Daily Dose Of Clozapine Research Articles

A retrospective study of clozapine and norclozapine concentration in patients with schizophrenia: Data from the Therapeutic Drug Monitoring Service, 2019–2022

ObjectiveThe aim of this research was to assess the therapeutic drug monitoring (TDM) of clozapine (CLO) and norclozapine (NCLO). MethodsTDM results of CLO and NCLO in patients obtained from the Xi'an Mental Health Center were retrospectively analyzed. ResultsTDM of CLO and NCLO was typically conducted only once in the majority of patients, particularly those receiving outpatient care. The CLO plasma concentrations were higher in inpatients and female patients. The interquartile (25th–75th) CLO concentrations ranged from 129.83 to 397.53 ng/mL, nearly 68.63% of the samples had subtherapeutic concentrations (<350 ng/mL). Receiver operating characteristic curve analysis showed that inpatients achieved the therapeutic level concentration of 350–600 ng/mL when their daily CLO dose was > 125 mg. ConclusionsIt was surprising to find such a large number of patients with CLO levels below the therapeutic range, there is still a window of improvement for optimizing pharmacological treatments in clinical practice.

The case of a geriatric female experiencing frequent falls and epileptic seizures during long-term low-dose clozapine and extended-release bupropion treatment

There are few reports describing the incidence of seizures in patients prescribed a combination of clozapine and bupropion for the treatment of psychiatric disorders, despite the known drug-drug interaction associated with concomitant use. We report the case of a 67-year-old geriatric woman who experienced multiple falls and seizures while receiving a low daily dose of clozapine 200 mg and bupropion extended-release (XL) 150 mg. There was no recurrence of seizure activity after discontinuation of bupropion and initiation of an antiepileptic drug, divalproex. This case report suggests that bupropion in combination with low-dose clozapine may increase the risk of seizures in elderly patients.

Hematological and Other Cancers in People Using Clozapine: Analysis of Australian Spontaneous Reports Between 1995 and 2020.

Recent observational study evidence suggests that clozapine, unlike other antipsychotics, may be associated with a small increased risk of hematological malignancy. This study described characteristics of hematological and other cancers in those taking clozapine reported to the Australian Therapeutic Goods Administration. We analyzed public case reports for "clozapine," "Clozaril," or "Clopine" from January 1995 to December 2020 classified as "neoplasm benign, malignant and unspecified" by the Australian Therapeutic Goods Administration. Data on age, sex, dose, clozapine start and cessation dates, Medical Dictionary for Regulatory Activities reaction terms, and date of cancer were extracted. Overall, 384 spontaneous reports of cancers in people taking clozapine were analyzed. The mean age of patients was 53.9 years (SD, 11.4 years), and 224 (58.3%) were male. The most frequent cancers were hematological (n = 104 [27.1%]), lung (n = 50 [13.0%]), breast (n = 37 [9.6%]), and colorectal (n = 28 [7.3%]). The outcome was fatal for 33.9% of cancer reports. Lymphoma comprised 72.1% of all hematological cancers (mean patient age, 52.1 years; SD, 11.6 years). The median daily dose of clozapine at the time of hematological cancer report was 400 mg (interquartile range, 300-543.8 mg), and the median duration of clozapine use before hematological cancer diagnosis was 7.0 years (interquartile range, 2.8-13.2 years). Lymphoma and other hematological cancers are overrepresented in spontaneous adverse event reports compared with other cancer types. Clinicians should be aware of the possible association with hematological cancers and monitor for and report any hematological cancers identified. Future studies should examine histology of lymphomas in people using clozapine and corresponding blood level of clozapine.

Factors impeding switching from clozapine to paliperidone among patients with chronic schizophrenia—A retrospective cohort study.

