Although clozapine is the most effective antipsychotic for people with treatment-resistant schizophrenia (TRS), only 40% of people with TRS respond, and there is limited evidence for augmentation agents. Cannabidiol (CBD) reduces positive symptoms in individuals with schizophrenia, but no trials have specifically examined its efficacy in those with clozapine-resistant schizophrenia.

To examine the clinical efficacy of CBD augmentation in people with clozapine-resistant schizophrenia.

This is a 12-week randomised, placebo-controlled, double-blind, parallel-group trial (registration number: ACTRN12622001112752). We will recruit 88 individuals with clozapine-resistant schizophrenia, randomised (1:1) to 1000 mg daily CBD versus placebo. Eligible individuals will be aged between 18 and 64 years, fulfil DSM-IV criteria for schizophrenia or schizoaffective disorder, have a total PANSS (Positive and Negative Syndrome Scale) score ≥60, have received oral clozapine for at least 18 weeks and have a clozapine level of >350 ng/mL. Interim analyses will be conducted at 25, 50 and 75% recruitment; these will also provide an opportunity to reallocate participants dependent on conditional power. The primary endpoint will be the difference in PANSS positive scores at the end of week 12. Secondary endpoints include depression, anxiety, sleep, quality of life, alcohol consumption, change in weight and metabolic syndrome components, and neurocognitive measures, as well as safety and tolerability.

Novel treatments for clozapine-resistant schizophrenia are urgently needed. If found to be effective, CBD may have a role as a novel and safe adjunct to clozapine.

Despite proven effectiveness in refractory schizophrenia, clozapine remains underutilised, and it is important to understand potential reasons for this. This study’s aim was to examine in a National sample of Consultant Psychiatrists their knowledge of, attitudes and perceived barriers to clozapine use.

A novel questionnaire was designed and distributed by email to 275 Consultant Psychiatrists in Republic of Ireland.

Twenty-eight percent (n = 77) completed the survey, with 55% of respondents practicing for 15 or more years. Clinicians expressed confidence in managing clozapine treatment and side effects and were well aware of clozapine’s clinical effectiveness and guideline-based use. A majority indicated insufficient experience managing rechallenge and half expressed insufficient experience managing adverse events. Perceived patient factors were highlighted as barriers with 69% of respondents reporting patients’ concern about effectiveness and 50% regarding tolerability. Sixty-four percent (n = 40) indicated that a specialised/tertiary clozapine service would facilitate initiation, with 57% (n = 36) reporting less frequent blood monitoring would aid clozapine prescribing. A majority identified that access to dedicated staff (81%, n = 51) and dedicated day hospital services (84%, n = 53) would facilitate community initiation.

Consultants are familiar with clozapine use and related guidelines. Dedicated staff and facilities for clozapine use is one identified structural change to enhance clozapine prescribing in Ireland. Tertiary service or clinical advice service would assist in clozapine rechallenge cases or in managing significant adverse events. More structured patient education regarding clozapine effectiveness and professional development programmes focused on managing side effects and rechallenge may promote clozapine use.

A significant proportion of people with clozapine-treated schizophrenia develop ‘checking’ compulsions, a phenomenon yet to be understood.

To use habit formation models developed in cognitive neuroscience to investigate the dynamic interplay between psychosis, clozapine dose and obsessive–compulsive symptoms (OCS).

Using the anonymised electronic records of a cohort of clozapine-treated patients, including longitudinal assessments of OCS and psychosis, we performed longitudinal multi-level mediation and multi-level moderation analyses to explore associations of psychosis with obsessiveness and excessive checking. Classic bivariate correlation tests were used to assess clozapine load and checking compulsions. The influence of specific genetic variants was tested in a subsample.

A total of 196 clozapine-treated individuals and 459 face-to-face assessments were included. We found significant OCS to be common (37.9%), with checking being the most prevalent symptom. In mediation models, psychosis severity mediated checking behaviour indirectly by inducing obsessions (r = 0.07, 95% CI 0.04–0.09; P < 0.001). No direct effect of psychosis on checking was identified (r = −0.28, 95% CI −0.09 to 0.03; P = 0.340). After psychosis remission (n = 65), checking compulsions correlated with both clozapine plasma levels (r = 0.35; P = 0.004) and dose (r = 0.38; P = 0.002). None of the glutamatergic and serotonergic genetic variants were found to moderate the effect of psychosis on obsession and compulsion (SLC6A4, SLC1A1 and HTR2C) survived the multiple comparisons correction.

