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Objective: Clozapine is used in the management of treatment-resistant schizophrenia and is effective in reducing aggression; however a subgroup of patients is poorly responsive. For violent patients in this group, there is limited literature on the use of strategies to augment clozapine with other agents. Here we present a case series of 6 schizophrenia patients, within a high-security hospital, who have a history of serious violence and who were treated with clozapine augmented with amisulpride., Methods: We reviewed case notes and health records for evidence of violence/aggression and positive factors such as engagement in activities, and Clinical Global Impression (CGI) scores were formulated. We also examined metabolic parameters before and after augmentation., Results: All 6 of the patients showed clinical improvement in symptoms and a reduction in their risk of violence to others. Five patients had a reduction in number of violent/aggressive incidents, and all patients showed improvement in engagement in occupational, vocational, and/or psychological work. Metabolic parameters were largely unchanged except for 1 patient whose Body Mass Index (BMI) increased. Five patients reported side effects as unchanged or improved., Conclusion: These schizophrenia patients with a history of violence showed clinical improvement and reduced aggression and violence with amisulpride augmentation of clozapine. To our knowledge, this is the first report of an antiaggressive benefit of this combination in forensic psychiatric patients. Further studies are warranted to establish the efficacy and anti-aggressive effects of amisulpride augmentation of clozapine.

Introduction: Clozapine is an atypical antipsychotic approved for treatment-resistant schizophrenia. Although effective, possible side effects make its underutilization still a current problem. The type of titration and dosages used differ worldwide. Objectives: To asses doses of clozapine and concomitant medications used in schizophrenia during 2012-2013 versus 2022-2023. Methods: A retrospective observational study analysing clozapine doses and concomitant treatment used in schizophrenia from 2012-2013 compared to 2022-2023. Data were collected from the medical charts of patients admitted to the Clinical Hospital of Psychiatry and Neurology Brasov, Romania, during 2012-2013 and 2022-2023. Results: In the total of 570 patients who were admitted in 2012-2013 with a diagnosis of paranoid schizophrenia, 69 (12,10%) of them were treated with clozapine.Of the 69 cases, 53,62% patients were females, mean age was 40,95 years (SD = ±10,32), with an average of onset age 23,17 (SD=±6,21). The average length of stay for hospitalization was 24,97 days (SD= ±12,65). The mean clozapine dose was 393,47 ((SD= ±183,69), with a minimum dose of 100mg/day and a maximum dose of 800mg/day. 37,68% of patients received concomitant treatment with benzodiazepines, mood stabilisers or sedative-hypnotic drugs. None of the patients received concomitant treatment with another antipsychotic.Among the total of 356 patients admitted with the diagnosis of paranoid schizophrenia during the 2022-2023 period, 72 (20,22%) of the patients were treated with clozapine. 72,22% patients were females, mean age was 49,12 years (SD = ±11,16), with an average of onset age 25,04 (SD=±6,40). The average length of stay for hospitalization was 18,58 days (SD= ±13,78). The mean clozapine dose was 275,34 (SD= ±146,7), with a minimum dose of 25mg/day and a maximum dose of 600mg/day. 72,22% of patients received concomitant treatment with benzodiazepines, mood stabilisers, sedative-hypnotic drugs or with another antipsychotic. Antipsychotics used in combination with clozapine were both oral (risperidone, amisulpride, quetiapine, aripiprazole) and long-acting injectable (aripiprazole, risperidone, paliperidone, flupentixol decanoate). Conclusions: Clozapine remains the drug of choice in treatment-resistant schizophrenia even after 10 years, but its mode of administration has changed over time. While the doses of clozapine used have decreased, the percentage of patients receiving concomitant treatment has doubled.Although some side effects of clozapine are dose-dependent, lowering doses and combining with other adjuvant treatment is not always a better option, as polypragmacy and possible adverse effects combined can lead to reduced adherence.The decision to increase the dose of clozapine or to use concomitant (combination) treatment depends on individual factors, including the patient's clinical condition, response to treatment, and the assessment of potential risks and benefits. Disclosure of Interest: None Declared [ABSTRACT FROM AUTHOR]

Aims: Clozapine is licensed for treatment-resistant psychosis and remains underutilised. This may berelated to the stringent haematological monitoring requirements that are mandatory in most countries. We aimed to compare guidelines internationally and develop a novel Stringency Index. We hypothesised that the most stringent countries would have increased healthcare costs and reduced prescription rates. Method: We conducted a literature review and survey of guidelines internationally. Guideline identification involved a literature review and consultation with clinical academics. We focused on the haematological monitoring parameters, frequency and thresholds for discontinuation and rechallenge after suspected clozapine-induced neutropenia. In addition, indicators reflecting monitoring guideline stringency were scored and visualised using a choropleth map. We developed a Stringency Index with an international panel of clozapine experts, through a modified-Delphi-survey. The Stringency Index was compared to health expenditure per-capita and clozapine prescription per 100 000 persons. Results: One hundred twocountries were included, from Europe (n = 35), Asia (n = 24), Africa (n = 20), South America (n = 11), North America (n = 7) and Oceania and Australia (n = 5). Guidelines differed in frequency of haematological monitoring and discontinuation thresholds. Overall, 5% of included countries had explicit guidelines for clozapine-rechallenge and 40% explicitly prohibited clozapine-rechallenge. Furthermore, 7% of included countries had modified discontinuation thresholds for benign ethnic neutropenia. None of the guidelines specified how long haematological monitoring should continue. The most stringent guidelines were in Europe, and the least stringent were in Africa and South America. There was a positive association (r = 0.43, p < 0.001) between a country's Stringency Index and healthcare expenditure per capita. Conclusions: Recommendations on how haematological function should be monitored in patients treated with clozapine vary considerably between countries. It would be useful to standardise guidelines on haematological monitoring worldwide. [ABSTRACT FROM AUTHOR]

