Effects of Clozapine on Cortical Inhibition: A Transcranial Magnetic Stimulation Follow-up Study.

BACKGROUND: Preclinical and clinical investigations have revealed deficits in cortical inhibition in individuals with schizophrenia. Transcranial magnetic stimulation, a commonly used noninvasive measurement technique, is used for assessing these deficits. Limited research has been conducted on the effects of antipsychotic medications on cortical inhibition. This study aimed to evaluate the effects of clozapine on cortical inhibition with transcranial magnetic stimulation longitudinally and compare it with unaffected controls. METHODS: Ten patients who started clozapine were assessed at baseline, with 8 reassessed after 4 months. Eight age- and sex-matched unaffected controls were included. Psychopathology, neurocognitive performance, formal thought disorder, and disability were assessed, and the cortical excitability parameters (resting motor threshold, cortical silent period, short-interval intracortical inhibition, intracortical facilitation, and short-latency afferent inhibition [SAI]) were measured at baseline and four months after clozapine treatment. RESULTS: Resting motor threshold, ICF, and SAI were significantly different between patients and controls at baseline, whereas resting motor threshold, SAI, and ICF became similar to controls after clozapine with only ICF having a trend for significance. Clozapine prolonged cortical silent period significantly in the patients. CONCLUSIONS: This is the first study to investigate the effect of clozapine on SAI, a potential cholinergic biomarker, and the first follow-up study to investigate the relationship between the effects of clozapine on cortical inhibition and cognition. Clozapine seems to cause an increase in cortical inhibition through GABAergic and possibly cholinergic mechanisms. However, additional follow-up studies with larger sample sizes are required to reach more robust conclusions.

A diffusion tensor imaging study in schizophrenia patients with clozapine induced obsessive compulsive symptoms.

OBJECTIVE: The aim of this study was to evaluate brain connectivity by diffusion tensor imaging (DTI) in schizophrenia patients with clozapine-induced obsessive compulsive symptoms (OCS). METHODS: Eighteen schizophrenia patients, nine of which had clozapine-induced OCS (Clz-OCS (+)), 9 without OCS (Clz-OCS (-)) and 9 healthy controls were included. Psychopathology was evaluated with Positive and Negative Syndrome Scale and Yale-Brown Obsession and Compulsion Scale in the patient groups. All groups were assesed with neurocognitive tests and DTI. RESULTS: Tract-Based Spatial Statistics based comparison of DTI revealed lower fractional anisotropy in the genu of corpus callosum (CC), right cingulum, left frontal white matter (WM) in the Clz-OCS (+) group, compared to controls. Fractional anisotropy was found to be lower in the bilateral occipital WM and higher in the bilateral medial temporal regions, anterior limb of internal capsule, cingulum, frontoparietal peripheral WM, right external capsule and genu of CC in Clz-OCS (+) patients compared to Clz-OCS (-). CONCLUSIONS: WM integrity in several pathways such as cortico-striato-thalamo-cortical circuitry and orbito-frontal tracts seems to be affected differently in patients with Clz-OCS (+). Different neuroplastic effects of clozapine leading to occurrence of OCS in a subgroup of patients is possible, and needs further evaluation by longitudinal follow-up studies.

Combination With Long-Acting Injectable Antipsychotics and Utilization of Nonstandard Formulations as Compliance Enhancing Methods for Clozapine Users: A Systematic Review and A Case Series.

