Aygun Ertugrul

Perception of stigma among patients with schizophrenia

Many individuals with schizophrenia are stigmatized by society. It is necessary to understand the factors contributing to stigma. This study investigated the relation of symptoms and other patient characteristics with perceived stigmatization in patients with schizophrenia. Sixty patients with schizophrenia were included in the study. Symptomatology was assessed with the Positive and Negative Syndrome Scale.Perceived stigmatization was measured by several questions which were included in the World Health Organization-Disability Assessment Schedule-II (WHODAS-II). Patients were grouped as positive or negative for perceived stigmatization. Characteristics of patients and severity of symptoms were compared between the two groups. The results showed that patients who reported to perceive stigmatization had more severe symptoms than the patients who did not perceive stigmatization. Positive symptoms and general psychopathology scores were significantly higher in the group perceiving stigmatization. Patients reporting stigmatization were significantly more disabled than the group negative for perceived stigmatization. Demographic variables were not different between the two groups. Stepwise regression analysis showed that depression and active social avoidance were the items which could predict the perception of stigmatization. The relation between perception of stigmatization and symptoms is a vicious circle in which the elements reinforce each other. Interruption of this circle will increase the adaptive abilities and decrease the disability of these patients.

The effect of clozapine on regional cerebral blood flow and brain metabolite ratios in schizophrenia: Relationship with treatment response

The purpose of this study was to investigate the effect of clozapine on regional cerebral blood flow (rCBF) and its relationship with response to treatment. In addition, we aimed to study the influence of clozapine on proton magnetic resonance spectroscopy ((1)H-MRS) findings in the dorsolateral prefrontal cortex (DLPFC) in a subgroup of patients. Psychopathology, neurocognitive functioning, and SPECT imaging of 22 patients were assessed at the baseline and 8 weeks after the initiation of clozapine treatment. In 10 of these patients intermediate-echo (TE: 135 ms) single-voxel (1)H-MRS was also performed at the baseline and after 8 weeks. Clozapine treatment increased the right frontal (superior and medial)/caudate perfusion ratio in the whole group, while it increased bilateral frontal (superior and medial)/caudate perfusion ratios in treatment responders. In addition, percentage changes in left and right frontal (superior and medial)/caudate perfusion ratios compared to the baseline were higher in treatment responders than in non-responders. The improvement in attention was related to the increase in percentage change in the right frontal (superior and medial)/caudate perfusion ratio, while the improvement in verbal fluency was related to the increase in percentage changes in both right and left frontal (superior and medial)/caudate perfusion ratios and to right frontal (superior and medial)/thalamus perfusion. Baseline frontal (superior and medial)/thalamus perfusion could explain 32% of the variability of percentage improvements in psychopathology. (1)H-MRS showed that the baseline PANSS general psychopathology score was inversely correlated with the baseline NAA/Cre ratio. An increased NAA/Cre ratio in DLPFC after 8 weeks of clozapine treatment was also revealed by (1)H-MRS. Our SPECT imaging results suggest the presence of an imbalance in fronto-striato-thalamic circuitry that changes with clozapine, especially in the responders, while (1)H-MRS results indicate a supportive effect of clozapine on neuronal integrity.

Effect of clozapine on white matter integrity in patients with schizophrenia: A diffusion tensor imaging study

Several diffusion tensor imaging (DTI) studies have reported disturbed white matter integrity in various brain regions in patients with schizophrenia, whereas only a few studied the effect of antipsychotics on DTI measures. The aim of this study was to investigate the effect of 12 weeks of clozapine treatment on DTI findings in patients with schizophrenia, and to compare the findings with those in unaffected controls. The study included 16 patients with schizophrenia who were assessed with the Positive and Negative Syndrome Scale, a neurocognitive test battery, and DTI at baseline and 12 weeks after the initiation of clozapine treatment. Eight unaffected controls were assessed once with the neurocognitive test battery and DTI. Voxel-wise analysis of DTI data was performed via tract-based spatial statistics (TBSS). Compared with the control group, the patient group exhibited lower fractional anisotropy (FA) in 16 brain regions, including the bilateral superior longitudinal fasciculi, inferior fronto-occipital fasciculi, superior and inferior parietal lobules, cingulate bundles, cerebellum, middle cerebellar peduncles, and left inferior longitudinal fasciculus, whereas the patients had higher FA in six regions, including the right parahippocampus, left anterior thalamic radiation, and right posterior limb of the internal capsule before clozapine treatment. After 12 weeks of treatment with clozapine, white matter FA was increased in widespread brain regions. In two of the regions where FA had initially been lower in patients compared with controls (left inferior fronto-occipital fasciculus and superior parietal lobule), clozapine appeared to increase FA. An improvement in semantic fluency was correlated with the increase in FA value in the left inferior fronto-occipital fasciculus. An increase in FA following 12 weeks of treatment with clozapine suggests that this treatment alters white matter microstructural integrity in patients with schizophrenia previously treated with typical and/or atypical antipsychotics and, in some locations, reverses a previous deficit.

