Although clozapine is more effective than other antipsychotics in the treatment of schizophrenia, the rate of its discontinuation is also high. The aim of this retrospective chart-review study was to investigate the causes of clozapine discontinuation in patients with treatment-resistant schizophrenia. This study included a total of 396 patients with schizophrenia, 240 still on clozapine therapy and 156 who discontinued clozapine, and compared their clinical characteristics. Those who discontinued clozapine had a longer history of illness and more hospitalizations before clozapine and tended to be older. Inadequate response was more common among clozapine discontinuers compared to continuers. The most common reason for discontinuation was the side-effects associated with clozapine (49%). Discontinuation from patient decision or by the psychiatrist due to noncompliance was the second (29.7%) and discontinuation due to lack of efficacy was the third most frequent reason (21.3%). The patients who discontinued clozapine because of cardiac side effects were younger, had shorter duration of clozapine use, and had lower maximum clozapine dose compared to the other discontinuers. Our findings point out the importance of enhancing psychiatrists' ability to handle manageable side effects to minimize discontinuations and maximize the benefits of clozapine in patients with treatment-resistant schizophrenia.

The central nervous system is functionally organized as a dynamic network of interacting neural circuits that underlies observable behaviors. At higher resolution, these behaviors, or phenotypes, are defined by the activity of a specific set of biomolecules within those circuits. Identification of molecules that govern psychiatric phenotypes is a major challenge. The only organic molecular entities objectively associated with psychiatric phenotypes in humans are drugs that induce psychiatric phenotypes and drugs used for treatment of specific psychiatric conditions. Here, we identified candidate biomolecules contributing to the organic basis for psychosis by deriving an in vivo biomolecule-tissue signature for the atypical pharmacologic action of the antipsychotic drug clozapine. Our novel in silico approach identifies the ensemble of potential drug targets based on the drug's chemical structure and the region-specific gene expression profile of each target in the central nervous system. We subtracted the signature of the action of clozapine from that of a typical antipsychotic, chlorpromazine. Our results implicate dopamine D4 receptors in the pineal gland and muscarinic acetylcholine M1 (CHRM1) and M3 (CHRM3) receptors in the prefrontal cortex (PFC) as significant and unique to clozapine, whereas serotonin receptors 5-HT2A in the PFC and 5-HT2C in the caudate nucleus were common significant sites of action for both drugs. Our results suggest that D4 and CHRM1 receptor activity in specific tissues may represent underappreciated drug targets to advance the pharmacologic treatment of schizophrenia. These findings may enhance our understanding of the organic basis of psychiatric disorders and help developing effective therapies.

The current literature globally highlights the efficacy of Clozapine in several psychiatric disorders all over the world, with an FDA indication for reducing the risk of repeated suicidal behavior in patients with schizophrenia or schizoaffective disorder. A growing field of research is also stressing a possible broader beneficial effect of Clozapine in promoting neuroprotection and neurotrophism. However, this drug is linked to several life-threatening side effects, such as agranulocytosis, myocarditis and seizures, that limit its use in daily clinical practice. For this work, a search was performed on PubMed using the terms "Clozapine indications", "Clozapine adverse effects", "Clozapine regenerative effects", and "Clozapine neuroplasticity" with the aim of reviewing the scientific literature on Clozapine's treatment indications, adverse effects and potential regenerative role. The results confirmed the efficacy of clozapine in clinical practice, although limited by its adverse effects. It appears crucial to raise awareness among clinicians about the potential benefits of using Clozapine, as well educating medical personnel about its risks and the early identification of possible adverse effects and their management.

Second generation antipsychotics (SGAs) induce glucometabolic side-effects, such as hyperglycemia and insulin resistance, which pose a therapeutic challenge for mental illness. Sphingolipids play a role in glycaemic balance and insulin resistance. Endoplasmic reticulum (ER) stress contributes to impaired insulin signalling and whole-body glucose intolerance. Diabetogenic SGA effects on ER stress and sphingolipids, such as ceramide and sphingomyelin, in peripheral metabolic tissues are unknown. This study aimed to investigate the acute effects of clozapine and olanzapine on ceramide and sphingomyelin levels, and protein expression of key enzymes involved in lipid and glucose metabolism, in the liver and skeletal muscle.