Clozapine is an old antipsychotic that is effective for schizophrenia, however undesirable side effects affect drug adherence. The present study aimed to investigate the predictors for failed switching from clozapine to paliperidone (FSCP) among patients with chronic schizophrenia. This 9-year (January 2010-December 2018) retrospective study included 78 individuals with schizophrenia who wished to switch from clozapine to paliperidone and resided in a nursing home in Taiwan. The univariate Cox proportional hazards regression model (Cox model) was applied to estimate the potential factors for subsequent FSCP, followed by a multivariate Cox model to determine significant predictors of FSCP after adjusting for other covariates. Thirty eight of the 78 participants (48.7%) failed to switch from clozapine to paliperidone. After forward selection in the Cox hazard regression model, a higher number of total admission days during 1 year before switching, longer duration of clozapine use before switching, and higher average daily dose of clozapine during 1 year before switching were significantly associated with FSCP. It is suggested that clinicians should discuss with their patients about the risk factors if they intend to switch from clozapine to paliperidone. Further studies are warranted to verify our findings and extend the applicability. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

A Case Report of Excessive Use of Clozapine Combined With Clonazepam

IntroductionFor patients with schizophrenia, clozapine (CLZ) in combination with clonazepam (CLNAZ) is one of the viable therapeutic options. We successfully reduced the doses of CLZ and CLNAZ to the safe range of a polydrug abuse patient. As far as we know, this is the first case of this problem. As there are no relevant guidelines to reduce CLZ or CLNAZ, we hope to share this case to provide a reference for the prevention and treatment of similar patients with multidrug abuse.Case PresentationThis case report describes a 46-year-old male with a 24-year history of schizophrenia. His main clinical manifestations are auditory hallucinations, persecutory delusion, and emotional instability. In 2012, the patient started taking rifampicin due to tuberculosis and gradually overused CLZ and CLNAZ. Before admission, he took 1,275 mg of CLZ every day and 26 mg of CLNAZ every night. With the help of Therapeutic Drug Monitoring (TDM) and pharmacogenetic testing, we gradually reduced his daily dose of CLZ and CLNAZ and formulated a more reasonable dosing schedule for him. At the time of discharge, the patient took CLZ 450 mg per day and CLNAZ 2 mg per night, with no obvious symptoms of psychosis.ConclusionIn the process of drug maintenance treatment of schizophrenia, it is necessary to adopt TDM strategy to reduce and treat the abuse of multiple prescription drugs.

Off-licence use of clozapine in patients with emotionally unstable personality disorder: a case series analysis

ObjectiveThis retrospective case series followed emotionally unstable personality disorder (EUPD) patients following initiation of clozapine on an off-licence basis, aiming to examine tolerance by determining side effect prevalence and treatment cessation frequency, as well as examining efficacy, by investigating number of hospital re-admissions and symptom control.Case reportThis case series captured the experiences of 11 EUPD patients under the care of Mersey Care NHS Foundation Trust, all of whom had, at some time in the past five years, been initiated on clozapine. All patients were white British females, with a median age of 31. The median daily dose of clozapine was 300 mg. Most patients had significant psychiatric comorbidities, as well as illicit substance and / or alcohol misuse.Whilst prescribed clozapine, patients were only admitted to hospital once on average and this was commonly for clozapine re-titration. Whilst in hospital, rates of self-harm were low, but ligaturing and suicide attempts showed higher prevalence. Patients still demonstrated self-harming behaviour out of hospital leading to A and E presentations. In the community, contacts with the police were minimal, with only two patients undergoing Section 136 assessments or arrests.All patients reported side effects from clozapine - usually hypersalivation, over-sedation and constipation. All 11 patients experienced sinus tachycardia. Eight patients temporarily ceased taking clozapine at some point. In three patients, discontinuation of clozapine was as a result of intolerable side effects. Three patients experienced neutropenia, which subsequently resolved. Only two patients had a body mass index within healthy range.DiscussionDespite patients reporting clozapine to provide symptomatic benefit for their EUPD, and improved their engagement with mental health services, prevalence of self-harm and of A and E presentations remained high, indicating the importance of community support and concomitant psychotherapeutic treatment. Patients with more robust community support showed greater adherence to clozapine.High prevalence of side effects and obesity in these patients, in addition to risk of developing neutropenia, highlights the importance of rigorous monitoring after initiating clozapine. It is reassuring that, despite development of neutropenia in some patients, this recovered quickly, and clozapine treatment could resume.ConclusionClozapine may be an effective pharmacological treatment for enabling EUPD patients to engage more therapeutically with services. Clozapine may be of greater benefit to those with more stable, less chaotic lives. Although diminished, patients still show self-harming behaviour and need for A and E admissions and re-hospitalisation. Side effects of clozapine are common and regular monitoring is required.