Background: Antipsychotic combination treatment without clozapine is common in the treatment of schizophrenia patients worldwide, despite clinical guidelines generally do not recommend such practice. This is potentially due to a high rate of non-response to monotherapies and a low-frequent adoption of Clozapine. Aim: This presentation briefly summarizes rational combination strategies without second generation antipsychotics other than clozapine and presents new results of a multi-center randomized, double-blind controlled trial comparing monotherapy of oral amisulpride (400-800 mg/day), or olanzapine (10-20 mg/day) with amisulpride-olanzapine combination treatment. Conclusions: Positive findings with small to medium effect sizes in favor of combination treatment with amisulpride and olanzapin have to be weight against a higher propensity to side effects since reduced sexual functions, weight gain and gain in waist circumference are higher in patients with combination treatment and olanzapine monotherapy than in patients with amisulpride monotherapy. Overall evidence in favor of combination treatment without clozapine is not strong when regarding its highly-frequent adoption in clinically practice. The strategy of combination treatment with amisulpride and olanzapine may be an alternative in certain clinical situations but should be carefully monitored and justified according to guideline recommendations for resistance to pharmacotherapy. Comments: The adoption of clozapine should be considered, before other antipsychotic combination treatment is indicated in clinical non-response to various monotherapies. Other factors that may lead to non-response or therapy resistance such as nonadherence, substance-abuse or high metabolization have to be excluded, before such strategy is appropiate. [ABSTRACT FROM AUTHOR]

Introduction: The coexistence of psychotic symptoms and obsessive-compulsive symptoms (OCS) has been known since the 19th century, with a high prevalence of bothOCS (25%) and obsessive compulsive disorder (OCD) (12%) in patients with schizophrenia. Objectives: The main objective is to assess the validity of the schizoobsessive disorder as a diagnostic entity for those patients who show symptoms of schizophrenia and OCD. Methods: We present the case of a 61-year-old male with a diagnosis of schizophrenia from the age of 28 and obsessive-compulsive symptoms in the last 5 years. Results: The patient has important negative symptomatology, with ideoaffective impoverishment, short speech, abulia, motor slowing, poor social skills, abandonment of self-care, tendency to isolation, obsessive thoughts and compulsions of doubt and verification. He describes the presence of magical thinking, having to leave the doors opened, with the fear of bad things happening instead, he washes hands ten times a day to get rid of the negative energy of the objects, leaves the shoes in the room always in the same way and in the same place to prevent something bad from happening. He also maintains a delusional ideation of unstructured, chronic damage, without behavioral repercussion. Complementary tests (blood test and cranial CT) were normal. Conclusions: The differential diagnosis is made between schizoobsessive disorder and comorbid schizophrenia with OCD. He is being treated with clozapine, which has shown an exacerbation of obsessive symptoms, which is why amisulpride and sertraline are added. The schizo-obsessive disorder has clinical, neurobiological and neurocognitive features distinct from both schizophrenia and OCD. [ABSTRACT FROM AUTHOR]

Currently, tardive dyskinesia (TD) remains an important clinical problem. The average prevalence is estimated at 30%. The appearance of antipsychotics has opened new paths. The extrapyramidal profile of these molecules is more favorable than that of conventional neuroleptics. In order to assess their prophylactic as well as curative potential, we reviewed the literature concerning four of these atypical antipsychotics: clozapine, risperidone olanzapine and amisulpride. Clozapine seems to induce fewer cases of TD than the conventional neuroleptics, and has a specific therapeutic effect. However, the risk of agranulocytosis reduces the possibility of utilisation. Risperidone appears to be an effective therapy, but several authors report cases of TD during treatment. Furthermore, larger studies and longer follow-ups are necessary to confirm the efficiency of olanzapine and amisulpride. Further studies and observations are still necessary before drawing any conclusion for these new atypical antipsychotic actions. They are doubtlessly promising, but we cannot ignore the notion of risk–benefit; regular monitoring and listening to the subjective experience of the patients must remain uppermost in the choice of therapy. [Copyright &y& Elsevier]

