Clozapine Treatment During Pregnancy and the Postpartum Period: A Systematic Literature Review.

Objective: The objective of this systematic review was to provide a critical appraisal of the evidence related to the safety of clozapine for schizophrenia during pregnancy and lactation.Data Sources: PubMed/MEDLINE, Embase, and the Cochrane Library were searched from inception through December 2020. Reference lists of included studies were hand-searched. The International Clinical Trials Registry Platform and ClinicalTrials.gov were searched for unpublished trials, and PROSPERO was searched for unpublished reviews. The current marketing authorization holder of the originator brands Clozaril and Leponex was also contacted for pharmacovigilance data.Study Selection: Original reports published in English, German, French, or Dutch containing clinical and preclinical data were included if they provided data on maternal, fetal, and neonatal outcomes after clozapine exposure during pregnancy or lactation.Data Extraction: Two reviewers independently extracted relevant data.Results: A total of 860 records were identified, and the full texts of 117 articles were reviewed. Forty-two studies met the inclusion criteria. Data on perinatal clozapine exposure are of limited quality and quantity. Although clozapine demonstrates partial placental passage, data thus far do not support that clozapine is teratogenic; that it increases the risk of stillbirth, abortion, or fetal disorders; or that it increases the risk of delivery complications or premature birth. Information about clozapine exposure through breast milk is scarce, but based on its chemical properties, it is likely that clozapine enters the breast milk of nursing mothers taking clozapine.Conclusions: When weighing the risks and benefits of clozapine continuation during pregnancy and lactation versus switching to another antipsychotic, one should include severity of illness and treatment history but also be aware of the limitations of the available safety data regarding perinatal clozapine use, including the fact that there are few studies.

Risk factors for repeated emergency compulsory psychiatric admissions.

BACKGROUND: The characteristics of patients who have repeated compulsory psychiatric admissions are largely unknown. AIMS: To investigate the frequency and risk factors for repeated emergency compulsory psychiatric admission (ECPA); and to identify targets for interventions to reduce repeated ECPA. METHOD: Data were collected from a database of electronic patient files (EPFs) held by three psychiatric emergency services (PES) in the Netherlands. Analyses were based on the data for adult patients (aged 18-75 years) with a first PES contact in 2010-2015. Using descriptive statistics and regression analysis, we studied the associations between baseline patient factors and repeated ECPA and time to readmission, within a 2-year follow-up period. RESULTS: We included 6059 patients: 15.6% had two or more ECPAs. In total, 66% of second ECPAs had occurred within 6 months of the first. About 30% of all ECPAs were repeated ECPAs. Two baseline factors were associated with a higher frequency of a second ECPA: history of receiving any mental healthcare treatment, whether in-patient or out-patient or both, and a lower level of self-care. Three were associated with a lower frequency: ethnicity (other than Dutch), older age and suicidality. Lower Global Assessment of Functioning (GAF) scores and housing problems were associated with a shorter time to compulsory readmission and persistent psychiatric problems with a longer time to compulsory readmission. CONCLUSIONS: We found that 15.6% of patients had two or more ECPAs. Two-thirds of the second ECPAs had occurred within 6 months of the first. Like earlier studies, the risk factors we identified suggest that interventions to reduce the risk of repeated compulsory psychiatric admission should seek to improve self-care, general daily functioning and homelessness.

Safety of clozapine use during pregnancy: Analysis of international pharmacovigilance data.

PURPOSE: Safety data on clozapine use during pregnancy are limited. The aim of this study was to determine disproportionality in case safety reports on adverse pregnancy outcomes between clozapine and other antipsychotics (OAP) used during pregnancy. METHODS: We included all reports of suspected adverse drug reactions (ADRs) to antipsychotics registered in the World Health Organization global individual case safety report (ICSR) database (VigiBase) in children younger than 2 years and women aged 12-45 years. A case/non-case approach was used to evaluate the association between several pregnancy-related ADRs and clozapine exposure during pregnancy, using 2×2 contingency tables to investigate disproportionality and Standard MedDRA Queries to select cases. Clozapine exposure was defined as all ICSR-ADR combinations with clozapine as (one of) the suspected drug(s). Non-exposure was defined as all ICSR-ADR combinations with OAP as (one of) the suspected drug(s). RESULTS: We identified 42 236 unique ICSR-ADR combinations related with clozapine exposure and 170 710 with OAP exposure. Of these, 494 and 4645 ICSR-ADR combinations involved adverse pregnancy outcomes related with clozapine exposure and OAP exposure respectively. Overall, no signal of disproportionate reporting associating clozapine with the studied adverse pregnancy outcomes was found compared with OAP exposure. CONCLUSION: Based on global pharmacovigilance data, we did not find any evidence that clozapine is less safe during pregnancy than OAP. Although this is not automatically equivalent to the relative safety of clozapine during pregnancy, these findings add to the convergence of proofs to allow final conclusions and decisions regarding the treatment of pregnant women with clozapine.