Audit on clozapine dose and plasma level correlation for patients with chronic treatment-resistant psychosis

AimsClozapine is associated with a risk of severe adverse events for which there are current monitoring systems are in place; however, there are no established regimens for monitoring of clozapine plasma levels. Recent Medicines and Healthcare products Regulatory Agency (MHRA) guidance advises clozapine levels should be monitored in certain clinical situations where toxicity may be suspected. This audit aimed to evaluate current practice of clozapine level monitoring within one Local Mental Health Team (LMHT).MethodElectronic (RiO) records of 41 patients (33 male, 8 female; aged from 27 to 76 years; mean age 45 years) registered to the ZTAS system within the Nottingham City Central LMHT were reviewed. 46% had been on clozapine for over 16 years. 73.3% of patients were within clusters 12 and 13; 25.4% of patients were in cluster 11, with one patient in cluster 8. Dates of clozapine plasma level tests for each patient between 2006 and 2020 were found on the electronic NoTIS system, along with clozapine, norclozapine and total clozapine levels. Concurrent clozapine dose and regimens were obtained from pharmacy records from 2018 onwards.Result273 clozapine plasma levels were conducted between 2006 and 2020. The average interval between levels taken was 10 months, 2 weeks but had a wide range, the shortest interval being 2 days, the longest being 13 years. 88 levels taken were &gt;600 ug/L, suggesting increased toxicity risk. 108 levels were &lt;350 ug/L, suggesting possible sub-optimal dosing or non-compliance. Statistical tests on correlation coefficient, although statistically non-significant (R = 0.37), showed a positive trend between total clozapine dose and the plasma level between all 3 parameters (i.e. clozapine, norclozapine and total clozapine).ConclusionThere does not appear to be any routine plasma clozapine level monitoring throughout the LMHT with an average interval between tests of 10 months. There was a non-significant but positive trend between total daily dose of clozapine and clozapine level. 32% of clozapine levels returned were higher than the recommended level. We would recommend as suggested in the guidelines from MHRA, clozapine plasma levels should be monitored in certain clinical situations with increased toxicity risk. Trough levels should be taken with records of time of previous dose taken. Limitations of this study included a small sample size (41 patients) with data collection reliant on electronic systems. It was unclear if these results represent trough levels, making values difficult to interpret. Multifactorial impact on clozapine metabolism causes wide patient variability in plasma levels.

Clinical correlates of sialorrhea in clozapine patients

Objective: Sialorrhea occurs more frequently in patients on clozapine than in those on other antipsychotics and has an adverse impact on the quality of life. We evaluated clinical correlates of sialorrhea. Method: 79 patients with schizophrenia (54 males, 25 females; mean age 43.3 years, SD=12.7) from an urban clozapine clinic participated. Their total daily 24 hour dose of clozapine ranged from 100 to 650mg with the average at 341.8, SD=133.1). The part administered at nighttime ranged from 25 to 600mg, with the average at 258.7, SD=106.7. Results: The scores on Nocturnal Hypersalivation Rating Scale (NHRS) ranged from 0 to 4 with the average at 1.7, SD=1.2. The symptom was absent in 17.7%, minimal in 36.7%, mild in 15.2%, moderate in 21.5%, and severe in 8.9% of patients. The intensity of sialorrhea was not significantly correlated to the daily clozapine dose, or its nighttime part, or duration of clozapine treatment, age, and gender. The presence of concurrent other antipsychotics slightly increased the NHRS scores (r=.37) and the presence of antihypertensive medication slightly reduced these sialorrhea scores (r=-.25). Discussion and Conclusions: About a half of the patients reported mild to severe nocturnal hypersalivation, but its intensity seems unrelated to the clozapine dose or to its nighttime administration. No gender or age differences in hypersalivation were found. Concurrent use of other antipsychotics could lightly intensify the sialorrhea.