Introduction: It is generally accepted that Clozapine is the gold standard treatment in patients with treatment resistant schizophrenia. Large numbers of patients treated with Clozapine discontinue treatment for various reasons including severe side-effects and insufficient response. There is limited literature supporting the next-step treatment option following the discontinuation of Clozapine. Objectives: The atypical antipsychotic Amisulpride as a next-step treatment option beyond Clozapine, is hypothesised to be useful in some patients due to its first pass metabolism which differs from other second generation antipsychotics. The authors present the clinical response from using Amisulpride in three Clozapine-resistant schizophrenic patients. Aims: The authors aim to demonstrate the role of Amisulpride monotherapy in patients with schizophrenia who are resistant to, Clozapine. Method: Three cases of individuals with residual psychotic symptoms despite Clozapine use and/ or with significant side effects precipitating discontinuation, are presented. They were changed to Amisulpiride and their response was evaluated by clinical assessment. Results: Positive clinical results were obtained in all three patients, with improvement of psychotic symptoms and of some of the more common side effects of Clozapine. Conclusion: The findings from these cases suggest that Amisulpride can be of benefit in treating Clozapine-resistant schizophrenic patients. Further, more structured trials are needed to understand these findings. [ABSTRACT FROM AUTHOR]

A 57-year-old female patient with a diagnosis of schizo-affective disorder since 1986 was commenced on clozapine due to persistent positive and negative psychotic symptoms in September 2014. After commencement of clozapine she was delusion free and demonstrated an improvement in negative symptoms. Three months after commencement of clozapine she developed a hypersensitivity reaction. Her symptoms continued to deteriorate despite being prescribed an anti-histamine. Clozapine was discontinued 6 days after the appearance of a generalised pruritic rash, as it was believed to be the probable cause. There was complete resolution of symptoms 1 week after discontinuation of clozapine. Clozapine was replaced with olanzapine and amisulpride. There has been no similar cutaneous or allergic reactions for the past 30 months.

Chue P, Stip E, Remington G, Kopala L. Switching atypical antipsychotics: a review. Atypical antipsychotics are increasingly used in the treatment of diverse psychiatric disorders; however, there is little information on the ‘why, when, and how’ of switching between the different atypical antipsychotics currently available. To review the data on switching and atypical antipsychotics. A literature search was initially conducted using the key words followed by a search of relevant articles including conference abstracts; relevant pharmaceutical companies were also contacted. Clinical trial data are limited in terms of parameters measured, and case reports describe specific problems. Few studies are based on real world populations of psychiatric patients over the long-term. Careful patient and drug selections matched to a carefully supervised and appropriate cross titration based upon the pharmacodynamic and pharmacokinetic properties of all of the drugs involved is important to avoid potential complications such as re-emergence or worsening of psychosis and withdrawal, rebound, and emergent phenomena including new or uncovered side-effects. Psychoeducation and involvement of patients and caregivers in the process are also necessary for a successful switch. Despite the prevalence of switching in real world clinical practice, there is a paucity of data to guide clinicians with respect to effective and safe strategies. There are no criteria defining a successful switch. With the increasing range and formulations of atypical antipsychotics available, there is a rationale for their early use to avoid the practical problems associated with switching from conventional antipsychotics as well as the opportunity to maintain patients on an optimal atypical antipsychotic monotherapy. [ABSTRACT FROM AUTHOR]

SUMMARY: Sialorrhoea (hypersalivation) is a common adverse effect of clozapine. If severe, it can affect patients' quality of life and adherence to the treatment. Clinicians therefore need to proactively manage this effect. At present, no drugs are licensed to manage clozapine-induced sialorrhoea, although there are many off-label treatment options, with variable effectiveness. Anticholinergic medications are commonly prescribed for it, but they have limited effect and can worsen constipation. This article gives a brief overview of other practical and pharmacological management options. [ABSTRACT FROM AUTHOR]

BackgroundEpidemiological investigations show that up to 30% of schizophrenic patients suffer from obsessive–compulsive symptoms (OCS) associated with negative impact on the general prognosis. It has been proposed that antiserotonergic second-generation antipsychotics (SGAs) might induce OCS, but investigations of large samples integrating psychopathology, neuropsychology and psychopharmacology are missing.MethodWe stratified 70 patients with schizophrenia according to their mode of antipsychotic treatment: clozapine and olanzapine (group I) compared with aripiprazole and amisulpride (group II). The groups were matched according to age, sex, educational levels and severity of the psychotic disorder (Positive and Negative Syndrome Scale). As the primary endpoint, we evaluated OCS severity (Yale–Brown Obsessive–Compulsive Scale).ResultsOCS were significantly more prevalent and severe in group I, in which OCS severity correlated with dosage of clozapine and duration of treatment. Pronounced cognitive deficits in group I were found in visuospatial perception and visual memory (Wechsler Adult Intelligence Scale-Revised block design, Rey–Osterrieth Complex Figure Test), impulse inhibition (go/no-go test), higher perseveration scores (Wisconsin Card Sorting Test) and reduced set-shift abilities (Trail Making Test Part B, Set-shift Task). These cognitive domains correlated with OCS severity.ConclusionsOCS in schizophrenia are associated with antiserotonergic SGA treatment, but longitudinal studies have to prove causality. Before starting treatment with antiserotonergic SGAs, specific neurocognitive domains should be evaluated, as visuospatial learning and impulse inhibition performance might allow early detection of OCS secondary to antipsychotic treatment in schizophrenia. [ABSTRACT FROM PUBLISHER]

Background: A significant proportion of people with clozapine-treated schizophrenia develop 'checking' compulsions, a phenomenon yet to be understood. Aims: To use habit formation models developed in cognitive neuroscience to investigate the dynamic interplay between psychosis, clozapine dose and obsessive–compulsive symptoms (OCS). Method: 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. Results: 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. Conclusions: We elucidated different phases of the complex interplay of psychosis and compulsions, which may inform clinicians' therapeutic decisions. [ABSTRACT FROM AUTHOR]