An intensive multimodal group programme for patients with psychotic disorders at risk of rehospitalization: a controlled intervention study.

BACKGROUND: On the basis of earlier experiences in Germany and England, we developed an intensive multimodal group programme (FACT Plus) for psychotic-spectrum patients. By combining it with regular Flexible Assertive Community Treatment (FACT) (care as usual), we intended to reduce psychiatric rehospitalizations and mental healthcare costs. METHODS: We included adult patients (>18 years) with a psychotic spectrum disorder who had had at least one psychiatric admission in the 2 years before inclusion. FACT Plus was delivered weekly for 9 months. The intervention group was recruited in northern Rotterdam (the Netherlands), and the control group was recruited in southern Rotterdam. The primary outcome measure was length of stay (LOS) and the secondary outcome measures were mental healthcare costs and compulsory admissions. RESULTS: We included 52 patients in the intervention group and 61 patients in the control group. During the 12-month observation period, the mean LOS per patient was 15.2 (intervention group) and 34.6 (control group). This represents a difference of 19.4 days (56.1%). This result was statistically significant (B = -.859, SE = .497, p = .042) in a regression model correcting for baseline differences between the groups. Mean total mental healthcare costs per patient were €21,098 in the intervention group) versus €25,054 in the control group, a difference of about €4000 per patient (16%). In addition, there were zero compulsory admissions in the intervention group and nine in the control group. CONCLUSIONS: After the addition of FACT Plus to regular FACT, psychiatric LOS was substantially lower in the intervention group than in the control group. This result was accompanied by a limited reduction in mental healthcare costs.

How dangerousness evolves after court-ordered compulsory psychiatric admission: explorative prospective observational cohort study.

BACKGROUND: Compulsory admission is commonly regarded as necessary and justified for patients whose psychiatric condition represents a severe danger to themselves and others. However, while studies on compulsory admissions have reported on various clinical and social outcomes, little research has focused specifically on dangerousness, which in many countries is the core reason for compulsory admission.AimsTo study changes in dangerousness over time in adult psychiatric patients admitted by compulsory court order, and to relate these changes to these patients' demographic and clinical characteristics. METHOD: In this explorative prospective observational cohort study of adult psychiatric patients admitted by compulsory court order, demographic and clinical data were collected at baseline. At baseline and at 6 and 12 month follow-up, dangerousness was assessed using the Dangerousness Inventory, an instrument based on the eight types of dangerousness towards self or others specified in Dutch legislation on compulsory admissions. We used descriptive statistics and logistic regression to analyse the data. RESULTS: We included 174 participants with a court-ordered compulsory admission. At baseline, the most common dangerousness criterion was inability to cope in society. Any type of severe or very severe dangerousness decreased from 86.2% at baseline to 36.2% at 6 months and to 28.7% at 12 months. Being homeless at baseline was the only variable which was significantly associated with persistently high levels of dangerousness. CONCLUSIONS: Dangerousness decreased in about two-thirds of the patients after court-ordered compulsory admission. It persisted, however, in a substantial minority (approximately one-third).Declaration of interestNone.

Predicting Unsuccessful Clozapine Treatment After First Use in Adult Patients With Psychotic Disorders.

