OBJECTIVE: The objective of this study was to investigate the relationship between the serum concentration of clozapine (C-CLZ), N-desmethylclozapine (N-CLZ) and the daily dose of CLZ (D-CLZ), and the relationships among CLZ and electroencephalogram (EEG) abnormalities. METHODS: Twenty-eight patients were recruited to this study, but 8 patients were excluded because clozapine was discontinued before the post-treatment measurement of EEG or C-CLZ. Ultimately, 20 patients (6 men, 14 women) with an average age of 36 years were enrolled. The subjects were divided into EEG normal and abnormal groups. C-CLZ and N-CLZ were measured at 4, 12, 26, and 52 weeks after initiating CLZ administration. RESULTS: All patients had normal baseline EEG signals, and 8 patients showed EEG abnormalities later. There were significant correlations between C-CLZ and D-CLZ, and between N-CLZ and D-CLZ. The C-CLZ/D-CLZ, N-CLZ/D-CLZ, and C-CLZ/N-CLZ ratio were not significantly different between the EEG normal and EEG abnormal groups. The EEG abnormal group had significant higher proportion of patients with high intra-individual variability in their C-CLZ/D-CLZ ratio. CONCLUSION: There is no relationship between C-CLZ and EEG abnormalities. However, patients with high intra-individual variability in their C-CLZ/D-CLZ ratio had greater possibility of exhibiting EEG abnormalities.
Asian Continental Ancestry Group ; Clozapine ; Electroencephalography ; Humans ; Male ; Schizophrenia

This study explored long-term changes in self-report auditory verbal hallucinations (AVHs) among patients with schizophrenia taking clozapine. Forty-four patients who were evaluated more than twice and were above the mild severity category on the Hamilton Program for Schizophrenia Voices Questionnaire (HPSVQ) were enrolled. The mean observation period was 492.5±350.1 days (median, 452 days). The mean total, physical, and emotional factor scores on the HPSVQ were significantly reduced from baseline to the final observations except for one item “interference with life,” which was not significantly reduced. Regarding the time-dependent longitudinal changes modeled using linear mixed-effect regression, the total and physical factor scores showed significant changes during the first year, but the emotional factor score did not satisfy a more stringent level of significance. Female gender was negatively associated with the reduction in total and physical factor scores. The duration of treatment with clozapine also had a negative relationship with the reductions in all three scores.
Clozapine ; Female ; Hallucinations ; Humans ; Schizophrenia ; Voice

Exposure to lead during pregnancy is a risk factor for the development of psychiatric disorders in the offspring. In this study, we investigated whether exposure to low levels of lead acetate (0.2%) in drinking water during pregnancy and lactation causes behavioral impairment and affects the expression of proteins associated with neurodevelopment. Lead exposure altered several parameters in rat offspring compared with those unexposed in open-field, social interaction, and pre-pulse inhibition tests. These parameters were restored to normal levels after clozapine treatment. Western blot and immunohistochemical analyses of the hippocampus revealed that several neurodevelopmental proteins were downregulated in lead-exposed rats. The expression was normalized after clozapine treatment (5 mg/kg/day, postnatal day 35–56). These findings demonstrate that downregulation of several proteins in lead-exposed rats affected subsequent behavioral changes. Our results suggest that lead exposure in early life may induce psychiatric disorders and treatment with antipsychotics such as clozapine may reduce their incidence.
Animals ; Antipsychotic Agents ; Behavior Rating Scale ; Blotting, Western ; Clozapine ; Down-Regulation ; Drinking Water ; Female ; Hippocampus ; Incidence ; Interpersonal Relations ; Lactation ; Lead Poisoning ; Models, Animal ; Neurodevelopmental Disorders ; Pregnancy ; Rats ; Risk Factors

Schizophrenic patients resistant to antipsychotics are diagnosed as having treatment-refractory schizophrenia, and they are treated with clozapine. However, clozapine is sometimes combined with electroconvulsive therapy (ECT) if clozapine monotherapy fails. In this report, a severe treatment-refractory schizophrenic patient who did not respond to clozapine even with ECT, but who recovered with asenapine monotherapy, is presented. Asenapine, considered a serotonin spectrum dopamine modulator, is a new atypical antipsychotic with unique pharmacological features that is used not only for schizophrenia, but also for bipolar disorder. The unique features of asenapine may be effective for some treatment-refractory schizophrenic patients.
Antipsychotic Agents ; Bipolar Disorder ; Clozapine ; Dopamine ; Electroconvulsive Therapy ; Humans ; Recurrence ; Schizophrenia ; Serotonin ; Suicide