We elucidated different phases of the complex interplay of psychosis and compulsions, which may inform clinicians’ therapeutic decisions.

Sialorrhea is a common and uncomfortable adverse effect of clozapine, and its severity varies between patients. The aim of the study was to select broadly genes related to the regulation of salivation and study associations between sialorrhea and dry mouth and polymorphisms in the selected genes.

The study population consists of 237 clozapine-treated patients, of which 172 were genotyped. Associations between sialorrhea and dry mouth with age, sex, BMI, smoking, clozapine dose, clozapine and norclozapine serum levels, and other comedication were studied. Genetic associations were analyzed with linear and logistic regression models explaining sialorrhea and dry mouth with each SNP added separately to the model as coefficients.

Clozapine dose, clozapine or norclozapine concentration and their ratio were not associated with sialorrhea or dryness of mouth. Valproate use (p = 0.013) and use of other antipsychotics (p = 0.015) combined with clozapine were associated with excessive salivation. No associations were found between studied polymorphisms and sialorrhea. In analyses explaining dry mouth with logistic regression with age and sex as coefficients, two proxy-SNPs were associated with dry mouth: epidermal growth factor receptor 4 (ERBB4) rs3942465 (adjusted p = 0.025) and tachykinin receptor 1 (TACR1) rs58933792 (adjusted p = 0.029).

Use of valproate or antipsychotic polypharmacy may increase the risk of sialorrhea. Genetic variations in ERBB4 and TACR1 might contribute to experienced dryness of mouth among patients treated with clozapine.

Despite recommendations to initiate clozapine after two unsuccessful trials of antipsychotics, clozapine is underprescribed and initiated too late. The aim of this study was to describe different antipsychotic treatment sequences in the 36 months before the initiation of clozapine and to characterize clusters of treatment trajectories.

Using the French National Health Insurance database, a historical cohort study of the population in an area in western France was performed. The data from all new users of clozapine with a diagnosis of schizophrenia or schizoaffective disorder in the period of 2017–2018 were evaluated. All outpatient reimbursements for antipsychotics during the 36 months before clozapine initiation were analysed. Successive reimbursements for identical treatments were grouped into treatment trials (TTs), and different trajectories were clustered using a state sequence analysis.

The results showed 1191 TTs for 287 individuals. The mean number of TTs per individual was 3.2. Risperidone, aripiprazole and haloperidol were the main treatments delivered. The frequencies of antipsychotics used differed between monotherapies and combination therapies. A three-cluster typology was identified: one cluster (n = 133) of ‘less treated’ younger individuals with fewer TTs and shorter TT durations; a second cluster (n = 53) of ‘more treated’ individuals with higher numbers of TTs and combinations of antipsychotics; and a third cluster (n = 103) of ‘treatment-stable’ older individuals with longer TT durations.

The results indicate that the median number of TTs during the 36 months before clozapine prescription was higher than the two recommended. The different trajectories were associated with individual characteristics and treatment differences, suggesting that additional studies of clinical parameters are needed to understand barriers to clozapine prescription.

To minimise infection during COVID-19, the clozapine haematological monitoring interval was extended from 4-weekly to 12-weekly intervals in South London and Maudsley NHS Foundation Trust.

To investigate the impact of this temporary policy change on clinical and safety outcomes.

All patients who received clozapine treatment with extended (12-weekly) monitoring in a large London National Health Service trust were included in a 1-year mirror-image study. A comparison group was selected with standard monitoring. The proportion of participants with mild to severe neutropenia and the proportion of participants attending the emergency department for clozapine-induced severe neutropenia treatment during the follow-up period were compared. Psychiatric hospital admission rates, clozapine dose and concomitant psychotropic medication in the 1 year before and the 1 year after extended monitoring were compared. All-cause clozapine discontinuation at 1-year follow-up was examined.

Of 569 participants, 459 received clozapine with extended monitoring and 110 controls continued as normal. The total person-years were 458 in the intervention group and 109 in the control group, with a median follow-up time of 1 year in both groups. During follow-up, two participants (0.4%) recorded mild to moderate neutropenia in the intervention group and one (0.9%) in the control group. There was no difference in the incidence of haematological events between the two groups (IRR = 0.48, 95% CI 0.02–28.15, P = 0.29). All neutropenia cases in the intervention group were mild, co-occurring during COVID-19 infection. The median number of admissions per patient during the pre-mirror period remained unchanged (0, IQR = 0) during the post-mirror period. There was one death in the control group, secondary to COVID-19 infection.