BACKGROUND: Combining clozapine with a long-acting injectable antipsychotic (LAI) or using different, nonstandard formulations of the compound may improve treatment outcomes. We aimed to investigate the utility of the clozapine-LAI combination and different formulations of clozapine for compliance problems of clozapine treatment, and to describe a case series on the combined treatment. PROCEDURES: We conducted a PubMed search with no date restriction. The number and length of hospitalizations, the results of clinical scales, and adverse events were recorded. We also present a case series of 18 patients using the clozapine-LAI combination. Data were collected from the medical charts and electronic records. RESULTS: We extracted 9 records describing the use of the clozapine-LAI combination. The case reports and mirror-image studies showed a significant reduction in the number of hospitalizations, length of hospital stays, and number of visits to the emergency department on the combined treatment with no serious adverse events. We included 11 articles for clozapine formulations. The case reports and retrospective data suggested that short-acting intramuscular clozapine was often well tolerated and resulted in an increased acceptance of oral clozapine in the acute phase of illness. In our case series, illness severity and the number of hospitalization per year significantly decreased after the combined treatment, besides a significant improvement in the functioning scores. Hyperprolactinemia and extrapyramidal side effects were reported due to concomitant LAIs. CONCLUSIONS: Despite the encouraging evidence, the present data are preliminary and mostly based on retrospective studies, and oral-dissolving tablets or oral liquid formulations of clozapine have insufficient evidence for clinical practice. Well-designed, controlled, follow-up studies are needed for both clozapine-LAI combination and different formulations of clozapine.

Renal effects of long-term lithium therapy, revisited.

OBJECTIVE: The aim of this study was to investigate the effect of lithium treatment on renal function and to determine influencing factors. In addition, the utility of spot urine protein/creatinine ratio in detection of lithium induced nephropathy was also investigated. METHODS: Serum concentrations of lithium, blood urea nitrogen (BUN), creatinine, estimated glomerular filtration rate (eGFR), and urinalysis including protein/creatinine ratio were measured in 375 patients using lithium. RESULTS: Patients taking lithium for ≥8 years had higher BUN, creatinine levels, percentage of proteinuria, percentages of stage 2 and 3 chronic kidney disease (CKD); lower urine density and eGFR compared to patients taking lithium <8 years. Urine density was lower in groups with >0.8 and 0.6-0.8 mmol/L lithium level than <0.6 mmol/L. Predictors of CKD were serum level of lithium, dose of lithium, cumulative duration of lithium use, age at onset of illness, and caffeine consumption. CONCLUSIONS: Detrimental effects of lithium on renal functions were detected after lithium use for ≥8 years. Proteinuria measured by spot urine protein/creatinine ratio can be detected even when eGFR is >90 ml/min/1.73 m2 . Spot urine protein/creatinine ratio, which is a cost-effective and practical laboratory test, can be used to monitor lithium-treated patients.

An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Should we routinely add CRP to clozapine titrations? - Learning from three cases.

Objectives: An international guideline recently provided certain personalized schedules for titrating clozapine in adult inpatients by considering: 1) DNA ancestry group, 2) sexsmoking subgroup, and 3) presence/absence of clozapine poor metabolizer (PM) status. Measuring CRP levels at baseline and during the first 4 weeks is recommended. Titrations too fast for the metabolism of specific patients can lead to clozapine-induced inflammations and CRP elevations. Methods: Three published cases are reinterpreted. Better outcomes might have been obtained by using the guideline. Results: Case 1 was a Chinese male non-smoker, a clozapine PM due to an underlying inflammation. Case 2 was a Turkish female non-smoker who developed clozapine-induced myocarditis in the context of 4 risk factors (undiagnosed infl ammation, obesity, valproate and olanzapine co-prescription). Case 3 was a United States patient of European ancestry with no known risk factors who developed myocarditis after a routine titration and had an unsuccessful rechallenge with 12.5 mg/day. Application of the international clozapine titration guideline may have prevented: 1) Case 1 by recommending against clozapine titration for a patient with an abnormal CRP level, 2) Case 2 by considering 4 risk factors and using a slow titration for clozapine PMs, and 3) Case 3 by using CRP elevations for early identification of a possible genetic PM. Conclusions: When baseline or prior CRPs are normal and then become abnormal during a clozapine titration, this indicates: 1) clozapine-induced inflammation associated with too-rapid titration for that specific patient, and/or 2) co-occurrence of an infection. Prospective studies need to verify this hypothesis.

The cognitive aspect of formal thought disorder and its relationship with global social functioning and the quality of life in schizophrenia.

