Atypical Weight Loss in Two Patients with Schizophrenia Treated with Clozapine: A Case Report

Clozapine is widely recognized as an effective antipsychotic medication for treatment-resistant schizophrenia, but it is typically associated with significant weight gain. This case report presents two unusual cases of patients with schizophrenia who experienced substantial weight loss while on long-term clozapine therapy. The first case involves a 35-year-old male who lost 21.3% of his initial body weight, and the second case describes a 54-year-old female who lost 30.2% of her initial weight, despite having comorbid hypothyroidism. Both patients showed improvement in psychiatric symptoms concurrent with the weight loss. Comprehensive investigations did not reveal other clear etiologies for the weight reduction. These cases challenge the conventional understanding of clozapine’s metabolic effects and highlight the potential for atypical responses in some individuals. The report discusses possible mechanisms for this unusual phenomenon, including genetic factors and altered pharmacokinetics. It also emphasizes the need for individualized monitoring and management strategies in clozapine therapy. These findings contribute to the growing body of evidence suggesting that metabolic responses to clozapine may be more complex and varied than previously thought, underscoring the importance of personalized approaches in schizophrenia treatment.

β_(2) and α_(2) adrenergic receptors mediate the proneurogenic in vitro effects of norquetiapine

Positive modulation of adult hippocampal neurogenesis may contribute to the therapeutic effects of clinically relevant antidepressant drugs,including atypical antipsychotics.Quetiapine,an antipsychotic which represents a therapeutic option in patients who are resistant to classical antidepressants,promotes adult hippocampal neurogenesis in preclinical studies.Norquetiapine,the key active metabolite of quetiapine in humans,has a distinctive receptor profile than the parent compound.The drug is indeed a high affinity norepinephrine transporter inhibitor and such activity has been proposed to contribute to its antidepressant effect.At present,no information is available on the effects of norquetiapine on adult neurogenesis.We extensively investigated the activity of quetiapine and norquetiapine on adult murine neural stem/progenitor cells and their progeny.Additionally,selective antagonists for β_(2)/α_(2) adrenergic receptors allowed us to evaluate if these receptors could mediate quetiapine and norquetiapine effects.We demonstrated that both drugs elicit in vitro proneurogenic effects but also that norquetiapine had distinctive properties which may depend on its ability to inhibit norepinephrine transporter and involve β_(2)/α_(2) adrenergic receptors.Animal care and experimental procedures were approved by the Institutional Animal Care and Use Committees(IACUC)at University of Piemonte Orientale,Italy(approval No.1033/2015PR)on September 29,2015.

Comparative effectiveness of quetiapine and haloperidol in delirium:A single blind randomized controlled study

AIM To evaluate the effectiveness of quetiapine and haloperidol in patients of delirium referred to psychiatry consultation liaison services.METHODS The study followed a single blind randomised controlled trial design.Thirty-two patients in the haloperidol group and 31 patients in the quetiapine group were assessed at the baseline and 6 consecutive days.Flexible dosing regimen(haloperidol:0.25-1.25 mg;quetiapine 12.5-75 mg/d) was used.Delirium Rating Scale-Revised-98(DRS-R-98) and mini mental status examination(MMSE) were the primary and secondary efficacy measures respectively.RESULTS Baseline DRS-R-98 severity score and MMSE scores did not differ between the 2 study groups.From baseline to day 6,there was significant reduction in the total DRS-R-98 scores,DRS-R-98 cognitive domain scores,DRS-R-98 non-cognitive domain scores and significant increase in the MMSE scores in both the groups.Both the groups did not differ on any of the assessments in terms of DRS-R98 and MMSE scores.The effectiveness of both the medications was similar in adult and elderly(≥ 60 years) patients.At the end of the trial,68.75% and 67.74% of subjects in the haloperidol and quetiapine group respectively had mean DRS-R-98 scores below 10.By 6th day,12(37.5%) patients in haloperidol group and 9(29.03%) patients in the quetiapine group hadDRS-R98 score of "0" with no significant difference between the two groups(P = 0.47).CONCLUSION Quetiapine is as effective as haloperidol in the management of delirium.