There was no evidence that the incidence of severe neutropenia was increased in those receiving extended monitoring.

Although clozapine is the most efficacious medication for treatment-refractory schizophrenia, not all patients will have an adequate response. Optimising clozapine dose using therapeutic drug monitoring could therefore maximise response.

Using individual patient data, we undertook a receiver operating characteristic (ROC) curve analysis to determine an optimal therapeutic range for clozapine levels to guide clinical practice.

We conducted a systematic review of PubMed, PsycINFO and Embase for studies that provided individual participant level data on clozapine levels and response. These data were analysed using ROC curves to determine the prediction performance of plasma clozapine levels for treatment response.

We included data on 294 individual participants from nine studies. ROC analysis yielded an area under the curve of 0.612. The clozapine level at the point of optimal diagnostic benefit was 372 ng/mL; at this level, the response sensitivity was 57.3%, and specificity 65.7%. The interquartile range for treatment response was 223–558 ng/mL. There was no improvement in ROC performance with mixed models including patient gender, age or length of trial. Clozapine dose and clozapine concentration to dose ratio did not provide significantly meaningful prediction of response to clozapine.

Clozapine dose should be optimised based on clozapine therapeutic levels. We found that a range between 250 and 550 ng/mL could be recommended, while noting that a level of >350 ng/mL is the most optimal for response. Although some patients may not respond without clozapine levels >550 ng/mL, the benefits should be weighed against the increased risk of adverse drug reactions.

Hypersalivation is a major side-effect of clozapine in patients with treatment-resistant schizophrenia.

We investigated the efficacy of topical anticholinergic formulation sofpironium bromide gel for improving hypersalivation in patients with treatment-resistant schizophrenia receiving clozapine.

A double-blind, controlled crossover study was conducted with sofpironium bromide gel and a placebo gel to treat clozapine-induced hypersalivation in 16 patients with treatment-resistant schizophrenia. Patients were randomly divided between groups A and B (each n = 8). Group A was treated with sofpironium bromide gel for 6 weeks, followed by a 2-week washout period and 6 weeks of placebo gel, after which they were observed for another 2 weeks. In contrast, group B was treated with placebo gel for 6 weeks, followed by a 2-week washout period, 6 weeks of sofpironium bromide gel and a 2-week observation period. One-minute saliva volume, objective salivation ratings (Drooling Severity and Frequency Scale and Nocturnal Hypersalivation Rating Scale) and subjective salivation ratings (Visual Analogue Scale) were assessed every 2 weeks.

All patients completed the trials. Three patients reported mild, spontaneously resolved skin itching. Compared with baseline values, the 1-min saliva volumes of both groups were significantly decreased by approximately 30% at the second week of sofpironium bromide gel treatment (P < 0.001), and significantly decreased by >40% at the fourth and sixth weeks of treatment (P < 0.001). The effects were maintained for over 2 weeks even after the treatment was discontinued.

We suggest that sofpironium bromide gel is effective in treating clozapine-induced hypersalivation in patients with treatment-resistant schizophrenia.

Several augmentation strategies have been used to improve symptomatology in patients not adequately responding to clozapine. Several randomised controlled trials (RCTs) have evaluated the efficacy of different strategies to augment clozapine. This systematic review and meta-analysis reviewed the available RCTs that have evaluated the clinical efficacy of various pharmacological agents, non-pharmacological strategies (occupational therapy, cognitive behaviour therapy), and somatic treatment [electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation, etc.)] as augmenting agents to clozapine.

Data were extracted using standard procedures, and risk of bias was evaluated. Effect sizes were computed for the individual studies.

Forty-five clinical trials were evaluated. The pooled effect size for various antipsychotic medications was 0.103 (95% CI: 0.288–0.493, p < 0.001); when the effect size was evaluated for specific antipsychotics for which more than one trial was available, the effect size for risperidone was −0.27 and that for aripiprazole was 0.57. The effect size for lamotrigine was 0.145, and that for topiramate was 0.392. The effect size for ECT was 0.743 (CI: 0.094–1.392). Risk of bias was low (mean Jadad score – 3.93). Largest effect sizes were seen for mirtazapine (effect size of 5.265). Most of the studies can be considered underpowered and limited by small sample sizes.

To conclude, based on the findings of the present systematic review and meta-analysis, it can be said that compared to other treatment strategies, clozapine non-responsive patients respond maximum to mirtazapine followed by ECT.