Clozapine induced gastrointestinal hypomotility: A potentially life threatening adverse event. A review of the literature.

The haematological and cardiac complications of clozapine have been well documented. Recent evidence from pharmacovigilance databases suggests that gastrointestinal (GI) complications are the leading cause of clozapine related deaths. This review aims to describe clinical features along with preventative and treatment options. A review of MEDLINE via PubMed searching for all articles published up to February of 2016. Inclusion criteria were articles that provided clinical or epidemiological information relating to the diagnosis, outcome, management or pathophysiology of clozapine related gastrointestinal disorders in humans. Three large case series were identified with 104 cases, 20 of these reported clinical details. A further 52 cases reports were included. Median age was 40, with 79% being male, mean daily clozapine dose was 453 mg. Mortality was 38% with survivors being younger (39 vs. 42), on lower daily doses (400 mg vs. 532 mg), more likely to be female (32% vs. 6%). Four patients were re-challenged with clozapine following CIGH, two suffered a recurrence. Risk factors for CIGH appear to be older age, male gender, patients in the first four months of treatment, co-prescription of constipating agents, higher daily dose of clozapine, and previous CIGH. Risk factors for death were older age and male gender. Patients receiving clozapine should be counselled about the dangers of constipation and to report new GI symptoms. Once severe CIGH has occurred clozapine should be halted and reviewed with bowel symptoms managed promptly. Re-challenging with clozapine may present substantial risks due to the severity of CIGH and a paucity of evidence. From the available evidence a treatment strategy has been proposed. Further prospective data regarding CIGH are needed to allow a better assessment of the scale of the problem with the development and testing of treatment strategies.

Leukocytosis in Clozapine-treated Patients: a Sign of Loss of Response to the Antipsychotic

Anecdotal evidence tends to suggest clozapine as a cause of leukocytosis in schizophrenic patients, however no conclusive evidence is available on this topic so far. Moreover, transient and persistent clozapine-related leukocytosis has received little attention in the literature. We report two clinical cases of two men, respectively 23 and 34 years old, affected by schizophrenia, showing persecutory and reference delusions, auditory hallucinations and aggressive behaviour. Both had been treated for several years with first and second generation antipsychotics, all at therapeutic doses, reporting only occasional ameliorations. In both patients the previous treatment was gradually tapered down and then discontinued, and clozapine was gradually introduced, at a dose of 200 mg/die in the first patient, and of 400 mg/die in the second one. After ten years of clinical compensation and without any abnormality of blood cell count, leukocytosis appeared in both cases. WBC and ANC counts ranged between 12.56x10 3 and 22.26x10 x10 3 /mm 3 and between 8.57x10 3 and 17.67x10 3 /mm 3 , respectively. When leukocytosis appeared, there was loss of response to clozapine and, consequently, psychopatological decompensation in both patients. Therefore a daily clozapine dose of 350 mg in the first patient and of 650 mg in the second one was reached within two weeks. No clinical amelioration was observed, but an increase in the previous WBC count was shown. Medical and hematological consultations found no evidence of systemic or myeloproliferative illness. These two clinical cases suggest that the onset of leukocytosis in clozapine-treated patients could be associated to loss of response to the antipsychotic.

Treatment of refractory substance-induced psychosis in adolescent males with a genetic predisposition to mental illness

This article presents two cases of adolescent males who were admitted to our inpatient psychiatric unit with a psychotic, disorganized presentation. Both males had a genetic vulnerability to mental illness and reported significant substance use. Their symptoms were refractory to treatment and required the use of clozapine. Both patients experienced significant side effects, which limited the maximum daily dose of clozapine. However, they responded to a dose that was much lower than that typically used in adults. There is significant evidence in the literature about cannabis use triggering psychotic breaks in vulnerable individuals. We speculate that substance use (including synthetic cannabinoids) triggers treatment-resistant psychosis that requires the use of clozapine. Further, lower doses of clozapine may be sufficient to treat the substance-induced psychotic symptoms than those typically used in adult schizophrenia.