Clozapine displays stronger systemic metabolic side effects than haloperidol and it has been hypothesized that therapeutic antipsychotic and adverse metabolic effects of these drugs are related. Considering that cerebral disconnectivity through oligodendrocyte dysfunction has been implicated in schizophrenia, it is important to determine the effect of these drugs on oligodendrocyte energy metabolism and myelin lipid production. Effects of clozapine and haloperidol on glucose and myelin lipid metabolism were evaluated and compared in cultured OLN-93 oligodendrocytes. First, glycolytic activity was assessed by measurement of extra- and intracellular glucose and lactate levels. Next, the expression of glucose (GLUT) and monocarboxylate (MCT) transporters was determined after 6 and 24 h. And finally mitochondrial respiration, acetyl-CoA carboxylase, free fatty acids, and expression of the myelin lipid galactocerebroside were analyzed. Both drugs altered oligodendrocyte glucose metabolism, but in opposite directions. Clozapine improved the glucose uptake, production and release of lactate, without altering GLUT and MCT. In contrast, haloperidol led to higher extracellular levels of glucose and lower levels of lactate, suggesting reduced glycolysis. Antipsychotics did not alter significantly the number of functionally intact mitochondria, but clozapine enhanced the efficacy of oxidative phosphorylation and expression of galactocerebroside. Our findings support the superior impact of clozapine on white matter integrity in schizophrenia as previously observed, suggesting that this drug improves the energy supply and myelin lipid synthesis in oligodendrocytes. Characterizing the underlying signal transduction pathways may pave the way for novel oligodendrocyte-directed schizophrenia therapies.

We tested the hypothesis that homocysteine levels are higher in blood of schizophrenic subjects on clozapine monotherapy than in healthy controls and they correlate with anthropometric measurements, laboratory tests and results of bioimpedance analysis of body composition. Data for 24 subjects with schizophrenia treated with clozapine and 24 age- and sex-matched healthy volunteers was analyzed. Regarding the whole group, homocysteine levels were significantly higher in men (17.0 ± 3.4 vs. 12.1 ± 4.0 μmol/L, p = 0.009). Homocysteine levels correlated with waist circumference (R = 0.58, p = 0.003), waist-to-hip ratio (R = 0.57, p = 0.003), basal metabolic rate (R = 0.48, p = 0.01), lean body mass [kg] (R = 0.53, p = 0.008), body water [L] (R = 0.53, p = 0.008) and triglycerides (R = 0.57, p = 0.003). There were no significant differences of homocysteine levels for impaired fasting glucose, abdominal obesity, obesity/overweight, and dyslipidemia. Homocysteine levels did not correlate with age, treatment duration, clozapine dose, weight, body mass index, abdominal circumference, blood pressure, total body fat, cholesterol, high density lipoproteins, low density lipoproteins, uric acid, calcium, glucose, insulin, homoeostasis model assessment of insulin resistance 1, and homoeostasis model assessment of insulin resistance 2. We did not find significant differences in blood homocysteine levels between subjects with schizophrenia and controls. Association with waist circumference may support homocysteine role as an important cardiovascular risk factor. Association with lean weight may explain why men have higher levels of homocysteine than women.

Patients receiving clozapine must undergo routine blood monitoring to screen for neutropenia, and to monitor for potential agranulocytosis. In Cork University Hospital, Cork, Ireland, clozapine is dispensed in the hospital pharmacy and the pharmacists are not aware of co-prescribed medicines, potentially impacting upon patient safety. The aim of this study was to examine the continuity of care of patients prescribed clozapine. A retrospective audit was conducted on patients attending the clozapine clinic at Cork University Hospital and assessed patients' (i) independent living, (ii) co-prescribed medicines and (iii) knowledge of their community pharmacists regarding co-prescribed clozapine. A list of prescribed medicines for each patient was obtained, and potential drug-drug interactions between these medicines and clozapine were examined using Lexicomp® and Stockley's Interaction checker. Secondary outcomes included patients' physical health characteristics, and a review of co-morbidities. Data were collected between the 29 May 2017 and 20 June 2017. Local ethics committee approval was granted. Patients were eligible for inclusion if they were receiving clozapine treatment as part of a registered programme, were aged 18 years or more, and had the capacity to provide written informed consent. Microsoft Excel was used for data analysis. Of 112 patients, (33% female; mean age (SD) 43.9 (11.3) years; 87.5% living independently/in the family home) 86.6% patients reported that they were taking other prescribed medicines from community pharmacies. The mean (SD) number of co-prescribed medicines in addition to clozapine was 4.8 (4) per patient. Two thirds of community pharmacists were unaware of co-prescribed clozapine. Interactions with clozapine were present in all but 3 patients on co-prescribed medicines (n = 97). Lexicomp® reported 2.9 drug-drug interactions/patient and Stockley's Interaction Checker reported 2.5 drug-drug interactions/patient. Secondary outcomes for patients included BMI, total cholesterol, and HbA1c levels, which were elevated in 75%, 54% and 17% respectively. Patients prescribed clozapine did not receive a seamless service, between primary and secondary care settings. Community pharmacists were not informed of clozapine, prescribed for their patients, in two thirds of cases. Patients in this study were exposed to clozapine-related drug-drug interactions and hence potential adverse effects. This study supports reports in the literature of substandard management of the physical health of this patient group. This study shows that there is an opportunity for pharmacists to develop active roles in the management of all clozapine-related effects, in addition to their traditional obligatory role in haematological monitoring. This study supports the need for a clinical pharmacist to review inpatients commencing on clozapine, monitor for drug-drug interactions and provide counselling.

