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BackgroundSchizophrenia is associated with lower intelligence and poor educational performance relative to the general population. This is, to a lesser degree, also found in first-degree relatives of schizophrenia patients. It is unclear whether bipolar disorder I (BD-I) patients and their relatives have similar lower intellectual and educational performance as that observed in schizophrenia.MethodThis cross-sectional study investigated intelligence and educational performance in two outpatient samples [494 BD-I patients, 952 schizophrenia spectrum (SCZ) patients], 2231 relatives of BD-I and SCZ patients, 1104 healthy controls and 100 control siblings. Mixed-effects and regression models were used to compare groups on intelligence and educational performance.ResultsBD-I patients were more likely to have completed the highest level of education (odds ratio 1.88, 95% confidence interval 1.66-2.70) despite having a lower IQ compared to controls (β = -9.09, S.E. = 1.27, p < 0.001). In contrast, SCZ patients showed both a lower IQ (β = -15.31, S.E. = 0.86, p < 0.001) and lower educational levels compared to controls. Siblings of both patient groups had significantly lower IQ than control siblings, but did not differ on educational performance. IQ scores did not differ between BD-I parents and SCZ parents, but BD-I parents had completed higher educational levels.ConclusionsAlthough BD-I patients had a lower IQ than controls, they were more likely to have completed the highest level of education. This contrasts with SCZ patients, who showed both intellectual and educational deficits compared to healthy controls. Since relatives of BD-I patients did not demonstrate superior educational performance, our data suggest that high educational performance may be a distinctive feature of bipolar disorder patients.

There is emerging evidence of social cognitive impairments in bipolar disorders (BD). Less evident is the question if social cognitive impairments are predictive of psychosocial functioning, independently of neurocognitive impairment. The aims of the study were to investigate if patients with BD-I showed impairments in facial emotion recognition and alterations in affective empathy, in relation to healthy controls, and if these impairments would predict psychosocial functioning, after accounting for neurocognitive impairments. Thirty-seven patients diagnosed with BD-I, in an euthymic state, and 37 matched healthy controls underwent an assessment including a facial recognition test (ERT) and a self-report scale of affective empathy (BEES). Patients additionally underwent an extensive neuropsychological assessment consisting of traditional tests. Patients with BD-I were significantly less able to recognize the emotion fear compared to healthy controls. However, the lower ability to recognize fear did not predict psychosocial functioning. In addition, it was not related to any of the other neuropsychological variables. The degree of self-reported empathy did not differ between patients and healthy controls. The results add to the evidence of a specific deficit in recognizing fear in BD-I; however, a link with psychosocial functioning was lacking. It is possible that the ability to recognize fear is related to a more narrow concept of interpersonal functioning than to the broad concept of psychosocial functioning. Future research should be directed towards aspects of social functioning in relation to social cognitive impairments, while taking account of subgroups of social cognitive functioning., (© 2025 The Author(s). Journal of Neuropsychology published by John Wiley & Sons Ltd on behalf of The British Psychological Society.)

Background: Currently, guidance on the most effective treatment for patients with clozapine-resistant schizophrenia-spectrum disorders (SSD) is lacking. While augmentation strategies to clozapine with aripiprazole and electroconvulsive therapy (ECT) have been demonstrated to be effective in patients with clozapine-resistant schizophrenia spectrum disorders (CRS), head-to-head comparisons between these addition strategies are unavailable. We therefore aim to examine the feasibility of a larger randomized, single-blind trial comparing the effectiveness, cost-effectiveness, and safety of aripiprazole addition vs. ECT addition in CRS., Methods: In this multi-center, randomized, single-blind feasibility study, the feasibility of recruiting 20 participants with CRS who will be randomized to either aripiprazole or bilateral ECT addition will be assessed. The main endpoint is the number of patients willing