Health literacy and the Clozapine patient

To estimate the prevalence of limited health literacy in patients receiving clozapine for schizophrenia. To develop and produce a pharmacist-designed clozapine patient information leaflet (PIL) which has a higher readability score than the company-produced PIL. This was a cross sectional prevalence study. Ethical approval for the study was granted by the local ethics committee. Patients, over 18 years, attending the Clozapine Clinic of a Cork urban teaching hospital, were asked to participate in the study. Demographics such as gender, age, employment and smoking status, were gathered from all participants. The total daily clozapine dose, duration of clozapine treatment, and information regarding the clozapine DVD was also noted. The Rapid Estimate of Adult Literacy in Medicine (REALM) health literacy (HL) screening tool was then administered to each patient. A user-friendly PIL on clozapine was designed by the pharmacist, which was assessed for readability and compared to the company-produced PIL using the FRES and FKGL. Data were analysed using SPSS Version 15. Forty patients (65% male, 95% unemployed and 70% smokers) of average age 38.0 years (+/- 11.2) completed the REALM. The average score was 60.6 (+/- 8.7). Twenty-nine patients (72.5%) were found to have "adequate" health literacy. The remaining eleven patients were found to have either "marginal" or "low" health literacy. The pharmacist-designed PIL would have been readable by 95% of the study population, in contrast to 72.5% with the company-designed PIL. More than a quarter of the population were found to have marginal or low health literacy. Patient information should be matched to the health literacy level of the target population.

Therapeutic drug monitoring of clozapine in schizophrenic outpatients

In the acute therapy of treatment-resistant schizophrenic patients a lower threshold of 350ng/ml clozapine is considered as optimal for response. For stabilization of outpatients under long-term treatment, however, literature based recommendations are so far lacking. This study analysed clozapine plasma levels parameters of schizophrenic outpatients with an F20.x diagnosis according to ICD-10 from a primary care unit treated with clozapine treated under a naturalistic conditions. Plasma levels were measured over a time of 27 months or until the first rehospitalisation. Seven of the 24 observed patients relapsed during this time. Patients who relapsed had a significantly lower median plasma level (344 vs. 481ng/ml, p=0.000). The median daily clozapine dose was 250mg in both groups (p=0.365). The average coefficient of variation of clozapine plasma concentrations was lower in subjects without re-hospitalization (29.2% vs. 41.7%), but not significant (p=0.112). Another remarkable result was that only one of the 7 patients treated with fluvoxamine augmentation strategy relapsed during the study. It is concluded that also under long-term treatment with clozapine sufficiently high plasma levels are needed. Moreover, TDM-controlled pharmacotherapy is helpful for sustainable long-term treatment to prevent relapses and re-hospitalizations. Augmentation with fluvoxamine might be an option to improve the stabilization which needs further investigations.

Ciprofloxacin Strongly Inhibits Clozapine Metabolism

We report on two cases of drug-drug interactions between ciprofloxacin and clozapine. The first case was a 46-year-old male patient receiving a daily dose of clozapine 900 mg. He was admitted to hospital with urosepsis and was treated with a 5-day course of ciprofloxacin and amoxicillin. Two days after completion of antibacterial therapy, the patient developed symptoms of rhabdomyolysis. Clozapine therapy was discontinued and measurement of the patient's clozapine plasma concentration 1 day after cessation of clozapine therapy and 3 days after cessation of ciprofloxacin treatment showed that it was in excess of recommended therapeutic levels. The second patient was a 58-year-old male patient treated with a daily dose of clozapine 300 mg. He was admitted to hospital because of delirium and suspected urinary tract infection or pneumonia. Treatment with ciprofloxacin was initiated. Measurement of clozapine plasma concentrations prior to and 3 days after commencement of ciprofloxacin showed that clozapine concentrations doubled over that time period. We suggest that inhibition of cytochrome P450 (CYP) enzymes 1A2 and 3A4 by ciprofloxacin resulted in delayed clozapine metabolism and elevated clozapine plasma concentrations. This might cause severe adverse effects. We advise using another antibacterial agent or reducing the clozapine dose and monitoring clozapine levels when this antipsychotic agent is used in combination with ciprofloxacin.