Background: Clozapine can be a life-saving and course-altering treatment for patients with psychosis, particularly treatmentresistant schizophrenia. Unfortunately, clozapine monotherapy rarely leads to a full symptomatic remission. Aims: This talk outlines key decision points in the use of clozapine: how to select patients for clozapine treatment and how to optimize clozapine's efficacy in patients with a poor response to an adequate clozapine monotherapy trial. Conclusions: Clozapine's main indication is for treatmentresistant schizophrenia. Therapeutic drug monitoring (TDM) should be used to optimize clozapine dosing during a clozapine trial and to rule-out pseudo-resistance. Up to 50% of patients do not respond to clozapine monotherapy and augmentation strategies can be utilized in such cases. Pharmacological add-on treatments are selected based on the most prominent symptom cluster (refractory psychosis, negative symptoms, depression and suicidality, aggression). Electroconvulsive therapy is the most effective augmentation strategy for refractory psychosis and suicidality. Non-pharmacological interventions and a focus on quality of life become important considerations in clozapine nonresponders. Comments: Clozapine is an important and underutilized tool in the management of treatment-resistant schizophrenia. It should be offered timely, as soon as treatment-resistance becomes apparent. Clinicians can use personalized augmentation strategies as part of a comprehensive treatment plan in order to achieve improvements even in patients with a poor response to clozapine alone. However, polypharmacy should be used judiciously, keeping in mind medical morbidity and quality of life. [ABSTRACT FROM AUTHOR]

Introduction: Treatment-resistant schizophrenia (TRS) affects 30% of people with a diagnosis of schizophrenia, and is defined as nonresponse to at least two trials of antipsychotic medication of adequate dose and duration. Clozapine is the only evidence-based treatment for TRS. Cariprazine may be considered significantly more efficacious than risperidone in improving negative symptoms of schizophrenia. Objectives: To describe the experience of using cariprazine in combination with clozapine in patients with refractory schizophrenia and negative symptoms. Methods: Qualitative design. We present a case report study of a 47-year-old male with a diagnosis of TRS, treated in our outpatient mental health clinic for twenty years. The patient experiences crystallized delusional ideas of harm, self-referential, paranoid and mystical-messianic content, phenomena of theft and thought reading, egodistonic auditory hallucinations. No substance use disorder was observed. He made several suicide attempts in the context of intense suffering and psychotic anguish. Clozapine 400mg/day was instituted after no response to treatment with amisulpride, paliperidone, olanzapine or aripiprazole. The intensity of positive symptoms was reduced (experiences of damage, commenting and insulting auditory hallucinations, self-referentiality), as well as the emotional and behavioral repercussions. Persistent negative symptoms appeared such as apathy, abulia, clinophilia, anergy, social isolation, affective flattening, impairing his functionality. Results: Neuroimaging and periodic blood tests results were normal. Oral cariprazine was added in ascending doses up to 4.5mg with good tolerance. The patient showed remission of apathy, enhancement of behavioral activation, socialization and motivation to perform occupational activities. Conclusions: Combinations of clozapine with partial agonists may improve the quality of life in refractory schizophrenia. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: Data were extracted using standard procedures, and risk of bias was evaluated. Effect sizes were computed for the individual studies. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

SUMMARY: Clozapine dose assessment in treatment-refractory schizophrenia is complicated. There is a narrow margin between an effective and a potentially toxic dose and wide inter-individual variation in clozapine metabolic capacity. Moreover, factors such as changes in smoking habit, infection/inflammation, co-prescription of certain drugs, notably fluvoxamine, and age alter the dose requirement within individuals. Therapeutic drug monitoring (TDM) of plasma clozapine and N -desmethylclozapine (norclozapine) can help assess adherence, guide dosage and guard against toxicity. This article gives an overview of clozapine pharmacokinetics and factors affecting clozapine dose requirements. It then outlines the procedures and processes of clozapine TDM, from taking the blood sample for laboratory assay or point-of-contact (finger-prick) testing (POCT) to interpreting and acting on the results. [ABSTRACT FROM AUTHOR]

Background: Current evidence on antipsychotic treatment and risk of psychiatric hospitalization in first-episode schizophrenia (FES) is largely based on the findings from randomized clinical trials (RCTs). However, the generalization of the findings to real-world patients is limited due to inherent caveats of the RCT. We aimed to investigate the treatment discontinuation and risk of psychiatric hospitalization using a nationwide population database. Methods: The Health Insurance Review Agency database in South Korea was obtained, and the observation period started from 1 January 2009 to 31 December 2016. We defined the maintenance period as the period from 6-month after the diagnosis of schizophrenia, which is utilized for the main results. For a total of 44 396 patients with FES, a within-individual Cox regression model was used to compare the risk of the treatment discontinuation and psychiatric hospitalization. Results: In group comparison, a long-acting injectable (LAI) antipsychotic group was associated with the lowest risk of the treatment discontinuation (0.64, 0.55–0.75) and psychiatric hospitalization (0.29, 0.22–0.38) in comparison with a typical antipsychotic group and no use, respectively. Among individual antipsychotics, the lowest risk of the treatment discontinuation was observed in LAI paliperidone (0.46, 0.37–0.66) compared to olanzapine. Clozapine was found to be the most effective antipsychotic in lowering the risk of psychiatric hospitalization as monotherapy compared to no use (0.23, 0.18–0.31). Conclusions: In real-world patients with FES, LAI paliperidone and clozapine were associated with low treatment discontinuation and better effectiveness in lowering the risk of psychiatric hospitalization. [ABSTRACT FROM AUTHOR]