Clozapine is commonly associated with hematological side effects. However, little research is available on the impact of adding other psychotropic medication on inducing blood dyscrasias.

The aim of the study was to explore the impact of associating psychotropic medication to clozapine in producing hematological abnormalities.

Our study was a longitudinal, retrospective chart review of adult psychiatric patients receiving clozapine treatment at our clozapine consultation between January 2000 and September 2020.

Our sample consisted of 15 women (23.5%) and 49 men (76.5%), mean age was 41.34 ±9.32 years. Polypharmacy was found in 70.3% of the cases. Association of clozapine to other psychotropic agents was found in 67.2% of the cases. Most prescribed add-on medication was valproic acid in 27 cases, benzodiazepines in 21 cases, promethazine and hydroxyzine in 16 cases, lithium in 8 cases and haloperidol in 6 cases. We found blood dyscrasias in 21 patients (32.8%). Hematological abnormalities were as follow: 2 cases of agranulocytosis, 8 cases of neutropenia, 13 cases of thrombocytopenia, 5 cases of leukocytosis, 5 cases of eosinophilia and 3 cases of anemia. In our sample we did not find a significant association between psychotropic polypharmacy and blood dyscrasias.

Many psychiatric patients on clozapine require polypharmacy to better stabilize their condition. Such co prescriptions may carry the risk of inducing more side effects especially blood dyscrasias. In our study, we did not find a significant association between psychotropic medication added to clozapine and hematological abnormalities. But further research is warranted to better explore this association.

No significant relationships.

Clozapine is highly effective in patients with treatment-resistant schizophrenia but, to ensure optimal clinical response it is important to optimize its use and this depends on adequate pharmacological monitoring.

Evaluate the therapeutic response rate according to clozapine plasma concentration.

It was a cross-sectional, retrospective and analytical study, carried out over a period of six months, in the F and A psychiatry departments of the Razi hospital in Tunis, including patients followed for treatment-resistant schizophrenia and receiving clozapine. We evaluated the response to clozapine using the Brief Psychiatric Rating Scale (BPRS).

The average age was 37.7 ± 9.4. The mean age of introduction of clozapine was 31 years and the mean time to its introduction was 9.3 years. Clozapine was administered as a single drug in 85% of cases. The mean dose of clozapine was 373 mg/day. The mean of clozapine plasma concentration was 386.5 ng/ml with a minimum of 89 ng/ml and a maximum of 913 ng/ml. The clinical response rate to clozapine was 25% with a BPRS good response threshold value of less than 35. Patients with clozapine levels above the conventional cut-off of 350 ng/ml (n=34) had a response rate of 34.6%. A response rate of 37% was observed in the group of patients with a clozapine plasma concentration interval of 200-350 ng/ml. There was no statistically significant difference in therapeutic response (p=0186)

Our study revealed a therapeutic response variation according to plasma clozapine concentration and showed the existence of a non-negligible and effective response rate.

No significant relationships.

Clozapine is a drug that can cause several side effects. Among the less commonly described is a drug-induced lung disease. Due to its non-specific clinical presentation, it represents a diagnostic challenge. The diagnosis is made based on: 1. Association of exposure to the agent and development of symptoms, 2. Pulmonary infiltration, 3. Exclusion of other causes, 4. Withdrawal of symptoms when the agent is excluded from therapy. To date, there have been only a few descriptions of this condition.

Case report of rare side effect of clozapine.

Case report

Case report: male patient (37) with schizophrenia, was hospitalized after a brutal suicide attempt. The PCR test for COVID-19 that was routinely performed on admission was negative. After the introduction of clozapine into therapy, the patient became febrile. There was a drop in oxygen saturation, a Lung CT scan showed inflammatory changes („ground-glass opacities“), and COVID-19 pneumonia was suspected. Due to the worsening of the mental state, the dose of clozapine was increased. The physical condition further deteriorated: febrile, sO2 declining. After repeated PCR tests for COVID-19 (all negative), interstitial pneumonia caused by clozapine was suspected, and clozapine was excluded from therapy. The physical condition started to improve. Quetiapine was introduced, and occasional episodes of agitation were relieved with intramuscular diazepam. In the following days, the patient’s mental state improved and he was discharged.

Despite its superiority over other antipsychotics, clozapine was with good rationale ranked third in treatment guidelines for schizophrenia.

No significant relationships.