PURPOSE: It was expected that using a comprehensive scale like the Thought and Language Disorder Scale (TALD) for measurement of FTD would enable assessing its heterogeneity and its associations with cognitive impairment and functionality. This study has aimed to analyze the relationship between formal thought disorder (FTD) and cognitive functions, functionality, and quality of life in schizophrenia. METHODS: This cross-sectional exploratory study included 46 clinical participants meeting the DSM-5 diagnostic criteria for schizophrenia and 35 healthy individuals as the control groups. Data were acquired by means of the Turkish language version of the TALD, the Positive and Negative Syndrome Scale, the Clinical Global Impression Scale, the Functioning Assessment Short Test, the Social Functioning Scale, the World Health Organization Quality of Life Instrument-Short Form, and a neuropsychological test battery on executive functions, working memory, verbal fluency, abstract thinking, and response inhibition. Correlation analyses were conducted to detect significant relationships. RESULTS: The clinical group scored failures in all cognitive tests. The objective positive FTD was associated with deficits in executive functions and social functioning. The objective negative FTD was associated with poor performance in all cognitive domains, physical quality of life, and social and global functioning. The subjective negative FTD was negatively correlated with psychological quality of life. CONCLUSION: This study demonstrated that objective FTD factors reflect different underlying cognitive deficits and correlate with different functioning domains. Significant correlation was determined between subjective negative FTD and psychological quality of life. Given the close relationship of FTD with functioning and quality of life, the FTD-related cognitive deficits should be the key treatment goal in schizophrenia.

Examination of formal thought disorder and its clinical correlates with the Turkish Version of the Thought and Language Disorder Scale (TALD-TR) in schizophrenia.

BACKGROUND: Formal thought disorder (FTD) is considered to be a fundamental feature of schizophrenia. This study aims to analyze psychometric properties of the Turkish version of "Thought and Language Disorder Scale (TALD)" and investigate the relationship between FTD and various clinical characteristics in patients with schizophrenia. METHODS: TALD was adapted into Turkish and applied to a total of 149 participants of which 114 had DSM-5 psychiatric diagnoses (schizophrenia N = 70, mania N = 20, depression N = 24) and 35 were healthy controls. Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scale, Young Mania Rating Scale, and Clinical Global Impression were administered to detect illness severity. RESULTS: The principal component analyses revealed that the Turkish version of TALD (TALD-TR) consisted of four factors including the Objective Positive (OP), Subjective Negative (SN), Objective Negative (ON) and Subjective Positive (SP) symptom dimensions which were in line with the original TALD factorial structure. It was concluded that TALD-TR shows strong construct validity and high interrater reliability. The correlation analyses with TALD-TR and PANSS showed that there are positive correlations between the TALD-TR total score and the PANSS total and subscale scores. Each diagnostic group showed the distinct pattern of FTD. The mania group exhibited the highest mean total score in the OP, whereas the schizophrenia group exhibited the highest mean total score in the ON factor. In the schizophrenia group, the severity of FTD correlated positively with duration of illness and negatively with age at onset of illness. CONCLUSION: Adaptation of TALD into different languages seems to be possible, bringing in an international tool for research on FTD.

The Role of Cannabis in the Development of Psychosis. / Esrarin Psikoz Gelisimindeki Rolü.