Aims and methodTo systematically review the literature on barriers to the use of clozapine and identify any interventions for optimizing clozapine use in treatment-resistant schizophrenia. Journal databases were searched from 1972 to March 2018. The following search terms were used: treatment-resistant schizophrenia, clozapine, barriers, use, prescription rates, implementation, clozaril and prescribing practices. Following a review of the literature, 15 papers were included in the review. RESULTS: The major barriers that were identified included mandatory blood testing, fear of serious side-effects and lack of adherence by the patients, difficulty in identifying suitable patients, service fragmentation, and inadequate training in or exposure to using clozapine.Clinical implicationsIn view of consistent evidence across the studies on inadequate knowledge and skills as a significant barrier, we suggest that a certification requiring competence in initiating and managing side-effects of clozapine becomes a mandatory requirement in training programmes.Declarations of interestNone.

The low efficacy of antipsychotic drugs (e.g., clozapine) for negative symptoms and cognitive impairment has led to the introduction of adjuvant therapies. Because previous data suggest the procognitive potential of the antidiabetic drug metformin, this study aimed to assess the effects of chronic clozapine and metformin oral administration (alone and in combination) on locomotor and exploratory activities and cognitive function in a reward-based test in control and a schizophrenia-like animal model (Wisket rats). As impaired dopamine D1 receptor (D1R) function might play a role in the cognitive dysfunctions observed in patients with schizophrenia, the second goal of this study was to determine the brain-region-specific D1R-mediated signaling, ligand binding, and mRNA expression. None of the treatments affected the behavior of the control animals significantly; however, the combination treatment enhanced D1R binding and activation in the cerebral cortex. The Wisket rats exhibited impaired motivation, attention, and cognitive function, as well as a lower level of cortical D1R binding, signaling, and gene expression. Clozapine caused further deterioration of the behavioral parameters, without a significant effect on the D1R system. Metformin blunted the clozapine-induced impairments, and, similarly to that observed in the control animals, increased the functional activity of D1R. This study highlights the beneficial effects of metformin (at the behavioral and cellular levels) in blunting clozapine-induced adverse effects.

This systematic review aimed to review neuroimaging studies comparing clozapine-resistant schizophrenia patients with clozapine-responding patients, and with first-line antipsychotic responding (FLR) patients. A total of 19 studies including 6 longitudinal studies were identified. Imaging techniques comprised computerized tomography (CT, n = 3), structural magnetic resonance imaging (MRI, n = 7), magnetic resonance spectroscopy (MRS, n = 5), functional MRI (n = 1), single-photon emission computerized tomography (SPECT, n = 3) and diffusion tensor imaging (DTI, n = 1). The most consistent finding was hypo-frontality in the clozapine-resistant group compared with the clozapine-responding group with possible differences in frontal-striatal-basal ganglia circuitry as well as the GABA level between the two treatment-resistant groups. Additional statistically significant findings were reported when comparing clozapine-resistant patients with the FLR group, including lower cortical thickness and brain volume of multiple brain regions as well as lower Glx/Cr level in the dorsolateral prefrontal cortex. Both treatment-resistant groups were found to have extensive differences in neurobiological features in comparison with the FLR group. Overall results suggested treatment-resistant schizophrenia is likely to be a neurobiological distinct type of the illness. Clozapine-resistant and clozapine-responding schizophrenia are likely to have both shared and distinct neurobiological features. However, conclusions from existing studies are limited, and future multi-center collaborative studies are required with a consensus clinical definition of patient samples, multimodal imaging tools, and longitudinal study designs.