Aims. 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. Methods. 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. Results. 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. Conclusions. 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. [ABSTRACT FROM AUTHOR]

Background: Individuals diagnosed with psychiatric disorders who are prescribed antipsychotics have lower rates of violence and crime but the differential effects of specific antipsychotics are not known. We investigated associations between 10 specific antipsychotic medications and subsequent risks for a range of criminal outcomes. Methods: We identified 74 925 individuals who were ever prescribed antipsychotics between 2006 and 2013 using nationwide Swedish registries. We tested for five specific first-generation antipsychotics (levomepromazine, perphenazine, haloperidol, flupentixol, and zuclopenthixol) and five second-generation antipsychotics (clozapine, olanzapine, quetiapine, risperidone, and aripiprazole). The outcomes included violent, drug-related, and any criminal arrests and convictions. We conducted within-individual analyses using fixed-effects Poisson regression models that compared rates of outcomes between periods when each individual was either on or off medication to account for time-stable unmeasured confounders. All models were adjusted for age and concurrent mood stabilizer medications. Results: The relative risks of all crime outcomes were substantially reduced [range of adjusted rate ratios (aRRs): 0.50–0.67] during periods when the patients were prescribed antipsychotics v. periods when they were not. We found that clozapine (aRRs: 0.28–0.44), olanzapine (aRRs: 0.46–0.72), and risperidone (aRRs: 0.53–0.64) were associated with lower arrest and conviction risks than other antipsychotics, including quetiapine (aRRs: 0.68–0.84) and haloperidol (aRRs: 0.67–0.77). Long-acting injectables as a combined medication class were associated with lower risks of the outcomes but only risperidone was associated with lower risks of all six outcomes (aRRs: 0.33–0.69). Conclusions: There is heterogeneity in the associations between specific antipsychotics and subsequent arrests and convictions for any drug-related and violent crimes. [ABSTRACT FROM AUTHOR]

Background: There is concern over the methods used to evaluate antipsychotic drugs.Aims: To assess the clinical relevance of findings in the literature.Method: A systematic review identified studies of antipsychotics that used the Brief Psychiatric Rating Scale (BPRS) and Positive and Negative Syndrome Scale (PANSS). A published method of translating these into Clinical Global Impression - Change scale (CGI-C) scores was used to measure clinical relevance.Results: In total 98 data-sets were included in the BPRS analysis and 202 data-sets in the PANSS analysis. When aggregated scores were translated into notional CGI-C scores, most drugs reached 'minimal improvement' on the BPRS, but few reached that level for PANSS. This was true of both first- and second-generation drugs, including clozapine. Amisulpride and olanzapine had better than average CGI-C scores.Conclusions: Our findings show improvements of limited clinical relevance. The CGI-C scores were better for the BPRS than for the PANSS. [ABSTRACT FROM AUTHOR]

The article presents the discussion on antipsychotic medications being the gold-standard treatment for psychotic patients. Topics include guidelines recommending long-term and continuous treatment with antipsychotic medication preventing relapse; and patients perceiving longterm antipsychotic use disrupting the individual efforts overcoming the condition and undermining the sense of agency.

Background: Clozapine, an antipsychotic with unique efficacy in treatment-resistant psychosis, is associated with increased susceptibility to infection, including pneumonia.Aims: To investigate associations between clozapine treatment and increased risk of COVID-19 infection in patients with schizophrenia-spectrum disorders who are receiving antipsychotic medications in a geographically defined population in London, UK.Method: Using information from South London and Maudsley NHS Foundation Trust (SLAM) clinical records, via the Clinical Record Interactive Search system, we identified 6309 individuals who had an ICD-10 diagnosis of schizophrenia-spectrum disorders and were taking antipsychotics at the time of the COVID-19 pandemic onset in the UK. People who were on clozapine treatment were compared with those on any other antipsychotic treatment for risk of contracting COVID-19 between 1 March and 18 May 2020. We tested associations between clozapine treatment and COVID-19 infection, adjusting for gender, age, ethnicity, body mass index (BMI), smoking status and SLAM service use.Results: Of 6309 participants, 102 tested positive for COVID-19. Individuals who were on clozapine had increased risk of COVID-19 infection compared with those who were on other antipsychotic medication (unadjusted hazard ratio HR = 2.62, 95% CI 1.73-3.96), which was attenuated after adjusting for potential confounders, including clinical contact (adjusted HR = 1.76, 95% CI 1.14-2.72).Conclusions: These findings provide support for the hypothesis that clozapine treatment is associated with an increased risk of COVID-19 infection. Further research will be needed in other samples to confirm this association. Potential clinical implications are discussed. [ABSTRACT FROM AUTHOR]