to be randomized. The number of screened individuals and reasons to decline participation will be recorded. Effects will be estimated for the benefit of the foreseen larger trial. To that end, differences between both arms in symptom severity will be assessed using blinded video assessments. In addition, tolerability (e. g., cognitive functioning), safety, quality of life, recovery, and all-cause discontinuation will be compared. The follow-up period is 16 weeks, after which non-responders will be given the option to switch to the other treatment., Discussion: Strengths of this feasibility trial include maintaining blinding with video assessment, a possibility to switch groups in case of non-response, and a broad set of outcome measures. Identification of factors contributing to non-participation and drop-out will generate valuable information on trial feasibility and may enhance recruitment strategies in a follow-up RCT., Trial Registration: The study has been approved by the Medical Research Ethics Committee of the Amsterdam University Medical Center, location AMC, and was registered on 1 May 2022 in the EU Clinical Trials Register (EudraCT) under the trial name 'EMECLO' (2021-006333-19)., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Pharmacovigilance studies indicate clozapine history is marked by adverse drug reactions (ADRs)., Objective: In a 2021 article, the United Kingdom (UK) had >90 % of European clozapine-related fatal outcomes in VigiBase, the World Health Organization's pharmacovigilance database. Two possibly opposing hypotheses could explain this disparity: 1) fewer reported fatal outcomes in other Western European countries mainly reflect underreporting to VigiBase, and 2) the higher number of UK reports reflects higher real relative mortality., Methods: VigiBase reports from clozapine's introduction to December 31, 2022, were studied for ADRs and the top 10 causes of fatal outcomes. The UK was compared with 11 other top reporting Western countries (Germany, Denmark, France, Finland, Ireland, Italy, Netherlands, Norway, Spain, Sweden and Switzerland). Nine countries (except Ireland and Switzerland) were compared after controlling for population and clozapine prescriptions., Results: The UK accounted for 29 % of worldwide clozapine-related fatal outcomes, Germany 2 % and <1 % in each of the other countries. The nonspecific label "death" was the top cause in the world (46 %) and in the UK (33 %). "Pneumonia" was second in the world (8 %), the UK (12 %), Ireland (8 %) and Finland (14 %). Assuming that our corrections for population and clozapine use are correct, other countries underreported only 1-10 % of the UK clozapine fatal outcome number., Conclusions: Different Western European countries consistently underreport to VigiBase compared to the UK, but have different reporting/publishing styles for clozapine-related ADRs/fatal outcomes. Three Scandinavian registries suggest lives are saved as clozapine use increases, but this cannot be studied in pharmacovigilance databases., Competing Interests: Declaration of competing interest In the last 3 years, JAG reports he is Vice President Scientific Affairs of HLS Therapeutics, Toronto, Canada which is the manufacturer of CLOZARIL in the USA and Canada; CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantic; RdF has received speaker fees from Janssen Pharmaceutica and travel support from Janssen Pharmaceutica and ROVI; GS has received speaker/consultation fees from Dexcel Pharma, HLS Therapeutics and Thermo Fisher. In the last 3 years, the remaining authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Up to 1/2 of outpatients prescribed clozapine may be partially/fully non-adherent, based on therapeutic drug monitoring (TDM). Three indices for measuring partial/full non-adherence are proposed a: 1) clozapine concentration/dose (C/D) ratio which drops to half or more of what is expected in the patient; 2) clozapine/norclozapine ratio that becomes inverted; and 3) clozapine concentration that becomes non-detectable., Methods: These 3 proposed indices are based on a literature review and 17 cases of possible non-adherence from 3 samples: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and a Uruguayan outpatient study., Results: The first index of non-adherence is a clozapine C/D ratio which is less than half the ratio corresponding to the patient's specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. The second index is inverted clozapine/norclozapine ratios in the absence of alternative explanations. The third index is undetectable concentrations. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to ≥1/2 of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio became inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9-11)., Conclusion: Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented)., Competing Interests: Declaration of competing interest GS has received speaker/consultation fees from HLS Therapeutics and Thermo Fisher. AEAY has received speaker/advisory board fees from Janssen, Abdi İbrahim Otsuka and Nobel, and has received investigator fees from Janssen. CBE received honoraria for conferences from Forum pour la formation médicale, Janssen-Cilag, Lundbeck, Otsuka, Sandoz, Servier, Sunovion, Sysmex Suisse AG, Takeda, Vifor-Pharma, and Zeller in the past 3 years. SRC received speaker/consultation fees from: Janssen-Cilag, Lundbeck, Otsuka and Servier and research funding from Janssen-Cilag, Lundbeck, Otsuka and Gilead. SHK has received research grants from Janssen and Dongwha. JGL has consulted/spoken on behalf of Saladax Biomedical. RMP has received speaker/consultation fees from Eisai, HLS Therapeutics, Jansen, Lundbeck, and Otsuka. HT has received grants from Daiichi Sankyo and Novartis Pharma; speaker's fees from EA. Pharma, Eisai, Kyowa, Janssen, Lundbeck, Meiji Seika Pharma, MSD, Otsuka, Sumitomo Pharma, Takeda, and Yoshitomiyakuhin; and consulting fees from Janssen, Mitsubishi Tanabe Pharma, Ono, and Sumitomo Pharma. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantic. In the last 3 years, the remaining authors report no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

After the introduction of clozapine eight Finnish patients died after developing agranulocytosis. Clozapine was withdrawn from the market and only reintroduced with strict mandatory white blood cell monitoring as long as treatment lasts and thresholds at which clozapine must be discontinued definitively. The fear of agranulocytosis and the need for intensive blood monitoring is the single most important barrier for prescribers and patients alike and leads to underprescription of the only effective and approved medication for treatment-resistant schizophrenia. We summarize evidence that the risk of agranulocytosis is smaller than perceived at the time of reintroduction, is concentrated in the first 18 weeks of treatment, is not greater than with other antipsychotics thereafter and that frequent blood monitoring has not demonstrably decreased the rate of agranulocytosis. Therefore we propose 1) mandatory monitoring of the absolute neutrophil count (ANC) exclusively during the first 18 weeks of clozapine treatment, 2) that thereafter the prescriber and the well-informed patient decide together about further monitoring frequency, 3) that clozapine treatment must be stopped if the ANC falls below 1.0 × 10 9 /L. Continuation of clozapine or a rechallenge are possible if prescriber and patient determine that the benefits outweigh the risks. 4) National registries which control the haematologic monitoring are unnecessary and do not help to reduce clozapine-induced agranulocytosis. They should at least be restricted to the first 18 weeks of clozapine use., Competing Interests: Declaration of competing interest No one of the authors has competing interests to declare. I declare for all authors that we have not received any financial support for the preparation of the article., (Copyright © 2023 Elsevier B.V. All rights reserved.)

During weak induction (from smoking and/or valproate co-prescription), clozapine ultrarapid metabolizers (UMs) need very high daily doses to reach the minimum therapeutic concentration of 350 ng/ml in plasma; clozapine UMs need clozapine doses higher than: 1) 900 mg/day in patients of European/African ancestry, or 2) 600 mg/day in those of Asian ancestry. Published clozapine UMs include 10 males of European/African ancestry, mainly assessed with single concentrations. Five new clozapine UMs (two of European and three of Asian ancestry) with repeated assessments are described. A US double-blind randomized trial included a 32-year-old male smoking two packages/day with a minimum therapeutic dose of 1,591 mg/day from a single TDM during open treatment of 900 mg/day. In a Turkish inpatient study, a 30-year-old male smoker was a possible clozapine UM needing a minimum therapeutic dose of 1,029 mg/day estimated from two trough steady-state concentrations on 600 mg/day. In a Chinese study, three possible clozapine UMs (all male smokers) were identified. The clozapine minimum therapeutic dose estimated with trough steady-state concentrations >150 ng/ml was: 1) 625 mg/day, based on a mean of 20 concentrations in Case 3; 2) 673 