Cannabis is known to cause psychotic disorders, and the increasing use of cannabis constitutes an important health problem. Growing evidence that cannabis causes the development of psychosis has led to an increase in the number of studies in this field. This review aims to clarify the role of cannabis use in the development of psychosis, discuss the current literature about the underlying neurobiological mechanisms. For this purpose PubMed was searched for the keywords "cannabis use, psychosis, schizophrenia, endocannabinoid system, pathophysiology, neurobiology"; the articles published in the last 10 years were reviewed. Epidemiological studies showed that cannabis use starting at an earlier age is associated with an increased risk of psychosis, this risk is more pronounced in people with genetic predisposition and increases with heavy and high potency cannabis use. Studies showed that the endocannabinoid system, which plays a role in nervous system development and functions as a homeostatic regulator in physiological processes, is affected by cannabis use during critical periods of development like adolescence; cannabis use affects physiological processes such as synaptic pruning due to the effects of this system on neurotransmitters like glutamate and dopamine leading to long-term behavioral and psychological consequences. Additionally, evidence that dysfunctions in the endocannabinoid system play a role in the etiology of schizophrenia suggests that cannabis affects the disease process by worsening existing dysfunctions in this system. Understanding the relationship between cannabis use and the development of psychosis and underlying neurobiological mechanisms will help to identify new treatment targets, and develop appropriate preventive approaches. Keywords: Cannabis Abuse, Psychotic Disorders, Schizophrenia, Endocannabinoids, Neurobiology.

Recurrent Psychotic Depression Associated with Chronic Subdural Haematoma: A Case Report.

Chronic subdural hematomas (CSDH) with isolated psychiatric presentation are rare. In this paper, we report a case of 77-year-old-female patient who had psychotic depression after repetitive head trauma without any neurological symptoms. The brain magnetic resonance imaging revealed an 20 mm subdural hematoma in the right frontoparietal region and a 7 mm subdural hematoma in the left frontal region. The psychiatric symptoms improved within the first week after evacuation but relapsed with the occurrence of right sided pneumocephalus. In the follow up, with the disappearance of the pneumocephalus, the psychiatric symptoms improved. It should be kept in mind that isolated psychiatric symptoms can be seen due to subdural hematoma and evacuation of the hematoma has an important role in improving the psychiatric symptoms.

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

OBJECTIVES: Glycogen synthase kinase 3ß (GSK-3ß) 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-3ß via phosphorylation of Serine9 residue. Acute electroconvulsive shock (ECS) has been reported to increase GSK-3ß phosphorylation transiently. In this study, the changes in the level of GSK-3ß and its phoshorylated form (phospho-Ser9-GSK-3ß) 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-3ß and phospho-Ser9-GSK-3ß 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-3ß 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-3ß was similar to sham following both acute and chronic ECS, in both regions. CONCLUSIONS: The transient increase in GSK-3ß 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-3ß.

A systematic chart review of pharmacological interventions in patients with clozapine-induced hypersalivation.

OBJECTIVES: To investigate the efficacy and tolerability of medications, such as mouthwash use of 1 % atropine sulfate and tropicamide drops, oral amitriptyline and amisulpride used for clozapine-induced hypersalivation (CIH). METHODS: The medical charts of inpatients with psychotic disorders between 2010 and 2022 were reviewed retrospectively. We detected 161 patients with eligible data who received or commenced clozapine. Primary outcome was defined as the percentage change in the diameter of a wet patch on the pillow (DWP) for improvements in CIH. RESULTS: The frequency of CIH was 42 % (n = 68). The first step medications for CIH were tropicamide drops (49 %), atropine drops (43 %) and amitriptyline (3 %). After the first step, the median DWP significantly decreased by -33 %. During the index hospitalization, in 18 patients with persistent CIH, the median DWP significantly decreased by -42 % with the second step medications which also included amisulpride. There were no reported serious adverse events. The change in DWP was significantly correlated with the duration of clozapine treatment (r = 306) and clozapine serum level at discharge (r = 0.294). A linear regression model showed a link between the change in DWP and reduced Positive and Negative Syndrome Scale scores. CONCLUSIONS: Our findings emphasize that mouthwash use of atropine or tropicamide drops has a satisfying and tolerable effect in treating CIH. Switching medications for CIH seems to be effective when CIH persists despite a first step agent. Controlled follow-up studies are needed to understand the relationship between CIH, clozapine serum levels, illness severity, and functioning.

Valproate, obesity and other causes of clozapine poor metabolism in the context of rapid titration may explain clozapine-induced myocarditis: A re-analysis of a Turkish case series.