PURPOSE/BACKGROUND: Cessation of clozapine therapy and insufficient response may result in relapse of psychotic symptoms and in clinical admissions. However, discontinuation rates are high. Identifying patients at risk for unsuccessful clozapine use might enable clinicians to direct specific attention to them. METHODS/PROCEDURES: Routinely collected data from a large insurance company were used to develop a simple prediction model for unsuccessful clozapine treatment in psychiatric patients 1 year after clozapine was first dispensed by a community pharmacy in the Netherlands. Multivariate logistic regression analyses were performed with the Nagelkerke R statistic as a measure of the predictive value of the model. FINDINGS/RESULTS: A total of 937 patients were dispensed clozapine for the first time by their community pharmacy between January 1, 2011, and December 31, 2015 (index date). Of these, 741 patients had started their clozapine treatment in hospital before the index date (inpatient starters); the remaining 196 patients started clozapine as outpatients on the index date (outpatient starters). In 191 patients (20.4%), clozapine treatment was unsuccessful 1 year after the index date. Unsuccessful treatment was more common among outpatient starters than among inpatient starters (32.1% vs 17.3%). Using backward selection of the variables, a model consisting of 61 variables had the best predictive value overall (Nagelkerke R = 0.301), whereas a model consisting of 52 variables had the best predictive value in outpatient starters (Nagelkerke R = 0.676). IMPLICATIONS/CONCLUSIONS: The likelihood of unsuccessful clozapine treatment after 1 year was higher among patients who started clozapine as outpatients. Despite the use of a diversity of variables and different statistical approaches, it was not possible to make a simple prediction model for unsuccessful clozapine treatment using relatively easily accessible data.

[Atypical presentation of depression leading to delay in treatment]. / Atypische presentatie van depressie leidend tot vertraging in de behandeling.

Major depression can present with atypical symptomatology and as a consequence, delay can occur in passing through the relevant algorithm for biological treatment. The case of a 62-year old female is presented who eventually was diagnosed with a major depressive episode, with psychotic features. The atypical presentation led to persistent diagnostic uncertainty both during outpatient treatment in several mental health care institutions and during inpatient observation. As a consequence, proceeding to the next step of the algorithm for biological treatment for major depression was delayed. Factors involved in this diagnostic uncertainty are discussed.

Religious delusions in older adults: Diagnoses, combinations, and delusional characteristics.

OBJECTIVE: Religious delusions (RDs) tend to occur relatively often in patients with affective or non-affective psychosis. Few studies exist about RDs in later life. The current study explores (1) the distribution of RDs across diagnosis, (2) how RDs relate to other types of delusions, and (3) how RDs relate to several dimensions or characteristics of delusions. METHODS: Inpatients and outpatients in a Geriatric Psychiatry Department in the Netherlands (N = 155; mean age 76.5 years), and who were diagnosed with an affective or non-affective psychotic disorder, participated in semi structured diagnostic interviews, using the Schedules for Clinical Assessement in Neuropsychiatry 2.1. RESULTS: Religious delusions were most common among patients with psychotic depression (47%) and schizophrenia (32%). The RDs frequently co-occurred with other types of delusions. When combined with delusions of grandeur, RDs were more often classified as bizarre and were accompanied by higher levels of positive psychotic symptoms. When combined with delusions of guilt, RDs were associated with higher levels of distress and a shorter disease duration. The delusional characteristics bizarreness, frequency of psychotic symptoms, and degree of distress were more prevalent for RDs than for any other type of delusion. CONCLUSIONS: The current study suggests that the prevalence of RDs in older adults is particularly high in late life psychotic depression. Also, in later life, RDs can be perceived of as independent marker of complex psychotic states, and as a denominator of severe arousal with respect to existential concerns.

Crucial factors preceding compulsory psychiatric admission: a qualitative patient-record study.

BACKGROUND: Compulsory admissions have a strong effect on psychiatric patients and represent a deprivation of personal liberty. Although the rate of such admissions is tending to rise in several Western countries, there is little qualitative research on the mental health-care process preceding compulsory admission. The objective of the study was to identify crucial factors in the mental health-care process preceding compulsory admission of adult psychiatric patients. METHODS: This retrospective, qualitative multiple-case study was based on the patient records of patients with severe mental illness, mainly schizophrenia and other psychotic disorders. Twenty two patient records were analyzed. Patients' demographic and clinical characteristics were heterogeneous. All were treated by Flexible Assertive Community Treatment teams (FACT teams) at two mental health institutions in the greater Rotterdam area in the Netherlands and had a compulsory admission in a predefined inclusion period. The data were analyzed according to the Prevention and Recovery System for Monitoring and Analysis (PRISMA) method, assessing acts, events, conditions, and circumstances, failing protective barriers and protective recovery factors. RESULTS: The most important patient factors in the process preceding compulsory admission were psychosis, aggression, lack of insight, care avoidance, and unauthorized reduction or cessation of medication. Neither were health-care professionals as assertive as they could be in managing early signs of relapse and care avoidance of these particular patients. CONCLUSION: The health-care process preceding compulsory admission is complex, being influenced by acts, events, conditions and circumstances, failing barriers, and protective factors. The most crucial factors are patients' lack of insight and cessation of medication, and health-care professionals' lack of assertiveness.