Prescribing and Monitoring Clozapine in Christchurch

The aim of the study was to identify the pattern of usage of clozapine in Christchurch, New Zealand, including daily dose, indication and use of drug concentration monitoring. Patients (n=353) were identified retrospectively from the pharmacy computer system. Data gathered included patient demographics, the daily clozapine dose and the number of occasions that clozapine drug concentration monitoring occurred. In addition, each psychiatrist who had prescribed clozapine was surveyed, regarding their indications for the use of clozapine and their use of clozapine drug concentration monitoring. The majority (63%) of patients on clozapine were male. The mean age of the patients was 43 years (range 15-88 years). The mean daily dose of clozapine was 325 mg (range 12.5-900 mg). Patients over the age of 65 years were on a significantly lower dose (mean=143 mg, 95% CI=103-183 mg) compared with those under 65 years of age (mean=350 mg, 95% CI=330-370 mg). The median duration of treatment on clozapine was 4 years. Fifty-one percent of patients had undergone drug concentration monitoring, the majority on multiple occasions. In females, increasing age correlated with an increase in dose-corrected plasma clozapine concentrations (r(2)=0.29, p<0.001). This was not demonstrated in the male population. Of the psychiatrists surveyed, 44% prescribed clozapine for unlicensed indications and 79% used clozapine drug concentration monitoring in their patients. This was most commonly performed to assess compliance or confirm toxicity. The mean daily dose of clozapine of 325 mg was similar to that found in other studies. An age-related decline in dose was observed, probably due to different indications, with many of the elderly patients receiving clozapine for Parkinsonian related symptoms. There was also an age-related decline apparent in clearance in females. Clozapine was often used for unlicensed indications, and a clear majority of psychiatrists use drug concentration monitoring.

Clozapine and Ziprasidone: A Useful Combination in Patients With Treatment-Resistant Schizophrenia

Back to table of contents Previous article Next article LETTERFull AccessClozapine and Ziprasidone: A Useful Combination in Patients With Treatment-Resistant SchizophreniaMarc Ziegenbein M.D.Iris T. Calliess M.D.,Marc Ziegenbein M.D.Search for more papers by this authorIris T. Calliess M.D.Search for more papers by this author,Published Online:1 Apr 2006AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail SIR: Typical and atypical antipsychotic drugs exhibit inadequate or poor response in 20%–40% of patients suffering from schizophrenia. 1 Considering that the problem of treatment-resistant schizophrenia is an important and difficult one, several approaches have been made by clinicians in order to deal with the clinical challenge. An overview of results suggests that combinations with clozapine and a second atypical antipsychotic were mostly beneficial in the described patients, with reduction of positive and negative symptoms. 2 , 3 Although augmentation strategies are poorly documented, they are fairly common in clinical practice. 4 Ziprasidone is a atypical antipsychotic. It has a greater affinity for serotonin 5-HT 2A receptors compared with its affinity for dopamine receptors. 5 Ziprasidone is an antagonist at each. Furthermore, ziprasidone is an agonist at the 5-HT 1A receptor. 5 In placebo-controlled studies, ziprasidone was shown to be effective and safe in improving positive symptoms in patients with schizophrenia. Adverse effects characteristic of ziprasidone commonly include headache, nausea and somnolence; infrequent effects include extrapyramidal side effects, weight gain and QTC prolongation. 5 Here the authors report our first observations with the combination of clozapine and ziprasidone in two patients with treatment-resistant schizophrenia. Two female patients of our outpatient clinic with paranoid schizophrenia (29 years and 51 years, meeting DSM-IV criteria) became resistant to the application of several atypical and typical antipsychotics. The authors found a suboptimal response to clozapine treatment (600 mg and 750 mg daily dosages, respectively) over the last 10 to 12 months with persistent paranoid dellusions and acoustic hallucinations. Both patients complained about side effects (sedation, hypersalivation, weight gain) which led to compliance problems. electrocardiogram, electroencephalogram, and computed tomography of the brain revealed no abnormal findings, whereas the blood tests showed increased liver enzymes. Forty mg ziprasidone daily was added in both cases and increased to 80 mg within 1 week. Productive positive symptoms decreased within 12 weeks, and clozapine could be reduced. After 24 weeks the daily clozapine dose was reduced to 400 mg and 625 mg without recurrence of the positive symptoms. As a result of the reduced dose of clozapine, the side effects subsided in both cases, with the focus on daytime fatigue, which in turn led to better compliance. By the end of week 24, the authors found a reduction in the Brief Psychiatric Rating Scale score in the patients greater than 20% (40 to 28 points in the 29 year-old, and 36 to 22 points in the 51 year-old woman).Our observations, although preliminary, suggest that the combination of clozapine and ziprasidone may benefit patients who are partially responsive to clozapine monotherapy and seems able to reduce side effects. The combined application of the two drugs follows a neurobiological rationale with a highly synergistic antipsychotic potency without increasing the risk of adverse effects. The authors believe that the efficacy of ziprasidone augmentation may be attributed to the complementary receptor profiles of the two drugs, rather than a pharmacokinetic phenomenon. Large controlled trials are needed before firm clinical recommendations can be made about clozapine augmentation. The risk/benefit evaluation of combining the two antipsychotics may require a long period of investigation to fully assess side effects and long-term risk.Department of Social Psychiatry and Psychotherapy, Medical School Hanover, Germany

