and a significant effect for NAA/CHO, but the anova did not show any significant effect even at a trend level for CHO/CRE. No main effect of hemisphere was found for any metabolite ratio. CONCLUSIONS: The presence of neuronal degeneration is suggested in OCD. Future longitudinal neuroimaging and neuropsychological studies with larger patient samples are warranted in order to confirm these preliminary findings to better characterize the relevance of neurochemical abnormalities in hippocampus in the pathophysiology of OCD.

Effect of sertindole on QTc interval in patients with schizophrenia.

Sertindole has been marketed and offered daily clinical practice only for 9 months in our country, so no data has been its QTc prolongation potential. In the present study, we performed a clinical trial to investigate the effects of sertindole on QTc in patients with schizophrenia. The study comprised 21 patients with schizophrenia. Sertindole was administered in the following dosing regime: treatment was initiated with 4 mg/day sertindole. From day 3 to day 6, the dose was increased to 8 mg/day, and up to day 9, it was raised to 12 mg/day. The protocol allowed up to dose of 20mg/day according to effectiveness and tolerability. QTc values were determined at beginning, months 3 and 6. In addition, Positive and Negative Syndrome Scale (PANSS) were scored concomitantly. At the beginning of 6-month period, the mean QTc interval of patients was 391.7+/-19.2 ms. At the end of this period, it was 402.8+/-23.8 ms. Although the mean QTc interval changing was significant throughout 6-month period, of the patients, at any evaluation point, only 1 female (451 ms) and 1 male (433 ms) had borderline prolongation at month 3 for both, without any exceeding the dangerous limits. In summary, our results suggest that sertindole is tolerable and despite dose-related QT prolongation, sertindole had not the proarrhythmic profile. Future studies with larger sample evaluating the effects of treatment are required.

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.

Serum leptin and cholesterol values in violent and non-violent suicide attempters.

Earlier studies have linked lipid metabolism to suicide and impulsive-aggressive behaviors. We previously reported that suicide attempters had significantly lower leptin and cholesterol levels than controls. Since lower cholesterol levels have been related to violence alone, we decided to evaluate serum total cholesterol and leptin levels in violent and non-violent suicide attempters. In the present study, 19 violent, 16 non-violent suicide attempters, and 20 age- and sex-matched healthy controls were compared for serum total cholesterol and leptin levels. Violent suicide attempters had significantly lower total cholesterol and leptin levels compared with those with non-violent suicide attempts. Our results suggest that low serum cholesterol and leptin levels are related to the following two dimensions of suicide attempts: suicidality and violence.

Antioxidant enzyme and malondialdehyde levels in patients with social phobia.

A growing body of reports have indicated that free radicals are involved in the etiopathogenesis of some neuropsychiatric disorders. In the present study, we aimed to evaluate whether antioxidant enzymes (superoxide dismutase; SOD, glutathione peroxidase; GSH-Px, and catalase; CAT) activity levels and malondialdehyde (MDA), a product of lipid peroxidation, were associated with social phobia (SP). Eighteen patients diagnosed with SP and 18 healthy controls were enrolled. A clinical evaluation and measurements of MDA, SOD, GSH-Px and CAT were performed. Additionally, all patients were assessed with the Liebowitz Social Anxiety Scale (LSAC). The mean MDA, SOD, GSH-Px and CAT levels in the patient group were significantly higher than those in the control group. There was a positive correlation between LSAC scores and MDA, SOD, GSH-Px and LSAC levels, and between the duration of illness, and MDA, SOD and CAT levels in the patient group. In conclusion, our results suggest that there may be a relationship between increased antioxidant enzyme levels and MDA, and SP.

P-wave dispersion in panic disorder.