No association of the T102C polymorphism of the serotonin 2A receptor gene (HTR2A) with suicidality in schizophrenia.

Additional evidence for a role of serotonin (5-HT) in the pathogenesis of suicidal behavior is provided by a recent report that the 5-HT2A (HTR2A) T102C polymorphism was associated with suicidality in patients with major depression. Three other studies have, however, failed to find an association between this polymorphism and suicidality in major depression. The goal of the present study was to test the association of allele C of T102C HTR2A polymorphism with suicidality in patients with schizophrenia or schizoaffective disorder. Seventy-one patients with DSM-III-R diagnosis of schizophrenia or schizoaffective disorder were included in the study. Patients were genotyped for the T102C HTR2A polymorphism. Information about lifetime suicidality was obtained during the course of SADS interviews. In addition, current suicidality was assessed by the Hamilton Depression Scale in 46 patients. There were no significant differences in allele frequencies and genotype distributions between suicidal and non-suicidal patients using lifetime or current suicidality measures. The results of this study did not demonstrate a robust association of the allele C of the T102C HTR2A polymorphism with lifetime or current suicidality in patients with schizophrenia. However, the mean Hamilton Depression Scale item for current suicidality was significantly higher in patient with genotype T/C compared to those with genotype C/C (p = 0.01) and marginally higher than for the patients with genotype T/T (p=0.06). The relatively small sample size suggests a study with a larger sample and greater power would be of interest.

Antipsychotic drugs in bipolar disorder

Antipsychotic drugs are useful in the treatment of acute mania and as maintenance treatment. While both typical and atypical antipsychotic drugs are able to diminish manic symptoms, agitation and aggression in acute mania, the atypical antipsychotic drugs enjoy a number of advantages, including significantly less extrapyramidal symptoms, diminished risk of tardive dyskinesia, lack of increase in serum prolactin levels (with the exception of risperidone), improvement in cognition, and possible decrease in suicidality. Most of the atypical antipsychotic drugs have been found to be effective as an add-on treatment (with mood stabilizers and antidepressant drugs) and sometimes as monotherapy in treatment-resistant bipolar patients. Long-acting typical neuroleptic drugs may be useful in the treatment of non-compliant bipolar patients. A small number of patients with schizophrenia treated with risperidone, olanzapine, or quetiapine experience a first episode of hypomania or mania. It is not apparent if this is a true drug-induced event or coincidental. Side-effects of note with the atypical antipsychotic drugs are weight gain (most prominently with olanzapine and clozapine), sedation, and agranulocytosis (clozapine). Atypical antipsychotic drugs are recommended for use in bipolar disorder for acute treatment, maintenance treatment, and for treatment-resistant patients.

Influence of clozapine on platelet serotonin, monoamine oxidase and plasma serotonin levels

The purpose of this study was to investigate the influence of clozapine on plasma serotonin, platelet serotonin and monoamine oxidase (MAO) levels in schizophrenic patients and to compare their results with those of unmedicated healthy controls. Groups of 20 outpatients with schizophrenia and 20 healthy controls matched for age, sex and smoking status were recruited for the study. Psychopathology, neurocognitive functioning, plasma serotonin, platelet serotonin and MAO levels were assessed after 1-week drug free interval, and 8 weeks after initiation of clozapine treatment in an open design. The mean clozapine dose at week 8 was 382.5+/-96.4 (range: 250-600) mg/day. In the patient group, at baseline, plasma serotonin and platelet MAO levels were significantly lower, and platelet serotonin levels were significantly higher than in controls. After 8 weeks of clozapine treatment, plasma serotonin and platelet MAO levels increased significantly, while a significant decrease in platelet serotonin levels was detected compared with baseline values. Baseline platelet MAO levels explained 22% of the variance in Clinical Global Impression - Improvement (CGI-I) and improvement in attention, while baseline platelet serotonin predicted 23% of the variance in the improvement in positive symptoms during clozapine treatment. Our data indicate that clozapine may be reversing or compensating for a pre-existing alteration in serotonergic neurotransmission in schizophrenic patients. The prediction of response to clozapine through peripheral biochemical markers may have important clinical implications if repeated in larger samples.