Although the majority of patients with schizophrenia are not actually violent, an increased tendency toward violent behaviors is known to be associated with schizophrenia. There are several factors to consider when identifying the subgroup of patients with schizophrenia who may commit violent or aggressive acts. Comorbidity with substance abuse is the most important clinical indicator of increased aggressive behaviors and crime rates in patients with schizophrenia. Genetic studies have proposed that polymorphisms in the promoter region of the serotonin transporter gene and in the catechol-O-methyltransferase gene are related to aggression. Neuroimaging studies have suggested that fronto-limbic dysfunction may be related to aggression or violence. By identifying specific risk factors, a more efficient treatment plan to prevent violent behavior in schizophrenia will be possible. Management of comorbid substance use disorder may help prevent violent events and overall aggression. Currently, clozapine may be the only effective antipsychotic medication to repress aggressive behavior. With the current medical field moving toward tailored medicine, it is important to identify vulnerable schizophrenia populations and provide efficient treatment.
Aggression ; Antipsychotic Agents ; Catechol O-Methyltransferase ; Clozapine ; Comorbidity ; Crime ; Humans ; Neuroimaging ; Promoter Regions, Genetic ; Risk Factors ; Schizophrenia ; Serotonin Plasma Membrane Transport Proteins ; Substance-Related Disorders ; Violence

Synaptic dopamine (DA) is mainly regulated by the presynaptic DA transporter (DAT). Single-photon emission computerized tomography (SPECT) with the DAT radiotracer [¹²³I]FP-CIT assesses changes in synaptic DA availability when endogenous DA displaces [¹²³I]FP-CIT or competes for DAT. Here, we investigated the effects of haloperidol (HAL) and clozapine (CLZ) on [¹²³I]FP-CIT binding in the rat striatum and midbrain to assess the utility of [¹²³I]FP-CIT SPECT to quantify changes in synaptic DA availability. Rats underwent [¹²³I]FP-CIT SPECT after intraperitoneal administration of normal saline (vehicle), HAL (1 and 7 mg/kg), CLZ (10 and 54 mg/kg) and bupropion (BUP, a DAT blocker, 20 and 100 mg/kg). In the striatum and midbrain, percent differences in the nondisplaceable binding potential (BP(ND)) of [¹²³I]FP-CIT compared to the vehicle were calculated for the various drugs and doses. In another experiment, changes in endogenous striatal DA concentration were measured by in vivo microdialysis under the conditions used in the SPECT study. BUP dose-dependently occupied DAT at considerable levels. Compared to the vehicle, HAL decreased [¹²³I]FP-CIT BP(ND) in the striatum (−25.29% and −2.27% for 1 and 7 mg/kg, respectively) and to a greater degree in the midbrain (−58.74% and −49.64% for 1 and 7 mg/kg, respectively), whereas the CLZ-treated group showed a decrease in the midbrain (−38.60% and −40.38% for 10 and 54 mg/kg, respectively) but an increase in the striatum (18.85% and 38.64% for 10 and 54 mg/kg, respectively). Antipsychotic-induced changes in endogenous striatal DA concentrations varied across drugs and doses. The data demonstrate that [¹²³I]FP-CIT SPECT may be a useful preclinical technique for detecting increases in synaptic DA availability in the midbrain and striatum in response to HAL, with results comparable to those of in vivo microdialysis.
Animals ; Bupropion ; Clozapine ; Dopamine ; Haloperidol ; Mesencephalon ; Microdialysis ; Rats ; Tomography, Emission-Computed, Single-Photon

OBJECTIVES: The present study is to investigate inflammatory markers and associated clinical factors between treatment resistant schizophrenia and non-treatment resistant schizophrenia.METHODS: Of the 116 schizophrenia subjects who were hospitalized for ac ute symptomatic treatment, 19 patients (16%) were treated with clozapine as a treatment resistant schizophrenia(TRS) and 97 patients(84%) were treated with other atypical antipsychotics as a non-treatment resistant schizophrenia(Non-TRS). Various inflammatory markers including C-reactive protein(CRP) and clinical factors were retrospectively evaluated with electrical medical records.RESULTS: There were significant differences between two groups in disease duration(p =0.015), number of admission (p =0.003), Clinical Global Impression(p <0.001) but other demographic and clinical variables including previous antipsychotics use did not show significant differences. In terms of hematologic profiles, TRS group demonstrated higher CRP level(p =0.006), lower neutrophil count(p =0.012), and lower hemoglobin level(p =0.003) compared with non-TRS group. Body mass index was significantly correlated with CRP(r=0.318, p =0.001).CONCLUSION: The elevated level of serum CRP in TRS suggests that treatment resistance in schizophrenia may be associated with inflammatory response. However, retrospective study design and small number of subjects could limit this interpretation.
Antipsychotic Agents ; Body Mass Index ; C-Reactive Protein ; Clozapine ; Humans ; Medical Records ; Neutrophils ; Retrospective Studies ; Schizophrenia