A Comparison Study of the Efficacy of Rapid Titration Quetiapine and Haloperidol in Agitated Adults in an Emergency Setting

Objective: Intramuscular (IM) Benzodiazepines and/or Haloperidol alone or with benzodiazepines are frequently used to treat agitation. Based on emerging literature regarding Quetiapine used for the control of anxiety we examined Quetiapine as a possible alternative in selected cases. Methods: This study was a single-blind randomized study comparing Quetiapine PO (300 mg) with a combination of Haloperidol (5 mg), Benztropine mesylate (2 mg) and lorazepam (2 mg) administered IM to treat agitated patients seeking care in a busy psychiatric emergency setting. Male or female patients (18 - 60), deemed by the attending (admitting) psychiatrist to be indicative of agitated and/or aggressive behavior and had a Positive and Negative Syndrome Score-Excited Component (PANSS-EC), as evaluated by the Research Psychiatrist, and total score equal to or greater than 15. Patients deemed competent were randomized into one of the following treatment groups: Quetiapine 300 or Haloperidol 5 mg, benztropine mesylate, or lorazepam given by the IM route. Two scales, PANSS-EC and CGI-C were used to assess patients in the trial. The primary outcome measure PANSS-EC at 2 hours after administration of the medication. Results: Sixty-eight patients were included in the study. There were no significant treatment group differences in baseline condition. There was no significant difference between the two conditions. There was, however, a significant within-group decrease from baseline condition. Conclusion: Finding no significant differences suggests that in general the two treatments were equivalent. To sum up, Quetiapine 300 mg as a single dose appeared safe and effective in agitated patients treated in an ER. The results were similar to a comparison group receiving an intra-muscular combination of Haloperidol, Lorazepam and Benztropine. This study has significant limitations. The study was single blind and the use of a placebo would have strengthened the design but would be considered unethical. The sample size was relatively small and the group of patients who come to the ER may not be representative of the population of patients who visit across the country. And finally it was a select subgroup who made up the study population and who were probably less severely ill than other subjects who came to our ER.

Quetiapine-related acute lung injury:A case report

BACKGROUND Quetiapine,known as a non-classical antipsychotic drug,is frequently used for the treatment of mental diseases,such as schizophrenia,bipolar disorder,and major depressive disorder.Acute lung injury,a rarely reported side effect of quetiapine,is described in this case report.CASE SUMMARY Due to terminal delirium,a 66-year-old man took a large dose of quetiapine and then developed severe pulmonary disease.His symptoms were not resolved after routine treatment,such as antibiotics,diuretic,and supportive therapies.Quetiapine-related acute lung injury was therefore suspected and hormonal therapy was initiated.Subsequently,his symptoms were alleviated and the radiological results improved dramatically.CONCLUSION Our findings in the present report highlight a potential adverse effect of quetiapine,drug-related acute lung injury,which deserves awareness in clinical practice.

Quetiapine augmentation of prolonged exposure therapy in veterans with PTSD and a history of mild traumatic brain injury: design and methodology of a pilot study

Background: Selective serotonergic reuptake inhibitors(SSRIs) are first-line pharmacologic treatments for patients with posttraumatic stress disorder(PTSD), but must be given over extended period of time before the onset of action. The use of SSRIs in PTSD patients with mild traumatic brain injury(m TBI) is problematic since SSRIs could exacerbate post-concussion syndrome(PCS) symptoms. VA/DOD guidelines identify trauma-focused psychotherapy as the best evidence-based treatment for PTSD, but overall effectiveness is limited by reduced levels of patient engagement and retention. A previous study from this research group suggested that quetiapine monotherapy, but not risperidone or valproate, could increase engagement in trauma-focused psychotherapy.Methods: We report the study protocol of a pilot study funded under the South-Central Mental Illness Research, Education, and Clinical Center pilot study program from the U.S. Department of Veterans Affairs. This randomized, open-label study was designed to evaluate the feasibility of completing a randomized trial of quetiapine vs. treatment as usual to promote patient engagement in PTSD patients with a history of m TBI.Discussion: We expect that the success of this ongoing study should provide us with the preliminary data necessary to design a full-scale randomized trial. Positive efficacy results in a full-scale trial should inform new VA guidelines for clinical practice by showing that quetiapine-related improvements in patient engagement and retention may be the most effective approach to assure that VA resources achieve the best possible outcome for veterans.Trial registration: NCT04280965.