Interventions to Reduce Compulsory Psychiatric Admissions: A Systematic Review and Meta-analysis.

IMPORTANCE: Compulsory admissions, defined as admissions against the will of the patient (according to local judicial procedures), have a strong effect on psychiatric patients. In several Western countries, the rate of such admissions is tending to rise. Its reduction is urgently needed. OBJECTIVE: To establish which interventions effectively reduce compulsory admissions in adult psychiatric patients in outpatient settings. DATA SOURCES: A systematic computerized literature search was performed using EMBASE, MEDLINE, Web of Science, PsycINFO, CINAHL, PubMed (not yet indexed for MEDLINE), Cochrane Central, and Google Scholar. Every database was searched from its inception until April 30, 2015. STUDY SELECTION: Randomized clinical trials (RCTs) that studied any kind of intervention designed to reduce compulsory admission rates in adult psychiatric patients (age range, 18-65 years) in outpatient settings were eligible. Eligibility was independently assessed by 2 of us. DATA EXTRACTION AND SYNTHESIS: Two of us independently extracted relevant data. The Cochrane Collaboration's tool was used for assessing risk of bias. Overall risk reduction (random-effects estimate) was calculated in the following 4 subgroups of interventions: advance statements, community treatment orders, compliance enhancement, and integrated treatment. MAIN OUTCOMES AND MEASURES: Relative risk (RR) was calculated on the basis of the number of patients who had been compulsorily admitted. RESULTS: Our meta-analyses included 13 RCTs comprising 2970 psychiatric patients. The meta-analysis of the RCTs on advance statements showed a significant 23% (RR, 0.77; 95% CI, 0.60-0.98; I2 = 2.2%) (n = 1102) risk reduction in compulsory admissions. In contrast, the RCTs on community treatment orders (RR, 0.95; 95% CI, 0.81-1.10; I2 = 0.0%) (n = 742), compliance enhancement (RR, 0.52; 95% CI, 0.11-2.37; I2 = 55.7%) (n = 250), and integrated treatment (RR, 0.71; 95% CI, 0.49-1.02; I2 = 49.0%) (n = 876) showed no significant risk reduction in compulsory admissions. CONCLUSIONS AND RELEVANCE: The meta-analysis of the RCTs on advance statements showed a statistically significant and clinically relevant 23% reduction in compulsory admissions in adult psychiatric patients, whereas the meta-analyses of the RCTs on community treatment orders, compliance enhancement, and integrated treatment showed no evidence of such a reduction. To date, only 13 RCTs have used compulsory admissions as their primary or secondary outcome measure. This demonstrates the need for more research in this field.

Successful clozapine continuation during chemotherapy for the treatment of malignancy: a case report.

CASE: The need for chemotherapy treatment in a cancer patient who uses clozapine raises a clinical dilemma because both therapies can cause agranulocytosis. A 45-year-old male diagnosed with schizophrenia used clozapine together with zuclopenthixol for more than 15 years. Non-Hodgkin's lymphoma was treated with chemotherapy twice, and clozapine was continued during both courses of chemotherapy. Agranulocytosis did not occur during the first treatment. During the second treatment, agranulocytosis occurred, but was attributed to chemotherapy, and blood counts recovered spontaneously. Successful concomitant use of clozapine and cancer chemotherapy is based on a limited number of case reports. However, two case reports describe persistent neutropenia or agranulocytosis, possibly related to this combination. CONCLUSION: Clozapine should only be continued during cancer chemotherapy if favoured by the risk-to-benefit ratio.