Introduction Treatment-resistant schizophrenia (TRS) affects 30% of people with a diagnosis of schizophrenia, and is defined as nonresponse to at least two trials of antipsychotic medication of adequate dose and duration. Clozapine is the only evidence-based treatment for TRS. Cariprazine may be considered significantly more efficacious than risperidone in improving negative symptoms of schizophrenia. Objectives To describe the experience of using cariprazine in combination with clozapine in patients with refractory schizophrenia and negative symptoms. Methods Qualitative design. We present a case report study of a 47-year-old male with a diagnosis of TRS, treated in our outpatient mental health clinic for twenty years. The patient experiences crystallized delusional ideas of harm, self-referential, paranoid and mystical-messianic content, phenomena of theft and thought reading, egodistonic auditory hallucinations. No substance use disorder was observed. He made several suicide attempts in the context of intense suffering and psychotic anguish. Clozapine 400mg/day was instituted after no response to treatment with amisulpride, paliperidone, olanzapine or aripiprazole. The intensity of positive symptoms was reduced (experiences of damage, commenting and insulting auditory hallucinations, self-referentiality), as well as the emotional and behavioral repercussions. Persistent negative symptoms appeared such as apathy, abulia, clinophilia, anergy, social isolation, affective flattening, impairing his functionality. Results Neuroimaging and periodic blood tests results were normal. Oral cariprazine was added in ascending doses up to 4.5mg with good tolerance. The patient showed remission of apathy, enhancement of behavioral activation, socialization and motivation to perform occupational activities. Conclusions Combinations of clozapine with partial agonists may improve the quality of life in refractory schizophrenia. Disclosure No significant relationships.

Clozapine is the only licensed pharmacotherapy for treatment-resistant schizophrenia. However, response to clozapine is variable. Understanding the demographic and clinical features associated with response to clozapine may be useful for patient stratification for clinical trials or for identifying patients for earlier initiation of clozapine. We systematically reviewed the literature to investigate clinical and demographic factors associated with variation in clozapine response in treatment-resistant patients with schizophrenia spectrum disorders. Subsequently, we performed a random-effects meta-analysis to evaluate differences in duration of illness, age at clozapine initiation, age of illness onset, body weight and years of education between clozapine responders and non-responders. Thirty-one articles were eligible for qualitative review and 17 of these were quantitatively reviewed. Shorter duration of illness, later illness onset, younger age at clozapine initiation, fewer hospitalisations and fewer antipsychotic trials prior to clozapine initiation showed a trend to be significantly associated with a better response to clozapine. Meta-analysis of seven studies, totalling 313 subjects, found that clozapine responders had a significantly shorter duration of illness compared to clozapine non-responders [g = 0.31; 95% confidence interval (CI) 0.06–0.56; p = 0.01]. The results imply that a delay in clozapine treatment may result in a poorer response and that a focus on prompt treatment with clozapine is warranted. [ABSTRACT FROM AUTHOR]

Introduction An under-recognized life-threatening adverse effect of clozapine is the gastrointestinal hypomotility. It represents a serious problem. Clozapine is an atypical antipsychotic which commonly produces ileus. The risk is higher when we associate clozapine to drugs, such us anticholinergic and tricyclic. Ileus can produce the death in our patients, therefore we will check constipation in our daily clinical practice as a measure to avoid these side effectS. Methods We looked through Medline for articles published since 2005 regarding Clozapine and Ileus. We will present the case of a patient who developed Ileus as the side effect of clozapine. Results Constipation is very common in patients with schizophrenia (until 50%). Risk factors developing ileus in psychotic patients are: women, age, anticholinergic drugs, first generation of antipsychotics, clozapine, opioids and tricyclic antidepressants. Taking into account that this side effect can be mortal some recommendations that can reduce gastrointestinal hipomotility in this population are: a high fiber diet, exercise and the use of a softening laxative. In the case a patient treated with clozapine suffers from ileus we should shift the clozapine to aripiprazole or Amisulpride treatment. Moreover, we can use prokinetic drugs and surgery in the most complicated cases. Then, clozapine can be introduced after the ileus problem has been solved. Conclusion 1 Gastrointestinal hypomotility has a high prevalence in psychotic treatments. 2 Avoiding the use of other drugs that produce constipation. 3 Offer advice to avoid the constipation. 4 If ileus is present, stop the clozapine treatment and shift it to aripiprazole or Amisulpride. [ABSTRACT FROM AUTHOR]