INTRODUCTION: Clozapine-induced myocarditis or any clozapine-induced inflammation may be a hypersensitivity reaction due to titration that was too rapid for the patient's clozapine metabolism. Clozapine metabolism is influenced by ancestry, sex, smoking and the presence of confounders including obesity, infections, and inhibitors (e.g., valproate) causing the patient to behave as a clozapine poor metabolizer (PM). A published study in a Turkish hospital identified 1 case of clozapine-induced pancreatitis and hepatitis and 9 cases of clozapine-induced myocarditis. To explore the hypothesis that the 10 patients were clozapine PMs, their serum clozapine concentrations were investigated using concentration-to-dose (C/D) ratios and their titrations carefully reviewed. METHODS: Dividing the trough serum concentration by the dose produces the clozapine C/D ratio. The dose required to reach 350ng/ml was considered the minimum therapeutic dosage and was used to classify patients according to clozapine PM status. Titration speed was assessed. RESULTS: All 10 patients were possibly clozapine PMs (3 of them had as minimum therapeutic doses: 72, 82 or 83mg/day). Nine of the 10 patients may have behaved as clozapine PMs due to obesity and/or valproate co-prescription during titration. One also had an undiagnosed infection. Of the 10 patients, 9 had at least 1 of 3 factors: too-rapid titration in the first or second weeks, or a final dosage that was too high. CONCLUSIONS: Future studies using clozapine levels and considering the role of clozapine PM status should explore whether or not all cases of clozapine-induced inflammation could be explained by lack of individualized titration.

Clinical risk factors, phenomenology and the impact of clozapine induced obsessive compulsive symptoms.

The aim of this study was to investigate the clinical risk factors, phenomenology and the impact of clozapine induced obsessive-compulsive symptoms (OCS) in patients with schizophrenia. One hundred twenty-two patients receiving clozapine treatment for at least 6 weeks were assessed with Structured Clinical Interview for Axis-I Disorders for DSM-IV, Positive and Negative Syndrome Scale, Yale-Brown Obsessive Compulsive Scale and Checklist, Calgary Depression Scale, Clinical Global Impression Scale and WHO-Disability Assessment Schedule-II. Information about past and current clinical status were gathered through clinical interviews and medical records. With clozapine 44.3% of the patients had de novo OCS, 33.6% had OCS both before and after clozapine, 21.3% didn't report any OCS. Clozapine doses, clozapine and norclozapine plasma levels were not significantly different. Severity of OCS was affected by clozapine and norclozapine plasma levels, and correlated with increased disability. Obsessions were less in clozapine induced OCS group, and compulsions, especially of checking subtypes, were predominant, compared to the group with prior history of OCS, who reported a significant increase in checking compulsion after clozapine treatment. Clozapine induced OCS should be considered during cost/benefit assessment of clozapine treatment, and understanding the risk factors and its different phenomenology may shed light into the underlying mechanisms.

Common Side Effects and Metabolic Syndrome due to Clozapine: Relationship with the Clinical Variables and Disability. / Klozapine Bagli Sik Görülen Yan Etkiler ve Metabolik Sendrom: Klinik Degiskenlerle ve Yetiyitimiyle Iliskisi.

OBJECTIVE: Common side effects of clozapine may affect the treatment process negatively. In this study, we aimed to assess the common side effects and the prevalence of metabolic syndrome in schizophrenia patients treated with clozapine, and to study their relationship with clinical variables and disability. METHOD: One hundred and twenty two patients who met DSM-IV criteria for schizophrenia, and were on clozapine treatment were included in the study. Clinical status was evaluated through a clinical interview and review of the medical records, and physical measures and laboratory tests were recorded. Patients were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders, UKU (Udvalg for Kliniske Undersogelser) Side Effect Rating Scale, World Health Organization (WHO)-Disability Assessment Schedule II, Positive and Negative Syndrome Scale, Global Assessment Scale, Clinical Global Impression Scale. RESULTS: Common side effects of clozapine were hypersalivation, fatigue, sedation and constipation. The relationship between constipation and clozapine dose, and dizziness and norclozapine plasma levels were significant. The prevalence of metabolic syndrome was 50%, and patients with metabolic syndrome had higher means of age and lifetime cigarette consumption. Disability was positively correlated with the severity of psychopathology and the number of side effects, and negatively correlated with the age at onset of illness. Severity of the psychopathology and the number of side effects predicted the severity of the disability. CONCLUSION: Clozapine was associated with various side effects and half of the patients had metabolic syndrome. Assessment of common side effects due to clozapine is important for reducing disability.

