Koray Basar

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.

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.

Effects of acute and chronic electroconvulsive shocks on glycogen synthase kinase 3β level and phosphorylation in mice.

Objectives Glycogen synthase kinase 3&bgr; (GSK-3&bgr;) is recently proposed as a novel target in the treatment of mood disorders. Recent evidence has suggested that acute and chronic administration of antidepressants led to inhibition of GSK-3&bgr; via phosphorylation of Serine9 residue. Acute electroconvulsive shock (ECS) has been reported to increase GSK-3&bgr; phosphorylation transiently. In this study, the changes in the level of GSK-3&bgr; and its phoshorylated form (phospho-Ser9-GSK-3&bgr;) following chronic ECS (cECS) were investigated in mice. Methods Mice were given daily ECS via bilateral corneal electrodes for 10 consecutive days in the chronic group and a single ECS in the acute group. Electrodes were applied without stimulation in corresponding sham groups. Immunoblotting for GSK-3&bgr; and phospho-Ser9-GSK-3&bgr; was performed with the frontal cortex and hippocampus samples, extracted 10 minutes after single ECS, and 24 hours after the last ECS in the chronic group. The optical densities of the bands obtained were compared between the active treatment and sham groups for each condition separately. Results The level of phospho-Ser9-GSK-3&bgr; was not different following chronic ECS, but significantly higher following acute ECS, compared with the corresponding sham group, in the hippocampus and frontal cortex. The level of GSK-3&bgr; was similar to sham following both acute and chronic ECS, in both regions. Conclusions The transient increase in GSK-3&bgr; phosphorylation observed following acute ECS in the mice hippocampus and frontal cortex was not found to persist 24 hours following chronic ECS. The mechanism of action of ECS does not seem to involve persistent change in the level and phosphorylation of GSK-3&bgr;.

Etomidate is associated with longer seizure duration, lower stimulus intensity, and lower number of failed trials in electroconvulsive therapy compared with thiopental.

Objective Induction agents used for electroconvulsive therapy (ECT) may alter seizure parameters. In this study, we aimed to investigate the effects of etomidate and thiopental on seizure-related variables. Methods Registries of patients who received ECT between 2010 and 2013 in a tertiary psychiatry clinic were evaluated retrospectively. The information of patients who were on the same induction agent and muscle relaxant during the whole treatment course was assessed. Primary outcome measures were total number of ECT sessions, mean peripheral and central seizure duration, cumulative stimulus intensity, and the number of adequate seizures per total number of stimuli. Secondary measures were maximum systolic-diastolic and mean blood pressure, peak heart rate, and the frequency of antihypertensive drug use during the sessions. Results Although the total number of ECT sessions is similar between the etomidate (n = 43) and thiopenthal (n = 31) groups, the mean seizure duration per stimuli was significantly longer whereas the cumulative stimulus intensity was lower in the etomidate group. The number of adequate seizures obtained in relation with the number of stimuli was also significantly higher, indicating increased probability of eliciting an adequate seizure with etomidate. During threshold determination, the number of stimuli needed to provide an adequate seizure was marginally less with etomidate. No group difference was observed in hemodynamic changes and the frequency of antihypertensive use. Conclusions Etomidate use, compared with thiopental as an induction agent, is associated with longer seizure duration with less cumulative intensity. The use of etomidate reduces the number of failed trials and may prevent the application of unnecessary electrical stimuli with a possibly safe hemodynamic profile.

A case of clozapine intoxication presenting with atypical NMS symptoms

Clozapine is an antipsychotic drug indicated for treatment-resistant schizophrenia. Clozapine at toxic doses may cause hyperthermia, alterations in consciousness, seizures, cardiac arrhythmias, excessive mucus production in bronchi, hypersalivation, miosis, blood dyscrasias, pancreatitis and hepatitis (Sartorius et al., 2002). Clozapine blood levels are influenced by age, gender, ethnicity, physical illnesses like liver failure, changes in the activity of the cytochrome oxidase enzymes due to genetic variability, concurrent medication use, smoking or caffeine consumption (Greenwood-Smith et al., 2003). Generally, plasma levels of over 1000 ng/ml are associated with central nervous system adverse effects (Varma et al., 2011). One potentially lethal side effect of antipsychotics including clozapine is neuroleptic malignant syndrome (NMS). Neuroleptic malignant syndrome is typically characterized by fever, altered mental status, leukocytosis, autonomic dysfunction and rigidity. Atypical antipsychotics including clozapine are associated less with NMS than typical antipsychotics, and when NMS occurs during treatment with atypical antipsychotics, associated symptoms are less typical (Trollor et al., 2012). In this case report, we present a patient using clozapine for treatment of schizophrenia who was admitted to the Emergency Room with NMS-like symptoms. We present a 53 yr old, female patient diagnosed with schizophrenia, who was on clozapine 500 mg/d for the past 3 yr. She had hyperlipidemia and chronic obstructive pulmonary disease (COPD) and was using rosuvastatin 20 mg/d. She was admitted to the Emergency Room (ER) with acute onset-confusion, shivering, meaningless talk and urinary incontinence. Her body temperature was 39.2°C, blood pressure 90/50 mmHg, pulse rate 117/min, RR: 17/min, SaO2:%96. Electrocardiogram (ECG) was normal. Her Glasgow Coma Score was 15. Blood tests showed hyponatremia (133.2 mEq/l), increased levels of creatinine (1.52 mg/dl), BUN (23.68 mg/dl), uric acid (7.07 mg/dl) and decreased levels of phosphorus (2.50 mg/dl). Liver and thyroid function tests and potassium, chloride and calcium levels were within normal range. Complete …

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) in Two Siblings with Neuropsychiatric Symptoms

erebral autosomal dominant arteriopathy with subcorti-cal infarcts and leukoencephalopathy (CADASIL) is arare hereditary disease that presents with various neurologicaland/or psychiatric symptoms, such as stroke, migraine with aura,cognitive changes, mood disorders, and dementia. Mutations inthe Notch3 gene have been documented in most of the patients.Clinically, the most useful diagnostic tool is cranial magneticresonance (MR) imaging, which demonstrates widespread sub-cortical leukoencephalopathy associated with hyperintensities inbasal ganglia, thalamus, and brainstem. Psychiatric symptomsare seen in 20%–41% of the patients, and are rarely the initialpresenting symptom. Here we present two siblings in their 40swith prominent psychiatric complaints. Clinical diagnosis ofCADASIL was made years later, after a careful personal andfamily history combined with typical MR imaging findings.Both patients had a missense mutation in exon 4 of Notch3. Ifpatients with various psychiatric symptoms have a history ofheadache, stroke-like episodes, or cognitive changes, and a pos-itive family history of similar complaints, they should undergocranial MR imaging. In case the imaging demonstrates unex-plained leukoencephalopathy, patients should be investigated forCADASIL.Cerebral autosomal dominant arteriopathy with subcor-tical infarcts and leukoencephalopathy (CADASIL) is a rarehereditary brain disease that in most patients occurs due tomutations of the notch 3 gene on chromosome 19q12.