Clozapine and Ziprasidone: A Useful Combination in Patients With Treatment-Resistant Schizophrenia

Back to table of contents Previous article Next article LETTERFull AccessClozapine and Ziprasidone: A Useful Combination in Patients With Treatment-Resistant SchizophreniaMarc Ziegenbein M.D.Iris T. Calliess M.D.,Marc Ziegenbein M.D.Search for more papers by this authorIris T. Calliess M.D.Search for more papers by this author,Published Online:1 Apr 2006AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail SIR: Typical and atypical antipsychotic drugs exhibit inadequate or poor response in 20%–40% of patients suffering from schizophrenia. 1 Considering that the problem of treatment-resistant schizophrenia is an important and difficult one, several approaches have been made by clinicians in order to deal with the clinical challenge. An overview of results suggests that combinations with clozapine and a second atypical antipsychotic were mostly beneficial in the described patients, with reduction of positive and negative symptoms. 2 , 3 Although augmentation strategies are poorly documented, they are fairly common in clinical practice. 4 Ziprasidone is a atypical antipsychotic. It has a greater affinity for serotonin 5-HT 2A receptors compared with its affinity for dopamine receptors. 5 Ziprasidone is an antagonist at each. Furthermore, ziprasidone is an agonist at the 5-HT 1A receptor. 5 In placebo-controlled studies, ziprasidone was shown to be effective and safe in improving positive symptoms in patients with schizophrenia. Adverse effects characteristic of ziprasidone commonly include headache, nausea and somnolence; infrequent effects include extrapyramidal side effects, weight gain and QTC prolongation. 5 Here the authors report our first observations with the combination of clozapine and ziprasidone in two patients with treatment-resistant schizophrenia. Two female patients of our outpatient clinic with paranoid schizophrenia (29 years and 51 years, meeting DSM-IV criteria) became resistant to the application of several atypical and typical antipsychotics. The authors found a suboptimal response to clozapine treatment (600 mg and 750 mg daily dosages, respectively) over the last 10 to 12 months with persistent paranoid dellusions and acoustic hallucinations. Both patients complained about side effects (sedation, hypersalivation, weight gain) which led to compliance problems. electrocardiogram, electroencephalogram, and computed tomography of the brain revealed no abnormal findings, whereas the blood tests showed increased liver enzymes. Forty mg ziprasidone daily was added in both cases and increased to 80 mg within 1 week. Productive positive symptoms decreased within 12 weeks, and clozapine could be reduced. After 24 weeks the daily clozapine dose was reduced to 400 mg and 625 mg without recurrence of the positive symptoms. As a result of the reduced dose of clozapine, the side effects subsided in both cases, with the focus on daytime fatigue, which in turn led to better compliance. By the end of week 24, the authors found a reduction in the Brief Psychiatric Rating Scale score in the patients greater than 20% (40 to 28 points in the 29 year-old, and 36 to 22 points in the 51 year-old woman).Our observations, although preliminary, suggest that the combination of clozapine and ziprasidone may benefit patients who are partially responsive to clozapine monotherapy and seems able to reduce side effects. The combined application of the two drugs follows a neurobiological rationale with a highly synergistic antipsychotic potency without increasing the risk of adverse effects. The authors believe that the efficacy of ziprasidone augmentation may be attributed to the complementary receptor profiles of the two drugs, rather than a pharmacokinetic phenomenon. Large controlled trials are needed before firm clinical recommendations can be made about clozapine augmentation. The risk/benefit evaluation of combining the two antipsychotics may require a long period of investigation to fully assess side effects and long-term risk.Department of Social Psychiatry and Psychotherapy, Medical School Hanover, Germany