[Augmentation of Clozapine Due to Inadequate Treatment Response in Schizophrenia: Comparison of Patients with Augmented and Non-augmented Treatments]. / Sizofrenide Klozapine Yetersiz Yanit Nedeniyle Tedavi Güçlendirme: Güçlendirme Yapilan ve Yapilmayan Hastalarin Karsilastirilmasi.

OBJECTIVE: Clozapine is considered to be a gold standard antipsychotic in treatment resistant schizophrenia. This study aims to investigate clozapine augmentation METHODS utilized in schizophrenia and compare the sociodemographic characteristics, clinical features and remission states of patients whose treatments are augmented and not. METHOD: This study included 122 outpatients diagnosed with DSMIV schizophrenia. Patients were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders, Positive and Negative Syndrome Scale, Clinical Global Impression Scale, Global Assessment of Functioning, Calgary Depression Scale for Schizophrenia, Panic Agoraphobia Scale, Yale-Brown Obsessive Compulsive Scale and the World Health Organization Disability Assessment Schedule II. The remission state of the patients was assessed utilizing the Remission in Schizophrenia Working Group criteria for schizophrenia. RESULTS: Combined antipsychotic drug use was the most prevalent method utilized for clozapine augmentation. Patients on augmentation treatment were on higher daily clozapine doses and their remission rates were lower. In addition, the severity of psychopathology related with schizophrenia and comorbid symptoms, the level of functioning and disability were worse in this particular patient group. History of antipsychotic combination use prior to clozapine was found to predict the future use of clozapine augmentation. CONCLUSION: Adding a second antipsychotic seems to be the most common method of augmenting clozapine treatment in schizophrenia. The group of patients whose clozapine treatment is augmented appears to represent a "more difficult to treat" patient group before clozapine is initiated.

Evaluation of SISCOM in routine regional cerebral blood flow alterations after clozapine, in schizophrenia.

Subtraction ictal single photon emission tomography (SPET) co-registered to magnetic resonance imaging (SISCOM) is an ictal-interictal brain perfusion SPET subtraction method, developed for evaluation of brain perfusion changes applied for the identification of epileptic foci. The aim of this study was to test whether regional cerebral blood flow (rCBF) alterations due to clozapine in schizophrenic patients could also be detected with SISCOM. We have studied the brain perfusion SPET data obtained both before (pre-SPET) and 8 weeks after (post-SPET) clozapine treatment, in 20 patients with schizophrenia. These data were used for SISCOM processing. In order to identify any alterations in the perfusion pattern using SISCOM, pre- and post-SPET data were subtracted from each other. Activation maps were created and merged on either pre- or post-SPET images. Visual interpretation of brain perfusion SPET studies were performed and compared with SISCOM findings. We found that final SISCOM images and visual evaluation of pre- and post-SPET studies were well concordant in 17/20 patients. Discordance was observed in 3 patients. In 1 of these 3 patients alterations observed with SISCOM were confirmed as subtle changes on visual re-evaluation of the images. In the remaining 2 of these 3 patients, SISCOM did not confirm the changes observed by visual analysis. Additionally, SISCOM depicted perfusion alteration in occipital cortex in 5 patients. In conclusion, the algorithm of SISCOM seemed to be useful and complementary to visual evaluation, to assess rCBF changes due to clopazine in outpatient schizophrenic patients who had treatment refractoriness or intolerance of previous antipsychotics and to provide additional information when both pre- and post-SPET data were subtracted from each other.