Superior Disembedding Performance in Childhood Predicts Adolescent Severity of Repetitive Behaviors: A Seven Years Follow-Up of Individuals With Autism Spectrum Disorder.

Previous research suggests that individuals with autism spectrum disorder (ASD) show a detail-focused cognitive style. The aim of the current longitudinal study was to investigate whether this detail-focused cognitive style in childhood predicted a higher symptom severity of repetitive and restrictive behaviors and interests (RRBI) in adolescence. The Childhood Embedded Figures Test (CEFT) and the Autism Diagnostic Observation Schedule (ADOS) were administered in 87 children with ASD at the age of 6-12 years old (T1), and the ADOS was readministered 7 years later when the participants were 12-19 years old (T2). Linear regression analyses were performed to investigate whether accuracy and reaction time in the complex versus simple CEFT condition and performance in the complex condition predicted T2 ADOS RRBI calibrated severity scores (CSS), while taking into consideration relevant covariates and ADOS RRBI CSS at T1. The CEFT performance (accuracy in the complex condition divided by the time needed) significantly predicted higher ADOS RRBI CSS at T2 (ΔR(2) = 15%). This finding further supports the detail-focused cognitive style in individuals with ASD, and shows that it is also predictive of future RRBI symptoms over time.

Childhood Facial Recognition Predicts Adolescent Symptom Severity in Autism Spectrum Disorder.

Limited accuracy and speed in facial recognition (FR) and in the identification of facial emotions (IFE) have been shown in autism spectrum disorders (ASD). This study aimed at evaluating the predictive value of atypicalities in FR and IFE for future symptom severity in children with ASD. Therefore we performed a seven-year follow-up study in 87 children with ASD. FR and IFE were assessed in childhood (T1: age 6-12) using the Amsterdam Neuropsychological Tasks (ANT). Symptom severity was assessed using the Autism Diagnostic Observation Schedule (ADOS) in childhood and again seven years later during adolescence (T2: age 12-19). Multiple regression analyses were performed to investigate whether FR and IFE in childhood predicted ASD symptom severity in adolescence, while controlling for ASD symptom severity in childhood. We found that more accurate FR significantly predicted lower adolescent ASD symptom severity scores (ΔR(2) = .09), even when controlling for childhood ASD symptom severity. IFE was not a significant predictor of ASD symptom severity in adolescence. From these results it can be concluded, that in children with ASD the accuracy of FR in childhood is a relevant predictor of ASD symptom severity in adolescence. Test results on FR in children with ASD may have prognostic value regarding later symptom severity.

Formal thought disorder in autism spectrum disorder predicts future symptom severity, but not psychosis prodrome.

Formal thought disorder (FTD) is a disruption in the flow of thought, which is inferred from disorganisation of spoken language. FTD in autism spectrum disorders (ASD) might be a precursor of psychotic disorders or a manifestation of ASD symptom severity. The current longitudinal study is a seven-year follow-up of 91 individuals aged 5-12 years with ASD. We tested (1) whether childhood FTD predicted prodromal symptoms of psychosis in adolescence and (2) whether childhood FTD was associated with greater ASD symptom severity in adolescence. ASD symptom severity was assessed in childhood (T1) and 7 years later (T2), using the autism diagnostic observation schedule (ADOS). At T1, the Kiddie-Formal Thought Disorder Rating Scale (KFTDS) was used to measure symptoms of FTD. At T2, the prodromal questionnaire (PQ) was used to assess prodromal symptoms of psychosis. FTD at T1 did not predict prodromal symptoms of psychosis at T2 in children with ASD. FTD symptoms at T1, namely illogical thinking, predicted ASD symptom severity at T2 and this effect remained significant after controlling for T1 ASD symptom severity. In children with ASD, illogical thinking predicts severity of ASD symptoms in adolescence, but FTD does not predict prodromal symptoms of psychosis.

Effects of escitalopram prophylaxis during antiviral treatment for chronic hepatitis C in patients with a history of intravenous drug use and depression.