Clozapine, an atypical antipsychotic medication, has been effectively used to treat refractory schizophrenia. However, the clinical usage of clozapine is limited due to a high incidence of neutropenia or agranulocytosis. We previously reported that clozapine protected dopaminergic neurons through inhibition of microglial activation. The purpose of this study was to explore the neuroprotective effects of clozapine metabolites clozapine N-oxide (CNO) and N-desmethylclozapine (NDC), as well as their propensity to cause neutropenia.

Clozapine is the most effective antipsychotic drug for schizophrenia, yet it can cause life-threatening adverse drug reactions, including myocarditis. The aim of this study was to determine whether schizophrenia patients with clozapine-induced myocarditis have a genetic predisposition compared with clozapine-tolerant controls. We measured different types of genetic variation, including genome-wide single-nucleotide polymorphisms (SNPs), coding variants that alter protein expression, and variable forms of human leucocyte antigen (HLA) genes, alongside traditional clinical risk factors in 42 cases and 67 controls. We calculated a polygenic risk score (PRS) based on variation at 96 different genetic sites, to estimate the genetic liability to clozapine-induced myocarditis. Our genome-wide association analysis identified four SNPs suggestive of increased myocarditis risk (P < 1 × 10-6), with odds ratios ranging 5.5-13.7. The SNP with the lowest P value was rs74675399 (chr19p13.3, P = 1.21 × 10-7; OR = 6.36), located in the GNA15 gene, previously associated with heart failure. The HLA-C*07:01 allele was identified as potentially predisposing to clozapine-induced myocarditis (OR = 2.89, 95% CI: 1.11-7.53), consistent with a previous report of association of the same allele with clozapine-induced agranulocytosis. Another seven HLA alleles, including HLA-B*07:02 (OR = 0.25, 95% CI: 0.05-1.2) were found to be putatively protective. Long-read DNA sequencing provided increased resolution of HLA typing and validated the HLA associations. The PRS explained 66% of liability (P value = 9.7 × 10-5). Combining clinical and genetic factors together increased the proportion of variability accounted for (r2 0.73, P = 9.8 × 10-9). However, due to the limited sample size, individual genetic associations were not statistically significant after correction for multiple testing. We report novel candidate genetic associations with clozapine-induced myocarditis, which may have potential clinical utility, but larger cohorts are required for replication.

Clozapine has superior efficacy in the treatment of refractory schizophrenia; however, use of clozapine is limited due to severe side effects, including myocarditis. Using non-integrative Sendai virus, we generated induced pluripotent stem cell lines from peripheral blood mononuclear cells of two patients with refractory schizophrenia, one clozapine-tolerant and one clozapine-induced myocarditis. Both cell lines exhibited a normal karyotype and pluripotency was validated by flow cytometry, immunofluorescence and their ability to differentiate into the three germ layers. These lines can be used to generate 2D and 3D patient-specific human cellular models to identify the mechanism by which clozapine induces myocardial inflammation.

Withdrawal symptoms are common upon discontinuation of psychiatric medications. Catatonia, a neuropsychiatric condition proposed to be associated with gamma-aminobutyric acid (GABA) hypoactivity due to its robust response to benzodiazepines, has been described as a withdrawal syndrome in case reports but is not a well-recognized phenomenon. The authors undertook a review of withdrawal catatonia with an aim to understand its presentation as well as the medications and psychoactive substances it is associated with. The review identified 55 cases of withdrawal catatonia, the majority of which occurred upon discontinuation of benzodiazepines (24 cases) and discontinuation of clozapine (20 cases). No other antipsychotic medications were identified as having been associated with the onset of a catatonic episode within 2 weeks following their discontinuation. Increasing GABA activity and resultant GABA receptor adaptations with prolonged use is postulated as a shared pharmacological mechanism between clozapine and benzodiazepines that underlie their association with withdrawal catatonia. The existing evidence for clozapine's activity on the GABA system is reviewed. The clinical presentations of benzodiazepine withdrawal catatonia and clozapine withdrawal catatonia appear to differ and reasons for this are explored. One reason is that benzodiazepines act directly on GABAA receptors as allosteric agonists, while clozapine has more complex and indirect interactions, primarily through effects on receptors located on GABA interneurons. Another possible reason for the difference in clinical presentation is that clozapine withdrawal catatonia may also involve receptor adaptations in non-GABA receptors such as dopamine and acetylcholine. The findings from our review have implications for the treatment of withdrawal catatonia, and treatment recommendations are provided. Further research understanding the uniqueness of clozapine withdrawal catatonia among antipsychotic medication may give some insight as to clozapine's differential mechanism of action.