PURPOSE: To report a case of corneal and lenticular pigmentation after prolonged clozapine therapy. CASE SUMMARY: A 56-year-old male visited our hospital with a progressive decline in vision that affected both eyes. He had a history of schizophrenia. He was being treated with 200 mg clozapine and 1 mg lorazepam daily, and had been treated with clozapine for 5 years. At the first visit, his best-corrected-visual acuity was 20/32 in both eyes. Slit lamp examination of the corneas showed bright, fine, grayish-brown deposits on the endothelium, and on dilation, bilateral central stellate opacity of the anterior portion of the lens capsule was revealed. CONCLUSIONS: Clozapine may induce corneal and lenticular pigmentation and thus may lead to a decline in vision. Patients on long-term clozapine therapy should be considered for regular ophthalmic review.
Clozapine ; Cornea ; Endothelium ; Humans ; Lorazepam ; Male ; Middle Aged ; Pigmentation ; Schizophrenia ; Slit Lamp

OBJECTIVES: Clozapine is the drug of choice in treatment-resistant schizophrenia. However, its use is often delayed and a significant proportion of clozapine treated patients fails to respond and experience potentially dangerous side-effects. The aim of this retrospective study was to describe the clinical characteristics of patients started on clozapine and the rate and reason of discontinuation of clozapine. METHODS: Medical records of 83 patients started on clozapine during the period of 2012–2016 were reviewed. RESULTS: Clozapine started on patients in chronic phase; the mean age of start was 38.1 years old and the mean number of psychiatric admission was 6.5. A majority (80.7%) of the patients had been subjected to antipsychotic polypharmacy prior to clozapine and most (61.5%) of them were being treated with polypharmacy including clozapine. Overall, 39 (47.0%) subjects had continued clozapine whereas 15 (18.1%) discontinued it; 29 (34.9%) were lost to follow-up. The most common reason for discontinuation was side-effects (n=13) including six life-threatening cases, most of which occurred within 6 months of its start. CONCLUSION: This study demonstrated that there is some evidence of delays to clozapine use, high rates of polypharmacy and significant rate of discontinuation during the early phase of clozapine treatment.
Antipsychotic Agents ; Clozapine ; Humans ; Lost to Follow-Up ; Medical Records ; Polypharmacy ; Retrospective Studies ; Schizophrenia

OBJECTIVES: Thyroid hormone deficiency during the neurodevelopmental period can impair brain development and induce psychiatric symptoms. This study examined the association between thyroid dysfunction and the severity of symptoms in schizophrenia patients, and the treatment response of patients with schizophrenia. METHODS: Three hundred thirty-eight schizophrenia patients, with no prior history of thyroid disease or taking medication associated with it, were studied. We assessed the blood thyroid hormone level, the Brief Psychiatric Rating Scale (BPRS) scores on the day of admission and discharge, admission period, dose of administered antipsychotics, and the number of antipsychotic combinations. The collected data were subsequently analyzed using the Kruskal-Wallis test and Pearson's chi-square test. RESULTS: The percentage of schizophrenia patients who presented with abnormal thyroid hormone level was 24.6%. High total triiodothyronine (TT3) (p = 0.003), low TT3 (p = 0.001), and high free thyroxine (fT4) (p < 0.001) groups showed a higher BPRS score on admission than did the normal thyroid hormone group, while thyroid stimulating hormone (TSH) levels were not significantly correlated with the severity of symptoms. Furthermore, thyroid hormone was not associated with the treatment response assessed by the rate of BPRS score reduction, admission days, use of clozapine, and dose of antipsychotics. CONCLUSIONS: The TT3 and fT4 hormone levels were significantly associated with the severity of symptoms in schizophrenia patients. These relations suggested that thyroid dysfunction may be associated with the severity of schizophrenia. And hence, further analysis of the results of the thyroid function test, which is commonly used in cases of psychiatric admission, is required.
Antipsychotic Agents ; Brain ; Brief Psychiatric Rating Scale ; Clozapine ; Humans ; Inpatients ; Schizophrenia ; Thyroid Diseases ; Thyroid Function Tests ; Thyroid Gland ; Thyroid Hormones ; Thyrotropin ; Thyroxine ; Triiodothyronine