Differential effects of antipsychotics on hippocampal presynaptic protein expressions and recognition memory in a schizophrenia model in mice

We compared the effects of subchronic clozapine and haloperidol administration on the expression of SNAP-25 and synaptophysin in an animal model of schizophrenia based on the glutamatergic hypothesis. Mice were first treated with a non-competitive NMDA antagonist MK-801 (0.3 mg/kg/day) or saline for 5 days, and then clozapine (5 mg/kg/day), haloperidol (1 mg/kg/day) or saline was administered for two weeks. The locomotion test, as a behavioral model of the positive symptoms of schizophrenia, was applied after MK-801/saline administration on day 6 for acute effects and after antipsychotic/saline administration on day 19 for enduring effects on mice activity. Memory function was assessed by the Novel Object Recognition (NOR) test, one day after the last day of antipsychotic/saline administration (day 20). Western Blotting technique was used to determine SNAP-25 and synaptophysin expressions in the hippocampus and frontal cortex. Both antipsychotics reversed the enhanced locomotion effects of MK-801. MK-801 and haloperidol decreased recognition memory performance. On the other hand, clozapine did not compromise memory. It also did not reverse the negative effects of MK-801 on memory performance. MK-801 did not change SNAP-25 and synaptophysin expressions in the hippocampus and frontal cortex. Clozapine increased hippocampal SNAP-25, decreased hippocampal synaptophysin expression, whereas frontal SNAP-25 and synaptophysin expressions remained unchanged. Haloperidol had no effects on levels of SNAP-25 and synaptophysin in the frontal cortex and hippocampus. These findings support the idea that the differential effects of clozapine might be related to its plastic effects and synaptic reorganization of the hippocampus.

Abnormal somatosensory evoked potentials in two patients with conversion disorder

Abstract  On clinical grounds, somatosensory evoked potentials (SEP) and motor evoked potentials (MEP) are currently used to discriminate between hysterical and neurological conditions. The present paper reports on two patients with severe gait disturbance who had the near‐total absence of SEP responses on the scalp during the symptomatic period, which normalized after recovery. These findings, along with others, may shed light on the brain correlates of conversion phenomena.

Semantic memory deficits based on category fluency performance in schizophrenia: Similar impairment patterns of semantic organization across Turkish and Japanese patients

Patients with schizophrenia exhibit a wide range of cognitive dysfunction, including impairments in semantic memory and verbal fluency. Previous studies report that semantic memory, i.e. associated meaning of words or knowledge, is specifically disorganized in patients who use the English or Japanese language. The purpose of the present study was to determine if semantic memory, as evaluated by verbal fluency data, shows similar patterns of semantic disorganization in non-English-speaking patients who do (Turkish) or do not (Japanese) use an alphabetical language. Turkish (N=20) and Japanese (N=22) patients with schizophrenia, as well as Japanese normal controls (N=22), entered the study. As a measure of semantic memory organization, two types of cluster analyses, i.e. ADDTREE and hierarchical cluster analysis, were performed on category fluency task data. The cluster analyses revealed a greater similarity between the Turkish patients vs. Japanese patients comparison than the Japanese patients vs. Japanese controls comparison. The results provide further support to the concept that impaired semantic memory organization is one of the core features of schizophrenia, and is independent of the language system or cultural backgrounds.

The influence of N-desmethylclozapine and clozapine on recognition memory and BDNF expression in hippocampus.

Clozapine, which is the most effective treatment option for treatment-refractory schizophrenia, has been reported to have both positive and negative effects on specific cognitive symptoms in patients with schizophrenia and in animal models of cognition. Clozapine has a major metabolite, N-desmethylclozapine (NDMC), which has been suggested to be more effective than clozapine itself to improve cognition. Enhancement of brain derived neurotrophic factor (BDNF) expression in the hippocampus has been proposed to contribute to the cognitive-enhancing effects of antipsychotic drugs. The aims of this study were to investigate the change in short and long term memory as assessed by the novel object recognition (NOR) test and BDNF expression in hippocampus produced by an acute hypoglutamatergic model of memory impairment in schizophrenia induced by administration of the NMDA receptor non-competitive antagonist, MK-801 and the ability of clozapine and NDMC to prevent the deleterious effects of MK-801. Both short (1 h) and long-term (24 h) memory were impaired in MK-801 (0.1 mg/kg) - and clozapine (5 mg/kg)-, but not NDMC (5 mg/kg)-treated rats. Neither NDMC (5 mg/kg) nor clozapine (5 mg/kg) reversed the effect of MK-801. Western blotting studies showed that BDNF levels in hippocampus were not different in rats administered MK-801 alone, clozapine or NDMC alone. These results show that in this model clozapine affects memory negatively, while NDMC does not. The absence of impairment of NOR with NDMC is consistent with previous evidence that it has a more benign effect on cognition than does the parent compound, and may support the efforts to study its effects on other cognitive functions. These findings do not provide any support for the role of BDNF in the MK-801-induced impairment in NOR or for differences between clozapine and NDMC.