BACKGROUND: P-wave dispersion (PWD) is defined as the difference between the maximum and the minimum P-wave (Pmax and Pmin, respectively) duration. Significant variation in cardiac atrial PWD has been correlated with changes in systemic autonomic tone such as during periods of anxiety. It is also known that the degree of PWD seen on 12-lead electrocardiogram (ECG) may be a predictor of susceptibility of the atrial myocardium to future atrial fibrillation (AF). Therefore, we firstly aimed to show an association between PWD and panic disorder, a state of high sympathetic tone. METHODS: PWD was measured in 40 outpatients with panic disorder and in 40 physically and mentally healthy age- and gender-matched controls. In addition, the Panic Agoraphobia Scale (PAS) and the Hamilton Depression Rating Scale (HDRS) were scored concomitantly. RESULTS: Both Pmax and Pmin were significantly higher than those of healthy controls. PWD was significantly greater in the panic disorder group than in the controls. As expected, the mean score on PAS was significantly higher for the panic disorder group than for the controls and correlated significantly with PWD. Heart rate (measured as RR intervals in milliseconds on electrocardiogram) did not differ significantly between the groups. CONCLUSIONS: The findings of the present study suggest that the disorder may be associated with an increase in PWD. This association may result from prolonged anxiety and increase in sympathetic modulation, which are main characteristics of panic disorder.

Plasma nitric oxide and leptin values in patients with olanzapine-induced weight gain.

We previously investigated leptin levels in antipsychotic-induced weight gain and found that atypical antipsychotic, especially clozapine and olanzapine-induced weight gain is related to increased levels of leptin. It has been suggested that nitric oxide (NO) is a potential regulator of leptin-induced lipolysis. To explore the pathophysiology of weight gain during atypical antipsychotic treatment, we planned to investigate olanzapine's influence on leptin and NO levels and weight gain. The study comprised 21 patients with schizophrenia who were enrolled in olanzapine monotherapy, and 21 healthy controls. The fasting plasma NO and leptin levels were measured in both patients and controls at baseline. The patients were also evaluated at sixth week according to the Positive and Negative Syndrome Scale (PANSS), body mass index (BMI), weight, serum leptin and NO levels. At baseline, the mean leptin level in the olanzapine group was not different compared to that in controls after BMI or age adjustment. A significant increase in leptin levels by means of olanzapine use was seen (P<0.01). Higher plasma NO levels were observed in patients with schizophrenia compared with the control group at baseline (P<0.01). At the evaluation of week 6, a significant decrease in the mean plasma NO level was found in the olanzapine group (P<0.05). The changes in total PANSS scores were correlated with change in leptin levels (r=0.58, P<0.05), and with the change in weight (r=0.54, P<0.05). In addition, there was a severe significant negative correlation between the changes in leptin levels and NO levels (r=0.73, P<0.01). The results confirmed that leptin and NO might be associated with olanzapine-induced weight gain.

Cingulate gyrus volumetry in drug free bipolar patients and patients treated with valproate or valproate and quetiapine.

In patients with bipolar disorder, recent brain imaging studies have reported cingulate cortex volume change. We performed a volumetric magnetic resonance imaging (MRI) study to assess the subregions of the cingulate gyrus; left anterior cingulate (LAC), left posterior cingulate (LPC), right anterior cingulate (RAC), and right posterior cingulate (RPC). Our sample consisted of bipolar patients that are either unmedicated (n=10), on valproate monotherapy (n=10) or on valproate plus quetiapine (n=10) versus healthy comparisons (n=10). Thirty right-handed bipolar disordered patients were recruited. Of them, 10 were first-applying patients who never had taken any drug for this condition (medication-naive group), 10 were on valproate treatment (valproate group) and 10 were on valproate plus quetiapine treatment (valproate plus quetiapine group). Cingulate gyrus volumes included both cortex and white matter. Drug-free patients had significantly smaller LAC and LPC volumes compared with valproate and valproate plus quetiapine groups and healthy controls. In addition, in post hoc comparisons, a trend toward significant difference was found between valproate plus quetiapine group and valproate group in regard to only LAC. Our findings suggest that valproate and quetiapine may have neuroprotective effects.

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.

Neopterin levels and dexamethasone suppression test in obsessive-compulsive disorder.