Aripiprazole Augmentation of??Clozapine??in Treatment-Resistant Schizophrenia

Therapeutic options for patients with treatment-resistant schizophrenia are limited, and combination treatment with atypical antipsychotic drugs is an often used strategy. We tested the hypothesis that the combination of aripiprazole and clozapine would lead to an improvement in this patient group. Eleven patients with treatment-resistant schizophrenia participated in this clinical trial and received a combination of aripiprazole and clozapine. Patients had to have remained on a stable dose of clozapine for at least 6 months in order to ensure a reasonable opportunity to respond to clozapine monotherapy. Clinical status was evaluated at baseline and at 3 months' follow-up using the Brief Psychiatric Rating Scale (BPRS). All patients completed 3 months' combination treatment. There was a significant reduction in the mean BPRS score in seven patients (63.6%) over the 3 months of combination treatment. Augmentation with aripiprazole in clozapine-treated patients did not result in a corresponding increase in adverse effects. Use of the combination allowed a significant reduction in the daily dose of clozapine. Combined application of clozapine and aripiprazole is in accordance with a neurobiological rationale and appears to be safe and well tolerated without increased risk of adverse effects.

Retrospective evaluation of the effect of omeprazole on clozapine metabolism

To study the effect of the replacement of omeprazole by pantoprazole on clozapine metabolism in 13 psychiatric patients, who used both clozapine and omeprazole. Retrospective study of the medical files. In comparison to smokers, a significant rise of the serum clozapine levels was observed in all non-smoking patients, whilst the daily dose of clozapine remained unchanged. This effect was probably caused by the discontinuation of enzyme induction of the cytochrome P450 enzyme 1A2 by omeprazole in non-smokers, whereas CYP1A2 remained induced in patients who smoked. Omeprazole only influenced clozapine metabolism in non-smokers. In none of the patients an adjustment of the clozapine dose was required.

Central Muscarinic Acetylcholine Receptor Availability in Patients Treated with Clozapine

Clozapine is the prototypical atypical antipsychotic. In vitro, clozapine antagonizes a broad range of receptors, including dopamine, serotonin and muscarinic acetylcholine receptors. In vivo, receptor occupancy studies have shown moderate dopamine D(2) receptor blockade as well as high serotonin 5HT(2) receptor blockade for clozapine. Using [I-123]IQNB SPECT, we explored the influence of clozapine on muscarinic receptors in vivo. Eight schizophrenia patients underwent a total of 12 [I-123]IQNB SPECT scans after treatment with low to moderate doses of clozapine (mean 210 mg/day, range 50-450 mg/day). Muscarinic receptor availability was determined for basal ganglia, cortex, thalamus, and pons. A group of 12 age- and sex-matched unmedicated schizophrenia patients was used for comparison. Compared to unmedicated patients, [I-123]IQNB binding was lower in all regions in subjects treated with clozapine and decreased with increasing dose. In patients treated with a daily clozapine dose of at least 200 mg (mean 275+/-88 mg/day), these differences were highly significant (p <0.003) with mean reductions of muscarinic receptor availability of 45% for basal ganglia, 58% for cortex, 66% for pons, and 79% for thalamus. These preliminary data indicate that reduction of muscarinic receptor availability by clozapine can be measured in vivo and that moderate daily doses are associated with moderate to high reductions of muscarinic receptor availability. These results may explain, at least in part, the lack of extrapyramidal side effects as well as some side effects seen with clozapine.