Dispersive Liquid-liquid Microextraction Combined with High-performance Liquid Chromatography for the Determination of Clozapine and Chlorpromazine in Urine

A simple method has been proposed for the determination of clozapine （CLZ） and chlorpromazine （CPZ） in human urine by dispersive liquid-liquid microextraction （DLLME） in combination with high-performance liquid chromatography-ultraviolet detector （HPLC-UV）. All important variables influencing the extraction efficiency, such as pH, types of the extraction solvent and the disperser solvent and their volume, ionic strength and centrifugation time were investigated and optimized. Under the optimal conditions, the limit of detection （LODs） and quantification （LOQs） of the method were 13 and 39 ng/mL for CLZ, and 2 and 6 ng/mL for CPZ, respectively. The relative standard deviations （RSDs） of the targets were less than 5.1% （C=0.100 μg/mL, n=9）. Good linear behaviors over the tested concentration ranges were obtained with the values of R20.999 for the targets. The absolute extraction efficiencies of CLZ and CPZ from the spiked blank urine samples were 98.3% and 97.8%, respectively. The applicability of the technique was validated by analyzing urine samples and the mean recoveries for spiked urine samples ranged from 93.3% to 105.0%. The method was successfully applied for the determination of CLZ and CPZ in real human urine.

Case Report: Augmentation with Blonanserin for a Schizophrenia Patient with Insufficient Response to Clozapine

Background: Clozapine is the most efficacious among antipsychotics for patients with schizophrenia. Nevertheless, clozapine is not effective in more than about 50% of treatment refractory schizophrenia patients, and several pharmacological strategies are used to augment it. Several reviews including meta-analyses have been published, but the efficacy of augmentation therapy for clozapine-resistant patients is not adequately supported. Though there is a weak connection between the oral dose and plasma concentration of clozapine, there is no report of augmentation therapy considering the plasma concentration of clozapine. Blonanserin is reported to be effective in treatment of both positive and negative symptoms of schizophrenia and well tolerated. Methods: We obtained consent to evaluate clinical presentations and clozapine plasma concentrations at the Okayama Psychiatric Medical Center and had not identified the individual for ethical reasons. This is a case report. Results: This case fulfilled the diagnostic criteria of neuroleptic-induced dopamine supersensitivity psychosis. Monotherapy with blonanserin was not effective, but augmentation of blonanserin with clozapine was effective and well tolerated by a clozapine-resistant schizophrenia patient. Conclusion: Because clozapine may ameliorate dopamine supersensitivity psychosis, the addition of blonanserin to clozapine may be effective even if monotherapy with blonanserin was not.

Amisulpride augmentation therapy improves cognitive performance and psychopathology in clozapine‑resistant treatment‑refractory schizophrenia:a 12‑week randomized,double‑blind,placebo‑controlled trial

Background:Although clozapine is an effective option for treatment-resistant schizophrenia(TRS),there are still 1/3 to 1/2 of TRS patients who do not respond to clozapine.The main purpose of this randomized,double-blind,placebocontrolled trial was to explore the amisulpride augmentation efficacy on the psychopathological symptoms and cognitive function of clozapine-resistant treatment-refractory schizophrenia(CTRS)patients.Methods:A total of 80 patients were recruited and randomly assigned to receive initial clozapine plus amisulpride(amisulpride group)or clozapine plus placebo(placebo group).Positive and Negative Syndrome Scale(PANSS),Scale for the Assessment of Negative Symptoms(SANS),Clinical Global Impression(CGI)scale scores,Repeatable Battery for the Assessment of Neuropsychological Status(RBANS),Treatment Emergent Symptom Scale(TESS),laboratory measurements,and electrocardiograms(ECG)were performed at baseline,week 6,and week 12.Results:Compared with the placebo group,amisulpride group had a lower PANSS total score,positive subscore,and general psychopathology subscore at week 6 and week 12(PBonferroni<0.01).Furthermore,compared with the placebo group,the amisulpride group showed an improved RBANS language score at week 12(PBonferroni<0.001).Amisulpride group had a higher treatment response rate(P=0.04),lower scores of CGI severity and CGI efficacy at week 6 and week 12 than placebo group(PBonferroni<0.05).There were no differences between the groups in body mass index(BMI),corrected QT(QTc)intervals,and laboratory measurements.This study demonstrates that amisulpride augmentation therapy can safely improve the psychiatric symptoms and cognitive performance of CTRS patients.