Neopterin, a biopterin precursor that is released by macrophages, is an important immunological marker in psychiatric disorders. It has been reported that glucocorticoids may cause suppression of cell-mediated immunity and consequently result in decreased neopterin levels. In the present study, we evaluated whether dexamethasone suppression test (DST) and neopterin findings were associated with pure obsessive-compulsive disorder (OCD) patients (OCD-D group) and the concomitant OCD and depression (OCD+D group). The sample comprised 44 patients with OCD (27 with OCD-D and 17 with OCD+D) and 30 control subjects. There was significantly higher DST nonsuppression in the OCD+D group than in the OCD-D group. With regard to mean neopterin levels, there was no significant difference between the OCD-D group and the control group, but there was a statistically significant difference between the OCD+D group and the control group. The OCD+D group had significantly lower neopterin levels than the 20 OCD-D group. We suggest that this distinction may reflect the fact that glucocorticoids can lead to suppression of cell-mediated immunity and consequently can result in decreased neopterin levels. In conclusion, our results suggest that not the OCD-D group had normal neopterin levels and DST results, and also that OCD may be a heterogeneous subtype characterized by some biological indicators or anxiety and affective disorders.

Volumetric investigation of brain regions in patients with conversion disorder.

Preliminary evidence revealed a decrease of regional cerebral blood flow in the thalamus and basal ganglia contralateral to the deficit and suggested that hysterical conversion deficits might entail a functional disorder in striatothalamocortical circuits. However, there is no systematic structural magnetic resonance imaging (MRI) study in the literature in patients with conversion disorder (CD). Therefore, we aimed to perform structural MRI to evaluate the brain regions of interest in first applying patients with CD. Morphometric MRI was used to compare regional brain volumes in ten women with CD and same number of healthy comparison subjects. Intracranial volume (ICV), whole brain volume, gray and white matter volumes did not differ between the patient and control groups. Patients with CD had significantly smaller mean volumes of the left caudate nucleus, lentiform nucleus (p<0.01 for caudate nucleus and p<0.05 for lentiform nucleus) and right caudate nucleus and lentiform nucleus (p<0.05 for both structures). In patients, the right thalamus was significantly smaller, and the left thalamus rendered to be smaller compared to healthy controls. Age at onset showed a significant relation with left caudate, and a near-significant trend with right thalamus volumes. In conclusion, our findings suggest that patients with CD have significantly smaller mean volumes of the left and right basal ganglia and smaller right thalamus, with a trend toward to smaller left thalamus compared to healthy controls and that these findings provide novel constraints for a modern psychobiological theory of hysteria.

Hippocampal 1H MRS in first-episode bipolar I patients.

Based on earlier structural and functional neuroimaging studies, we specifically wanted to assess N-acetylaspartate (NAA), choline-containing compounds (CHO), and creatine+phosphocreatine (CRE) levels in brain hippocampus previously demonstrated to be involved in the pathophysiology of bipolar disorder which have not been evaluated in first-episode patients. Twelve patients meeting DSM-IV criteria for bipolar disorder who consecutively applied to our department and 12 healthy controls were studied. The patients and controls underwent proton magnetic resonance spectroscopy ((1)H MRS), and measures of NAA, CHO, and CRE in hippocampal regions were obtained. ANOVA revealed in the hippocampus a significant effect of diagnosis for NAA/CRE and for NAA/CHO but not for CHO/CRE. Post hoc analysis showed that patients had a significant bilateral reduction of NAA/CRE and of NAA/CHO. No significant correlation was found between hippocampus volume and ratio measures. Correlation analyses exhibited significant correlation between NAA values and the YMRS for both side of the hippocampus, but not any other clinical variables (age, age at onset, and duration of illness). In summary, hippocampal neuronal abnormalities seem to be present at the onset of bipolar I disorder. These data suggest that neuronal abnormalities in hippocampus may be associated with the severity of bipolar I disorder. As these data were obtained in patients in their first-episode (all the patients were manic), they cannot be explained by chronicity of illness or pharmacological treatment.

Serum leptin and triglyceride levels in patients on treatment with atypical antipsychotics.