The aim of this study was to investigate the effect of clozapine use on bone tissue by applying computerized tomography, dual-energy X-ray absorptiometry, and histological and biomechanical analyses in an experimental rat model.

The atypical antipsychotic clozapine has shown superior efficacy compared with other antipsychotics and is the gold standard for treating otherwise treatment resistant schizophrenia. However, multiple studies have found that clozapine is underutilised in most parts of the world. A few reviews of literature addressing barriers to clozapine prescribing have been conducted. While there is some variation in the literature included in these reviews, a common feature of the studies included is that they primarily focus on clinical staff's attitudes and perceived barriers for prescribing. Studies of patient perspectives are only sparsely included. A preliminary literature search revealed though, that additional literature on the subject exists, including literature on patient perspectives. It is therefore difficult to conclude if the formerly synthesised literature is representative of current evidence or if the topic has been adequately investigated to inform clinical practice. A scoping review is warranted in order to map and synthesise primary literature on patients' and psychiatrists' perspectives on clozapine treatment, and to identify gaps for future research.

Positron emission tomography (PET) and selective radioligands were used to determine central D1- and D2-dopamine- and 5-HT2-receptor occupancy in clozapine-treated patients with schizophrenia. In 16 patients, the mean D2-receptor occupancy was 47% (range, 20%-67%), which is lower than that previously demonstrated in patients treated with classical neuroleptics (range, 70%-89%). In 11 patients, the mean D1-receptor occupancy was 44% (range, 33%-59%), which is high when compared with that for classical neuroleptics. In a group of 5 patients, including some treated with low doses of clozapine, the mean 5-HT2-receptor occupancy was a high 89% (range, 84%-94%). By comparison to classical neuroleptics, clozapine is atypical with regard to central binding characteristics in the brain of treated patients.

Many studies have been reported the efficacy of intravenous lipid emulsion (ILE) as an antidote on acute lipophilic drug toxicity. Clozapine, highly lipophilic dibenzodiazepine neuroleptics, is an important medication in the schizophrenia therapy regimen. Acute intoxication with antipsychotics is one of the main reasons for the referral of poisoned patients to the hospital. We expected that ILE could be used for the therapy of acute clozapine intoxicated patients.

The striatal dopamine D2 receptor (D2R) is generally accepted to be involved in positive symptoms of schizophrenia and is a main target for clinically used antipsychotics. D2R are highly expressed in the striatum, where they form heteromers with the adenosine A2A receptor (A2AR). Changes in the density of A2AR-D2R heteromers have been reported in postmortem tissue from patients with schizophrenia, but the degree to which A2R are involved in schizophrenia and the effect of antipsychotic drugs is unknown. Here, we examine the effect of exposure to three prototypical antipsychotic drugs on A2AR-D2R heteromerization in mammalian cells using a NanoBiT assay. After 16 h of exposure, a significant increase in the density of A2AR-D2R heteromers was found with haloperidol and aripiprazole, but not with clozapine. On the other hand, clozapine, but not haloperidol or aripiprazole, was associated with a significant decrease in A2AR-D2R heteromerization after 2 h of treatment. Computational binding models of these compounds revealed distinctive molecular signatures that explain their different influence on heteromerization. The bulky tricyclic moiety of clozapine displaces TM 5 of D2R, inducing a clash with A2AR, while the extended binding mode of haloperidol and aripiprazole stabilizes a specific conformation of the second extracellular loop of D2R that enhances the interaction with A2AR. It is proposed that an increase in A2AR-D2R heteromerization is involved in the extrapyramidal side effects (EPS) of antipsychotics and that the specific clozapine-mediated destabilization of A2AR-D2R heteromerization can explain its low EPS liability.

Clozapine, an antipsychotic with unique efficacy in treatment-resistant psychosis, is associated with increased susceptibility to infection, including pneumonia.