Effects of acute and chronic administration of MK-801 on c-Fos protein expression in mice brain regions implicated in schizophrenia and antagonistic action of clozapine

Objective To investigate the effects of acute and chronic administration of the non-competitive NMDA receptor antagonists MK-801 on c-Fos protein expression in different brain regions of mice and an-tagonistic action of clozapine.Methods Immunohistochemistry was used to detect the expression of c-Fos protein.Results MK-801(0.6 mg·kg-1)acute administration produced a significant increase in the expression of c-Fos protein in the layers Ⅲ-Ⅳ of posterior cingulate and retrosplenial(PC/RS)cortex,which was consistent with the previous reports.Moreover,we presented a new finding that MK-801(0.6 mg·kg-1)chronic administration for 8 days produced a significant increase of c-Fos protein expression in the PC/RS cortex,prefrontal cortex(PFC)and hypothalamus of mice.Among that,c-Fos protein expression in the PC/RS cortex of mice was most significant.Compared acute administration with chronic administration,we found that MK-801 chronic administration significantly increased the expression of c-Fos protein in the PC/RS cortex,PFC and hypothalamus.Furthermore,pretreatment of mice with clozapine significantly decreased the expression of c-Fos protein induced by MK-801 acute and chronic administration.Conclusions Marked expression of c-Fos protein induced by MK-801 is associated with neurotransmitters' change noted in our previous studies,and c-Fos protein,the marker of neuronal activation,might play an important role in the chronic pathophysiological process of schizophrenic model induced by NMDA receptor antagonist.

Effect of clozapine on the serum total bile acid, glucose and lipid metabolism in patients with schizophrenia

Objective:To observe the effect of clozapine on the serum total bile acid (TBA), glucose and lipid metabolism in patients with schizophrenia.Methods:A total of 80 patients with first-episode schizophrenia who were admitted in our hospital from January, 2015 to January, 2016 were included in the study and randomized into the observation group and the control group with 40 cases in each group. The patients in the observation group were given clozapine, while the patients in the control group were given risperidone. The serum TBA, T-Bil, D-Bil, I-Bil, glucose and lipid metabolism before and after treatment in the two groups were compared. Results:The comparison of TBA before and after treatment between the two groups was not statistically significant (P>0.05). T-Bil, D-Bil, and I-Bil after treatment were significantly reduced when compared with before treatment (P<0.05), but the comparison between the two groups was not statistically significant (P>0.05). BMI, waistline, hipline, and waist-hip ratio after treatment in the two groups were significantly elevated when compared with before treatment (P<0.05), and BMI, waistline, hipline, and waist-hip ratio after treatment in the observation group were significantly higher than those in the control group (P<0.05). The comparison of FBS, TC, TG, HDL-C, and LDL-C levels before treatment between the two groups was not statistically significant (P>0.05). FBS, TC, TG, and LDL-C levels 12 months after treatment were significantly elevated when compared with before treatment (P<0.05), but HDL-C was significantly reduced when compared with before treatment (P<0.05). FBS, TC, TG, and LDL-C levels 12 months after treatment in the observation group were significantly higher than those in the control group (P<0.05), but HDL-C was significantly lower than that in the control group (P<0.05).Conclusions:Clozapine has no obvious effect on TBA in patients with schizophrenia. Both of the two medications can produce effects on the glucose and lipid metabolism, but the effect by clozapine is more obvious;therefore, it should be paid attention in the clinical application.

Curcumin Inhibits Adipogenesis Elicited by Clozapine in 3T3-L1 Cells

Although clozapine (CZP), which is used for schizophrenia treatment, causes weight gain, the mechanism remains unclear. We recently reported that the naturally occurring compound curcumin (CUR) suppresses adipogenesis in 3T3-L1 cells. The aims of the present study were to determine the mechanism by which CZP induces adipocyte differentiation of 3T3-L1 cells, and whether CUR reduces CZP-induced adipogenesis. We found that cells grown in the presence of CZP had significantly higher triacylglycerol levels, numbers of lipid-filled adipocytes, and mRNA expression levels of CCAAT-enhancer binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ) than those grown without CZP. Treatment with CZP plus CUR resulted in major reductions in these four parameters. These results suggest that CZP enhances adipogenesis in 3T3-L1 cells via the C/EBPα-PPARγ pathway and that by interrupting CZP’s effects, CUR might be a potent agent for preventing CZP-induced weight gain.