Clozapine is widely known as the drug of choice in treating refractory schizophrenia. However, clozapine prescription requires close clinical and biological monitoring to prevent harmful side effects like agranulocytosis, neutropenia and myocarditis.

To show the benefits of lithium carbonate in the clozapine rechallenge of a patient with neutropenia under clozapine.

We present the clinical case of a patient who developed neutropenia under clozapine, we rechallenged with clozapine after lithium treatment to stimulate hematopoietic functions.

A 42-year-old man diagnosed with refractory schizophrenia, under clozapine for 11 years with a good clinical response at a dosage of 500mg per day (clozapine serum level 328ng/ml), developed a neutropenia (BCC at 840/mm3) within an interval of 2 months. Clozapine treatment was suspended and the patient presented a severe psychotic relapse requiring hospitalization. During hospitalization the patient remained symptomatic under haloperidol 15mg daily. At week 3 of clozapine cessation, neutrophil count reached 1510/mm3. After week 4 we introduced lithium carbonate and while reaching 500mg per day we observed an increase in the neutrophil count to 4850/mm3. We rechallenged with clozapine at week 12 after a poor clinical response, with incremental dosage to 150mg per day in 17 weeks. The blood cell count did not show any abnormalities and the patient had a good clinical response up to 11 months after the clozapine rechallenge.

Despite the lack of guidelines assessing clozapine rechallenge after neutropenia, the use of lithium carbonate may be considered to stimulate hematopoietic functions.

No significant relationships.

The response to antipsychotic treatment in patients with schizophrenia varies from 14 to 34% in first episodes, and from 45 to 61% in more chronic patients. Nevertheless, the concept of treatment resistant schizophrenia (TRS) is still a matter of great controversy. Recently, an international group of experts has developed the TRRIP criteria to define treatment resistant schizophrenia (TRS), including an ultra-resistance category for clozapine resistant patients. Up till now, there is a scarcity of epidemiological data of TRS with TRRIP criteria.

This study attempts to identify the population diagnosed of schizophrenia that fulfils the minima TRRIP criteria for TRS in our mental health catchment area.

A descriptive and retrospective study has been developed on the patients diagnosed of schizophrenia (ICD.10, F.20) in the catchment area of the Mental Health Service at Jerez Hospital between 2018 and 2019. TRRIP criteria were applied for two independent researchers and, in case of disagreement, consensus was reached by using the LEAD procedure.

The total number of ICD-10 schizophrenic patients identified was 590, from a population of 456.752 in 2019. A group of these, 206 patients (35%) qualified as TRS according to the minima TRRIP criteria, 50% were positive subtype and the rest the negative one. 46.8% were treated with clozapine.

Consensus criteria of TRS minimise the heterogeneity of epidemiological data in literature. Our data suggest a prevalence rate of TRS lower than that of similar studies. Accordingly, a comprehensive understanding of this population would undoubtedly contribute to improve preventive and therapeutic strategies.

No significant relationships.

Clozapine, a unique antipsychotics, is well known for its adverse effects. Myocarditis is a rare but life-threatening complication, however not monitored at a global scale.

This work aims to review the literature on clozapine-induced myocarditis.

Pubmed and Google Scholar search using Mesh terms clozapine, myocarditis, clozapine-induced myocarditis.

Clozapine-induced Myocarditis (CIM) is potentially fatal, with mortality rates environ 21%. According to the World Health Organization Monitoring Program, notification rate is 0,93%, nonetheless incidence found in literature varies dramatically. Highest rates are reported in Australia, where this relationship was first established and a complete monitoring protocol is compulsory in all patients starting clozapine, which causes some authors to defend this condition is generally undernotified. Underlying mechanisms are not fully understood, but an imunomediated hypersensitive reaction occurring in the first 3-4 weeks after treatment is suggested. CIM is rare after 6 weeks. Risk factors include age, cardiac disease, initial high dose, rapid titration and simultaneous valproate or other antipsychotics use. The most common symptoms, fever, tachycardia, dyspnea and malaise, are non-specific and can be indistinguishable from other clozapine benign adverse effects. Analytically, C-reactive protein and Troponine elevation are the most specific diagnostic markers, therefore the most suitable for monitoring. Prompt cardiological observation for further evaluation should be seeked whenever CIM is suspected.

Diagnosis of CIM can be challenging. Systematic monitoring is not consensual but may increase detection, prevent severe outcomes and help clinicians decide whether to keep or suspend therapy. Clozapine is beneficial and shouldn’t be avoided or unjustifiably discontinued.

No significant relationships.