mg/day, based on a mean of 4 concentrations in Case 4; and 3) 648 mg/day, based on a mean of 11 concentrations in Case 5. Based on these limited studies, clozapine UMs during weak induction may account for 1-2% of clozapine-treated patients of European ancestry and <1% of those of Asian ancestry. A clozapine-to-norclozapine ratio <0.5 should not be used to identify clozapine UMs., Competing Interests: Declaration of competing interest GS has received speaker/consultation fees from HLS Therapeutics and Thermo Fisher. SRC received speaker/consultation fees from: Janssen-Cilag, Lundbeck, Otsuka and Servier and research funding from Janssen-Cilag, Lundbeck, Otsuka and Gilead. SH Kim has received research grants from Janssen and Dongwha. HT has received grants from Daiichi Sankyo and Novartis Pharma; speaker's fees from EA. Pharma, Eisai, Kyowa, Janssen, Lundbeck, Meiji Seika Pharma, MSD, Otsuka, Sumitomo Pharma, Takeda, and Yoshitomiyakuhin; and consulting fees from Janssen, Mitsubishi Tanabe Pharma, Ono, and Sumitomo Pharma. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantic. In the last 3 years, the remaining authors report no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose/background: A recent article in this journal presented a US perspective regarding the modernization of clozapine prescription and proposed an escape from the long shadow cast by agranulocytosis., Methods: Here, an international group of collaborators discusses a point of view complementary to the US view by focusing on worldwide outcomes of clozapine usage that may be uneven in terms of frequency of clozapine adverse drug reactions., Findings/results: Studies from the Scandinavian national registries (Finland and Denmark) did not find increased mortality in clozapine patients or any clear evidence of the alleged toxicity of clozapine. Data on clozapine-associated fatal outcomes were obtained from 2 recently published pharmacovigilance studies and from the UK pharmacovigilance database. A pharmacovigilance study focused on physician reports to assess worldwide lethality of drugs from 2010 to 2019 found 968 clozapine-associated fatal outcomes in the United Kingdom. Moreover, the United Kingdom accounted for 55% (968 of 1761) of worldwide and 90% (968 of 1073) of European fatal clozapine-associated outcomes. In a pharmacovigilance study from the UK database (from 2008 to 2017), clozapine was associated with 383 fatal outcomes/year including all reports from physicians and nonphysicians. From 2018 to 2021, UK clozapine-associated fatal outcomes increased to 440/year., Implications/conclusions: The interpretation of fatal outcomes in each country using pharmacovigilance databases is limited and only allows gross comparisons; even with those limitations, the UK data seem concerning. Pneumonia and myocarditis may be more important than agranulocytosis in explaining the uneven distribution of fatal outcomes in clozapine patients across countries., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: It is unknown whether increasing the clozapine plasma level to 400, 750, or even 1000 ng/mL is a feasible and effective strategy in patients with treatment-resistant schizophrenia (TRS). We investigated this in long-stay patients with TRS., Methods: In long-stay TRS patients, doses of clozapine were increased gradually to reach target plasma levels of 400, 750, or 1000 ng/mL, depending on the clinical response and tolerability. After an effective or tolerated level was reached, positive and negative syndrome scale scores were evaluated after 3 months and 1 year., Results: Twenty-eight patients were included. Overall, 54% of the patients, and especially patients 60 years and older, could not achieve one of the clozapine target levels because of adverse effects. Three physically vulnerable patients died, probably not directly related to clozapine use. Although only 21% of patients achieved a more than 20% reduction in total symptoms at the 1-year follow-up, the mean severity of positive symptoms decreased from 18.18 to 15.10 ( P < 0.01). The largest decrease in positive symptoms was seen in TRS patients who achieved a plasma level of 750 ng/mL of clozapine., Conclusions: Most TRS patients older than 60 years could not tolerate high clozapine levels and so this should not be attempted in older or otherwise physically vulnerable patients. Increasing clozapine levels to approximately 750 ng/mL in middle-aged patients with longstanding TRS may modestly reduce the severity of positive symptoms and improve the response rate., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To investigate the safety of