Background: Although clozapine is often discontinued, there is a paucity of guidelines and evidence on treatment options after clozapine discontinuation. Moreover, it is currently unknown whether reinstating clozapine in patients formerly using clozapine should be avoided.Aims: To compare the real-world effectiveness of antipsychotics after clozapine cessation.Method: From Finnish registry data (1995-2017), we identified 2250 patients with schizophrenia who had been using clozapine for ≥1 year before treatment cessation. The primary analysis consisted of adjusted within-individual analyses of psychiatric ward readmission owing to psychosis and treatment failure. Secondary analyses concerned between-individual mortality differences.Results: Compared with no use of antipsychotics, risk of psychiatric ward readmission was lowest for reinitiation of clozapine (adjusted hazard ratio (aHR) 0.49; 95% CI 0.40-0.61; P < 0.0001), oral olanzapine (aHR 0.58; 95% CI 0.48-0.71; P < 0.0001) and antipsychotic polypharmacy (aHR 0.62; 95% CI 0.53-0.72; P < 0.0001). Risk of treatment failure was lowest for aripiprazole long acting injectable (aHR 0.42; 95% CI 0.27-0.65; P < 0.0001), reinitiation of clozapine (aHR 0.49; 95% CI 0.43-0.57; P < 0.0001) and oral olanzapine (aHR 0.69; 95% CI 0.61-0.77; P < 0.0001). Mortality risk was lowest for reinitiation of clozapine (aHR 0.18; 95% CI 0.09-0.36; P < 0.0001) and oral olanzapine (aHR 0.26; 95% CI 0.17-0.40; P < 0.0001).Conclusions: Clozapine and olanzapine are the most effective and safest treatment options in those discontinuing clozapine for undefined reasons. Clozapine should therefore be reconsidered in patients with schizophrenia who previously discontinued this compound. [ABSTRACT FROM AUTHOR]

Background: Around 30% of patients with schizophrenia are considered treatment resistant (TRS). Only around 40% of TRS patients respond to clozapine. Long acting injectable antipsychotics could be a useful augmentation strategy for nonresponders. Methods: We conducted a multicenter, observational, naturalistic, retrospective, 6-month mirror-image study to evaluate the efficacy and tolerability of clozapine and paliperidone palmitate association in 50 patients with TRS and other psychotic disorders. Clinical outcomes and side effects were systematically assessed. Results: Six months after starting the combined treatment, participants showed a significant relief of symptoms, decreasing the Brief Psychiatric Rating Scale total score from 18.32-7.71 to 7.84-5.16 (p < 0.001). The number of hospitalizations, the length of hospital stays and the number of visits to emergency services also decreased, while an increase of the functionality was observed (Personal and Social Performance total score increased from 46.06-118.7 to 60.86-18.68, p < 0.001). There was also a significant decrease in the number and severity of side effects with the combination therapy, decreasing the Udvalg for Kliniske Undersogelser total score from 10.76-8.04 to 8.82-6.63 (p = 0.004). Conclusions: This study provides the first evidence that combining clozapine with paliperidone palmitate in patients with TRS and other psychotic disorders could be effective and safe, suggesting further research with randomized controlled trials of augmentation strategies for clozapine nonresponder patients. Policy Significance Statement: Patients with psychotic disorders such as schizophrenia show a variable response to antipsychotic treatments. Around 30% of patients are considered treatment resistant, indicated by insufficient symptom control to at least two different drugs. In these resistant cases, clozapine should be indicated, as it has shown to be superior to other options. However, only 40%of patients respond to clozapine, being necessary to establishwhich treatments could best potentiate clozapine action. Combining clozapine with long acting injectable antipsychotics, and particularly paliperidone palmitate, could be a useful strategy. We conducted a multicenter study of 50 patients with treatment-resistant schizophrenia and other psychotic disorders comparing the efficacy and tolerability in the 6month-period prior and after starting the clozapine and paliperidone palmitate association. Our study suggests that this combination could be effective and safer, laying the groundwork for future clinical trials with this combination. [ABSTRACT FROM AUTHOR]

Pisa syndrome is known to be a condition in which there is sustained involuntary flexion of the body and head to one side and slight rotation of the trunk so the person appears to lean like the Leaning Tower of Pisa. The development of Pisa syndrome is most commonly associated with prolonged treatment with antipsychotics. Although less frequently, Pisa syndrome has been reported, in patients who are receiving other medications (such as cholinesterase inhibitors and antiemetics), in those not receiving medication (idiopathic Pisa syndrome) and also patients with neurodegenerative disorders like Alzheimer''s disease and multiple system atrophy. We report a case of a 67 year- old male diagnosed with Schizophrenia for 20 years. He has been following a treatment with Clozapine 400mg/day for 4 years. Amisulpiride was added to the established regimen of antipsychotic and increased during the last month reaching the doses of 600mg/day. Three weeks later he was observed walking with a tilt toward the right. A first physical examination revealed sustained tonic flexion of the trunk to the right side. No deficits or mental status changes during neurological exploration were shown. We prescribed biperidene hydrochloride therapy. After 24hour side effects disappeared. As far as we know, no many cases of amisulpride-induced Pisa syndrome in the literature have been reported. This abstract presents a case of amisulpride induced Pisa syndrome. [Copyright &y& Elsevier]

Introduction Clozapine has been long used for the treatment-resistant schizophrenia. Its effectiveness in the vast schizophrenia symptoms is well established. However, its wide range of adverse effects has limited its use. Objectives/aims To present a new strategy in order to continue with clozapine treatment despite extrapyramidal adverse effects. Methods/case report Extrapyramidal symptoms are rarely reported with clozapine. Although, cases of patients with clozapine-induced tics have been described. We report the case of a 28 year-old patient with history of refractory schizophrenia that developed motor tics with clozapine 150 mg total dose. Tics consisted on eye blinking, eyebrow elevation, mouth twitching, facial grimacing, lip licking, tongue protrusion and shoulder shrugging. Reduction of clozapine dose to 50 mg qd was indicated to decrease the motor tics, however exacerbation of psychosis occurred. We added amisulpride and titrated it up to 600 mg qd without response. By using the same principle of levodopa's washout in Parkinson disease and in order to establish a therapeutic threshold, we conducted a one-week clozapine washout. Results After this therapeutic manoeuvre, tics disappeared and no relapse was observed after clozapine reinitiation along with remission of psychotic symptoms. Conclusions Wash out might be a new strategy for treatment reinitiation after clozapine induced extrapyramidal side effects in patients with treatment-resistant schizophrenia. To our knowledge no previous report of this strategy has been reported, however further studies are needed to support its effectiveness. [ABSTRACT FROM AUTHOR]