Relationships between clozapine and norclozapine plasma concentrations, clozapine dose, and clinical response in Tunisian patients with schizophrenia-treatment resistance

The present study investigated relationships between clozapine dose, clozapine and norclozapine plasma concentrations, and clinical responses to clozapine treatment in Tunisian schizophrenics. Fourteen schizophrenia-treatment resistant patients, recruited for this study, were treated with clozapine for 45 days. Patient health improvement was assessed before and after each cycle of two weeks of clozapine therapy, using the Brief Psychiatric Rating Scale (BPRS). Plasma clozapine and norclozapine concentrations were determined by high-performance liquid chromatography (HPLC). No significant correlations between plasma clozapine and norclozapine concentrations and clinical health improvement among our schizophrenic patients were found. However, a significant correlation was observed between clinical health improvement given by BPRS scores and norclozapine plasma concentration to daily clozapine dose ratio (NCZ/D). Despite the small sample size of our study, our findings suggest that the clozapine therapy response variations observed in our patients may be, in part, explained by the interindividual differences in plasma norclozapine concentration to clozapine dose ratio (NCZ/D). So the NCZ/D parameter could be used as a good indicator for adjusting the clozapine dose-adaptation strategy and consequently for improving the clinical psychopathological state of schizophrenia-treatment resistant patients.

Delaying clozapine: how long is too long?

Background Although clozapine is the most effective drug for treatment-resistant schizophrenia,its use remains restricted in clinical practice in India.The delay in initiating treatment with clozapine and its impact on disease outcome needs evaluation.Aim To identify the implications of delaying clozapine initiation in clinical outcomes among people with treatment-resistant schizophrenia.Methods Subjects with treatment-resistant schizophrenia,stabilised on clozapine monotherapy,were recruited from the outpatient clinic of a general hospital psychiatry unit offering tertiary care services in Thrissur district,Kerala,India.A retrospective cohort design was employed,and information on duration of illness,total duration of treatment and duration of treatment with clozapine was collected.Present symptom status was measured using the Positive and Negative Syndrome Scale.Factors associated with higher symptom scores were analysed using an independent sample f test,Spearman correlation and multiple linear regression.Results Forty subjects stabilised on long-term clozapine therapy formed the study sample.The mean dose of clozapine used in the study population was 200 mg.The mean duration of antipsychotic treatment before starting clozapine was 89.3 months(7.4 years).The duration of treatment before starting clozapine was found to have a significant positive association with the total Positive and Negative Syndrome Scale score(correlation coefficient 0.40;p=0.01)and negative symptom score(correlation coefficient 0.33;p=0.04).The multiple regression analysis adjusting for covariates showed that the duration of treatment before starting clozapine was an independent factor associated with a higher negative symptom score in the Positive and Negative Syndrome Scale(slope p=0.05;p=0.02;R2=0.27).Conclusion Poor treatment outcomes in treatmentresistant schizophrenia could be secondary to a delay in initiating clozapine therapy.

Acute onset clozapine-induced hyperglycaemia: A case report

Clozapine is an atypical antipsychotic which is described to have higher efficacy among all available antipsychotic medications. Clozapine is reserved especially for resistant schizophrenia due to its side effects. Clozapine-induced metabolic syndrome and hyperglycaemia are common longterm side effects and are responsible for increased mortality in patients with schizophrenia. In this case, a patient with resistant schizophrenia was presented with acute-onset hyperglycaemia and delirium with the use of clozapine within a week. Withdrawal of clozapine in the patient led to the improvement in delirium and hyperglycaemia without the use of any hypoglycaemic agent. This case s叩ports the notion that in certain cases clozapine can induce hyperglycemia through possible direct pathophysiological mechanisms within a shorter time frame.

Re-Challenge with Clozapine after Neuroleptic Malignant Syndrome and Seizure in a Patient with Di-George Syndrome: Case Report and Review of Literature

Background: Individuals with 22q11.2DS, a genetic subtype of Schizophrenia, respond as well to clozapine as those with other forms of Schizophrenia. It has been reported that serious and rare adverse events like seizures, and myocarditis have been associated with clozapine treatment in this population. To the best of our knowledge, the incidence of neuroleptic malignant syndrome (NMS) as an adverse effect of antipsychotic use in patients with this disorder has not yet been reported. Aim: In this article, we discuss a case of clozapine-induced NMS and subsequent re-challenge in a patient with 22q11.2DS-associated schizophrenia. The aim of this study is to accumulate scientific data about rare presentations, and serve as a major educational tool, and highlight the unique challenges faced when using clozapine in a patient with DiGeorge Syndrome. Methods: This is a descriptive case report of a patient encountered in the inpatient unit which includes retrospective review of the patient’s electronic medical record and a literature review of antipsychotic medications-induced NMS. Conclusion: This study demonstrates a successful re-challenge with clozapine after the patient developed NMS and seizures during the initial treatment and also highlights how, in addition to drug level monitoring, considering pharmacogenetic testing early in treatment might help minimize adverse drug reactions in individuals with known genetic disorders such as 22q11.2DS.