BACKGROUND: Weight gain is a common adverse effect associated with the use of most antipsychotic drugs. Leptin has been reported to be associated with antipsychotic-induced weight gain. Previous studies have demonstrated a relationship between the atypical antipsychotics clozapine and olanzapine and serum leptin levels. We planned to comparatively investigate the effects of the atypical antipsychotics quetiapine, olanzapine, risperidone, and clozapine on leptin and triglyceride levels and weight gain. METHOD: The study population comprised 56 patients with DSM-IV schizophrenia, who were divided into 4 treatment groups: quetiapine (N = 14), olanzapine (N = 14), risperidone (N = 14), or clozapine (N = 14) monotherapy, and a control group of 11 patients receiving no psychopharmacologic treatment. The patients were evaluated at baseline and at the sixth week according to the Positive and Negative Syndrome Scale (PANSS), body mass index (BMI), weight, and fasting serum leptin and triglyceride levels. Data were gathered in 2001 and 2002. RESULTS: Olanzapine and clozapine caused a marked increase in weight and serum triglyceride and leptin levels, though increases in these variables were modest in the patients receiving quetiapine and minimal in those receiving risperidone. There were positive correlations between serum leptin levels and BMI and triglyceride levels. Clinical efficacy, as indicated by decrease in total PANSS scores, was associated with leptin levels in all atypical antipsychotic groups. CONCLUSION: Our results suggest that leptin may be associated with olanzapine- and clozapine-induced weight gain and that quetiapine appears to have modest influence and risperidone appears to have minimal influence on leptin and triglyceride levels and weight gain compared with olanzapine and clozapine.

Serum iron levels in schizophrenic patients with or without akathisia.

The pathophysiology of akathisia still remains controversial. Iron deficiency was proposed to be an important factor in the development of akathisia. In the present study, it was aimed to compare levels of serum iron and linked variables in chronic akathisic (n=30), and non-akathisic patients (n=30) with schizophrenia and healthy controls (n=30) because of the controversy in the association of iron and akathisia. The Barnes Akathisia Scale for akathisia and Simpson-Angus Rating Scale for extrapyramidal side effects were used. Serum iron and linked variables and hematological profile of the patients and control subjects were determined. Serum iron levels were significantly lower both in akathisic and non-akathisic groups compared to the control group (P<0.001). Moreover, akathisic patients had significantly lower iron levels than non-akathisic patients (P<0.05). Total iron binding capacity was significantly higher in patients with akathisia compared to the control group (P<0.01). Although non-akathisic patients had a mild increase in total iron binding capacity, it was not statistically significant compared to the control group (P>0.05). Ferritin levels were determined to be significantly lower in both groups compared to the control group (P<0.01). In addition, there was a significant difference in ferritin levels between the patients with and without akathisia (P<0.05). In conclusion, our results support the hypothesis that an association between akathisia and iron metabolism exists.

Quetiapine is not associated with increase in prolactin secretion in contrast to haloperidol.

BACKGROUND: Typical antipsychotic drugs frequently cause hyperprolactinemia and even galactorrhea. In addition, these side effects may result in noncompliance with antipsychotic treatment. Capacity to avoid hyperprolactinemia has been accepted as one atypical criterion. The aim of the present study was to compare effects of haloperidol, the most commonly used antipsychotic, and quetiapine, a novel antipsychotic agent used in Turkey, on serum prolactin (PRL) levels. METHODS: The study consisted of 35 females diagnosed with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, 4(th) ed. (DSM-IV). Thirty-five patients in a drug-free period for at least 2 weeks were included to randomized quetiapine (n = 18) and haloperidol (n = 17) treatment group. All patients were assessed by Brief psychiatric rating scale (BPRS), Positive and negative syndrome scale (PANSS), and Extrapyramidal symptoms rating scale (ESRS). PRL levels were measured both at the beginning and at the sixth week of the study. RESULTS: Both treatment groups exhibited significant improvements in clinical signs as evaluated by BPRS and PANSS. While there was no significant difference in PRL level between groups at the beginning of the study, control prolactin (PRL) levels were significantly lower in quetiapine compared to haloperidol group. While no quetiapine group patients exhibited galactorrhea, we observed that two patients from the haloperidol group had galactorrhea related to hyperprolactinemia. CONCLUSIONS: The present study revealed that quetiapine is not associated with increase in PRL secretion in contrast to the conventional antipsychotic haloperidol.