Introduction Clozapine-induced sialorrhea (CIS) is a common, treatment-limiting and stigmatizing side effect. All systemic agents that are used for hypersalivation may increase clozapine side effects such as blood pressure changes, constipation, or arrythmias. Oral application of topical anti-muscarinic agents may be a low side effect option for treatment of CIS. Objective The aim of this case report was to propose an off-label treatment of tropicamide drops to CIS and to stimulate further investigation. Case report A 33-year-old male inpatient with schizophrenia has been on clozapine 800 mg and amisulpride 600 mg/day. His drooling was occasional and severe as drool drips off his chin during the day and night. Wet area over the pillow, visual analog scale (VAS), the short form of health survey (SF-36), UKU side effect rating scale, scale for the assessment of negative symptoms (SANS), scale for the assessment of positive symptoms (SAPS) were applied at baseline and in one-week intervals. Oral application of one drop of tropicamide % 0.5 (5 mg/mL) to left and one drop to right side before going to bed in the first week and two drops to each side were administered subsequently. Informed consent was given by the patient. Results No psychological, neurological, autonomic and other side effects were observed associated with tropicamide. On VAS, the patient rated hypersalivation 5/7 at baseline, 4/7 after one drop each, 3/7 after two drops each. Conclusions The reduction of CIS by oral use of tropicamide eye drops is promising and should be explored with randomized controlled trials. [ABSTRACT FROM AUTHOR]

Numerous studies in different countries throughout the world have shown that 30-60% of schizophrenia patients, when treated with antipsychotic drugs, receive two or more antipsychotics simultaneously. Reasons for antipsychotic polypharmacy are not often well described, they might be insufficient efficacy (was the maximal tolerable dosage given?), tolerability problems (severe or transient, treatable by other drugs?) or an “unfinished switching procedure”: Cross-tapering from antipsychotic A to antipsychotic B is stopped halfway at a reduced dosage of A and a sub-therapeutic dosage of B, because this combination seems to work. However, it is not known whether B alone would be better. Most often, antipsychotics with different receptor binding and side effect profiles are combined, although scientific evidence supporting the common practice is rather limited. Most controlled studies did not reveal an advantage of the combination versus monotherapy. Particularly for clozapine, where anecdotal reports and open trials indicated the usefulness of a combination with amisulpride, aripiprazole or risperidone, double-blind trials were mostly negative. However, in individual patients, hard or impossible to define, well-reflected combinations might be justified. The few controlled studies and the resulting suggestions for everyday practice are presented to answer the following questions: When (after how many weeks of monotherapy) is a combination justified? Are there any criteria to decide switching the antipsychotic versus combining antipsychotics? Which combination(s) of antipsychotics might be useful? [Copyright &y& Elsevier]

Abstract: To establish the impact of antipsychotic medication on the incidence of diabetes, we have analysed data from the prospective French Cohort study of mortality in schizophrenia. This generated a large database of 3470 patients with schizophrenia initially enrolled in 1993 for which data collection on comorbidity has been collected systematically every three years since. The primary objective of the study was to evaluate the mortality rate in the study cohort. From this database, the prevalence and incidence of diabetes can be studied. In 1993, nine patients in 10 were prescribed conventional antipsychotics and the remainder amisulpride and clozapine. Since the introduction of risperidone and olanzapine, atypical antipsychotics are now used in one-third of patients. Multiple antipsychotic medications are used in many patients, with the exception of those receiving clozapine. At inclusion, 2.2% of patients in the study cohort had a diagnosis of diabetes. Morbidity rates were higher in females than in males (3.4% and 1.6%, respectively) and it was only in females that the standard morbidity ratio with respect to the general population was significantly elevated (2.2; 95% confidence intervals: 1.6 and 2.9). The prevalence of diabetes in the study cohort rose over the course of the study. Multivariate regression analysis was performed in order to identify potential determinants of diabetes. For pre-existing diabetes, four factors were identified: age at first hospitalisation, age, obesity and duration of schizophrenia. The same factors with the exception of length of illness were identified for the incident cases. There was no evidence for an interaction between the class and type of antipsychotic medication and risk of treatment emergent diabetes. However, the use of multiple antipsychotic treatments makes the individualisation of specific risks associated with any other antipsychotic drug impossible. [Copyright &y& Elsevier]

This article describes a case study of the therapeutic effect and tolerability of the augmentation of clozapine with paliperidone in treatment-resistant schizophrenia. The clinical history of the patients is discussed, as well as observations of the results of augmentation of clozapine with paliperidone in the patients. A review of previous related literature is provided.