COVID-19 vaccination in patients on clozapine as regards plasma clozapine concentration and haematological parameters., Methods: We conducted a multicentre observational cohort study from 22 February 2021 to 2 September 2021. Primary outcomes were clinically relevant increase in clozapine blood levels (>100 μg/L increase compared to baseline) and clozapine alert levels (>1000 μg/L). Secondary outcomes were granulocytopenia, leukocytopenia and lymphocytopenia. Outcomes were measured approximately 5 days after the first and (where applicable) second dose of COVID-19 vaccine., Results: This study included 139 patients. Compared to baseline, clozapine blood levels increased significantly (ES = 0.28, p = 0.003) after the second vaccination. Clinically relevant increases in clozapine blood levels occurred in 20/92 patients (22%) and in 16/56 patients (29%) during the first and second phases, respectively. Clozapine alert levels developed in one patient (1%) following the first dose and in three patients (5%) after the second dose. In both phases, changes in white blood cells (WBC) were limited to mild granulocytopenia (3% and 5%), moderate granulocytopenia (1% and 0%) and leukocytopenia (2% and 3%) without cause for extra monitoring according to the guideline., Conclusion: In general, as regards WBC counts COVID-19 vaccination seems to be safe in patients with SMI. Changes in WBC had no clinical implications. Psychoeducation on the symptoms of clozapine intoxication is recommended, especially in patients with clozapine blood levels approaching the upper limit of the therapeutic range. Increase in the C-reactive protein (CRP) level can signal inflammation rapidly and help to prevent clozapine intoxication following vaccination., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration., Competing Interests: In the last 3 years, the following authors had no conflict of interest: Drs. de Leon, Schoretsanitis, Molden, Smith, Solismaa, Švancer, Olmos, Ricciardi, Iglesias-Garcia, Iglesias-Alonso, Spina, Ruan, Chuan-Yue Wang, Gang Wang, Tang, Lin, Lane, Rajkumar, González-Esquivel, Jung-Cook, Baptista, Rohde, Nielsen, Verdoux, Quiles, Sanz, De las Cuevas, Cohen, Schulte, Chopra, McCollum, Shelton, Kaithi, Farooq, McGrane, Lana, Arrojo-Romero, Rădulescu, Every-Palmer, Bebawi, Bhattacharya, Otsuka, Lazary, Torres, Yecora, Motuca, Chan, Zolezzi, Ouanes, De Berardis, Grover, Kirilochev, Soloviev, Ayub, Silva, Bonelli, Temmingh, Decloedt, Pedro, Pacheco Palha, LLerena, Fernandez-Egea, Siskind, Masmoudi, Mohd Saffian, Leung and Buckley. In the last 3 years several authors report conflicts of interests. Dr. Seppälä is permanent medical advisor, received lecture fees and is an advisory board member from Viatris that markets clozapine in Finland and other European countries. Dr. Kopeček participated in speakers/advisory boards and lectured with the support of Angelini, Janssen Pharmaceuticals, Lundbeck and Richter Gedeon. Dr. Yong Sik Kim received grants, research support and honoraria from Janssen, Otsuka, Whan in Pharm and Bukwang Pharm (Sumitomo Dannipon Pharma). Dr. Se Hyun Kim received research grants from and/or served as a lecturer for Janssen, Eli Lilly, and Dongwha. Dr. Ertuğrul has received speaker’s honoraria from Abdi İbrahim Otsuka. Dr. Anıl Yağcıoğlu has received speaker’s honoraria and consulting fees from Janssen and Abdi İbrahim Otsuka. Dr. Cotes has received research funding from Otsuka, Lundbeck, Roche, Alkermes, and is a consultant for Saladax Biomedical. Dr. Kane reports personal fees from Alkermes, personal fees from Allergan, personal fees from Bristol-Myers Squibb, personal fees from IntraCellular Therapies, Janssen, Lundbeck, Minerva, Neurocrine, Otsuka, Pierre Fabre, Reviva, Sunovion, Takeda, Teva, outside-the-submitted work from LB Pharma, MedAvante and The Vanguard Research Group. Dr. Ng had served as consultant for Grunbiotics, Lundbeck, Servier, and Janssen-Cilag, and received research speaker honoraria from Servier, Janssen-Cilag and Pfizer.IMcG received royalties from Hogrefe Publishing Corp. T.L. Dr. Bilbily is supported by the National Institute on Drug Abuse training grant 5T32DA007261-30 (MPI). Dr. Hiemke received speaker’s honoraria from Otsuka. Dr. López-Jaramillo reports financial support for research from Financial support from the National Institute of Mental Health, USA, MinCiencias, Colombia and the Universidad de Antioquia, Colombia. Dr. Eap received honoraria for conferences or teaching CME courses from Janssen-Cilag, Lundbeck, Otsuka, Sandoz, Servier, Sunovion, Vifor-Pharma, and Zeller. Dr. Seifritz has received honoraria from Schwabe GmbH