Hippocampal 1H MRS in patients with bipolar disorder taking valproate versus valproate plus quetiapine.

BACKGROUND: No study to date has examined the effects of mood stabilizer alone and the combination of mood stabilizer and atypical antipsychotic, quetiapine, on hippocampal neurochemical markers of bipolar disordered patients concurrently. We therefore undertook a proton magnetic resonance spectroscopy (1H MRS) study of drug-free patients with bipolar disorder (drug-free group), patients undergoing valproate treatment (valproate group), patients administered valproate+quetiapine (valprote+quetiapine group) and healthy controls, focusing on the in vivo neuroanatomy of the hippocampus. METHOD: Thirty patients from the Firat University School of Medicine Department of Psychiatry and 10 healthy controls gave written informed consent to participate in the study. The patients and controls underwent proton magnetic resonance spectroscopic imaging (1H MRSI), and measures of N-acetylaspartate (NAA), choline-containing compounds (CHO), and creatine+phosphocreatine (CRE) in hippocampal regions were obtained. RESULTS: The drug-free patients had significantly lower NAA/CRE and NAA/CHO ratios compared with the valproate and valproate+quetiapine groups and the healthy controls. The lower NAA/CRE and NAA/CHO ratios remained statistically significant even after covarying for age or whole brain volume compared with the valproate and valproate+quetiapine groups and healthy controls. In post hoc comparisons, a significant difference was found between the valproate+quetiapine group and the valproate group only with regard to NAA/CHO. CONCLUSION: Our findings suggest that valproate has a neuroprotective effect. In post hoc comparisons, a significant difference was found between the valproate+quetiapine and the valproate group with regard to NAA/CHO, indicating that the addition of quetiapine further increases the level of NAA and provides an additional neuroprotective effect.

Total antioxidant response in patients with schizophrenia.

There is a large amount of convincing data demonstrating that reactive oxygen species (ROS) are involved in initiation and development of many different forms of neuropsychiatric disorders. The levels of oxidants and antioxidants in schizophrenia have been evaluated. However, measurements of total antioxidant response (TAR) were not evaluated up to now. Therefore, the objectives of this study are to investigate plasma TAR levels in schizophrenia subtypes. A total of 76 patients with schizophrenia and 25 healthy volunteers were included in the study. Positive and Negative Syndrome Scale (SANS and SAPS, respectively) were applied to patients. TAR values were determined in the plasma of normal healthy controls and patients with schizophrenia. Plasma TAR levels of each schizophrenia subtype were significantly lower than healthy controls (P < 0.01 for disorganized, residual and undifferentiated subtypes and P < 0.01 for paranoid subtype). When intragroup comparisons were performed, paranoid subtype had higher plasma TAR levels compared to other subtypes (P < 0.01). Accordingly, as a whole group, patients with schizophrenia had lower plasma TAR levels compared to controls. Plasma TAR levels were significantly and negatively correlated with SANS scores, and duration of illness was evaluated but not related to other parameters. Consequently, the present study further emphasizes the growing consideration that free radical damage may have an important etiopathogenetic role on the development of schizophrenia and suggests that decreased plasma total antioxidant levels may be related to the progression of illness.

Serum ghrelin and cholesterol values in suicide attempters.

In our previous study, we demonstrated that suicide attempters had statistically significant lower leptin and cholesterol levels compared with healthy controls. In keeping with our previous report regarding lower serum cholesterol and leptin levels in suicide attempters compared with healthy controls, the relationship between cholesterol and leptin, and ghrelin, we aimed to evaluate serum total cholesterol and ghrelin levels in suicide attempters. In the present study, 30 patients with suicide attempts (aged 18-47 years) and the same number of healthy controls were compared with regard to serum total cholesterol and ghrelin levels. The mean cholesterol level of the patients was significantly lower than that of the controls. On the other hand, the suicide attempters had significantly higher ghrelin levels compared with the controls. The results suggest that suicide attempts seem to be associated with decreased serum cholesterol and higher ghrelin values.