OBJECTIVE: We aimed to identify those patients with hepatitis C virus who benefit most from prophylactic treatment with selective serotonin reuptake inhibitors (SSRIs) during antiviral therapy. METHOD: We performed post hoc analyses on a prospective randomized controlled trial (n = 79) of escitalopram versus placebo during antiviral therapy with pegylated interferon and ribavirin, conducted between August 2005 and June 2008. Our primary outcome measure was the association of baseline characteristics with the development of depression and/or depressive symptoms. Further, we studied effects of prophylactic escitalopram on depressive symptoms. Presence of a major depression was diagnosed using Mini-International Neuropsychiatric Interview (MINI), a short, structured interview used to diagnose DSM-IV-TR and ICD-10 disorders. Depressive symptoms were monitored during treatment by using the depression scale of Symptom Checklist-90 (SCL-90), Montgomery-Asberg Depression Rating Scale (MADRS), and Beck Depression Inventory (BDI) at baseline and weeks 4, 12, and 24 of antiviral therapy. RESULTS: Depression occurred in 14 patients receiving placebo and in 5 patients receiving escitalopram (Pearson χ², P = .01). Combination of history of depression and intravenous drug use was associated with depression (odds ratio = 12.60; 95% CI, 2.47-64.34; P < .01). Moreover, treatment with selective serotonin reuptake inhibitor compared to placebo was associated with a significant reduction in estimated mean depressive symptoms measured by SCL-90 (P = .03) and BDI (P = .048), but not with MADRS (P = .64). CONCLUSIONS: Patients infected by hepatitis C virus with a history of depression and intravenous drug use carry the highest risk to develop interferon-induced depression. In this subset of patients, prophylaxis with escitalopram results in the most substantial decrease of interferon-induced depressive symptoms on the SCL-90 depression scale and the BDI.

Sound improves diminished visual temporal sensitivity in schizophrenia.

Visual temporal processing and multisensory integration (MSI) of sound and vision were examined in individuals with schizophrenia using a visual temporal order judgment (TOJ) task. Compared to a non-psychiatric control group, persons with schizophrenia were less sensitive judging the temporal order of two successively presented visual stimuli. However, their sensitivity to visual temporal order improved as in the control group when two accessory sounds were added (temporal ventriloquism). These findings indicate that individuals with schizophrenia have diminished sensitivity to visual temporal order, but no deficits in the integration of low-level auditory and visual information.

Clinical aspects of comorbid schizophrenia and idiopathic Parkinson's disease.

The comorbidity of schizophrenia and idiopathic Parkinson's disease (IPD) is illustrated by a case description of a schizophrenic patient who develops motor symptoms finally diagnosed and treated as comorbid IPD. Several aspects of the clinical challenges of this comorbidity are discussed and an overview of earlier reported cases is presented. IPD must be distinguished from neuroleptic-induced parkinsonism by clinical course and characteristics. A SPECT scan is helpful for diagnosis. We recommend antiparkinsonian treatment to be prescribed only with the protection of antipsychotic agents, of which clozapine and quetiapine are the best choices.

Deficient multisensory integration in schizophrenia: an event-related potential study.

BACKGROUND: In many natural audiovisual events (e.g., the sight of a face articulating the syllable /ba/), the visual signal precedes the sound and thus allows observers to predict the onset and the content of the sound. In healthy adults, the N1 component of the event-related brain potential (ERP), reflecting neural activity associated with basic sound processing, is suppressed if a sound is accompanied by a video that reliably predicts sound onset. If the sound does not match the content of the video (e.g., hearing /ba/ while lipreading /fu/), the later occurring P2 component is affected. Here, we examined whether these visual information sources affect auditory processing in patients with schizophrenia. METHODS: The electroencephalography (EEG) was recorded in 18 patients with schizophrenia and compared with that of 18 healthy volunteers. As stimuli we used video recordings of natural actions in which visual information preceded and predicted the onset of the sound that was either congruent or incongruent with the video. RESULTS: For the healthy control group, visual information reduced the auditory-evoked N1 if compared to a sound-only condition, and stimulus-congruency affected the P2. This reduction in N1 was absent in patients with schizophrenia, and the congruency effect on the P2 was diminished. Distributed source estimations revealed deficits in the network subserving audiovisual integration in patients with schizophrenia. CONCLUSIONS: The results show a deficit in multisensory processing in patients with schizophrenia and suggest that multisensory integration dysfunction may be an important and, to date, under-researched aspect of schizophrenia.