for educational lectures. He has further received educational grants and consulting fees from Janssen Cilag, Lundbeck, Angelini, Otsuka, Servier, Recordati, Vifor, Sunovion, and Mepha. Dr. Bousman is a member of the Clinical Pharmacogenetics Implementation Consortium (CPIC) and Pharmacogene Variation Consortium (PharmVar). Dr. Kelly has served as a consultant for Alkermes, Lyndra and Sunovion. Dr. Procyshyn has been on the speaker's bureau and attended advisory board meetings for Janssen, Lundbeck, and Otsuka. Dr. Adebayo was on the advisory board of Janssen for a Long Acting Injectable Paliperidone palmitate in Nigeria. Janssen is not involved in Clozapine in Nigeria. Dr. Fountoulakis has received grants in the past, served as consultant, advisor or CME speaker, or received support to attend congresses by the following entities: AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka, Pfizer, the Pfizer Foundation, Sanofi-Aventis, Servier, Shire and others. Since January 2020 he has been the director of Cochrane Greece and completely free from any conflict of interest. Dr. Wilkowska has received research support from Angelini, Biogen, Eli Lilly and Company, Janssen-Cilag, Lundbeck, Polpharma, Sanofi and Valeant. Dr. Cubała has received research support from Alkermes, Allergan, Auspex, Biogen, Celon, Ferrier, Forest Laboratories, Janssen, Otsuka, and Sanofi; he has served on speaker bureaus for Angelini, Celon, Janssen, and Sanofi, and he has served as a consultant for GW Pharmaceuticals, Janssen, Celon and Sanofi. Dr. Villagrán-Moreno has received speakerʼs honoraria from Janssen and have developed lectures and presented clozapine lectures for Adamed, which sells clozapine in Spain; he has participated in advisory boards for Rovi and in research projects for Otsuka. Dr. Crespo-Facorro has received funding unrelated to the present work for research projects and/or honoraria as a consultant or speaker from the following entities: Angelini, Janssen-Cilag, Lundbeck, Otsuka, Mylan, Sanofi-Aventis, ADAMED, Agencia Española de Investigacion, Instituto de Salud Carlos III, the EU Seventh Framework Program and Horizon 2020. Dr. Takeuchi has received speaker’s fees from EA Pharma, Kyowa, Janssen, Lundbeck, Meiji Seika Pharma, Mochida, Otsuka, Sumitomo Dainippon Pharma, Takeda, and Yoshitomiyakuhin. Dr. Tsukahara has received speaker's honoraria from Eisai Inc. Dr. Gründer has served as a consultant for Allergan (Dublin, Ireland), Boehringer Ingelheim (Ingelheim, Germany), Institute for Quality and Efficiency in Health Care (IQWiG, Cologne, Germany), Janssen-Cilag (Neuss, Germany), Lundbeck (Copenhagen, Denmark), Otsuka (Chiyoda, Japan), Recordati (Milan, Italy), Sage (Cambridge, USA), and Takeda (Osaka, Japan). He has served on the speakers’ bureau of Gedeon Richter (Budapest, Hungary), Janssen Cilag, Lundbeck, Otsuka, Recordati. He has received grant support from Boehringer Ingelheim, Lundbeck and Saladax (Bethlehem, USA). He is co-founder and/or shareholder of Mind and Brain Institute GmbH (Zornheim, Germany), Brainfoods GmbH (Zornheim, Germany), OVID Health Systems GmbH (Berlin, Germany) and MIND Foundation gGmbH (Berlin, Germany). Dr. Sagud participated in lectures for the following companies: Alkaloid, Belupo, Elli Lilly, Gedeon Richter, Jadran Galenski Laboratorij, Johnson / Johnson, Lundbeck, Makpharm, Pliva, Stada and participated in the clinical trial: Eli Lilly, Krka and Gedeon Richter. Dr. Celofiga received speaker’s honoraria from Ely Lilly, Lundbeck, Richter Gedeon, Krka, Lek, Pliva, Angelini Pharma and participated in advisory boards for Janssen Pharmaceuticals and Lundbeck. Dr. Ignjatovic Ristic developed and presented clozapine lectures with the support of Mylan, received speakerʼs honoraria from Mylan, Teva Serbia, Pharm Swiss, Krka and Janssen. Dr. Ortiz has been a consultant and has received honoraria from Janssen-Cilag. Dr. Elkis received research grants from the São Paulo Research Support Foundation (FAPESP) and honoraria for participation as a member of advisory boards, speaker, or travel support from the following pharmaceutical companies: Aché, Cristalia, Daiichi-Sankyo, Janssen, Mantecorp-Hypera, Sandoz, and Teva. Dr. Weizman received speakerʼs honoraria from Lundbeck, Lilly, Teva, Trima, Jansen, Medison, Novartis and AstraZeneca. These activities were unrelated to the current study. Dr Marder reports consultation fees from Roche, Sunovion, Merck, Boehringer Ingelheim and Otsuka. He reports research support from Boehringer-Ingelheim, and GW Pharma. Dr. Citrome has engaged in collaborative research with, or received consulting or speaking fees, from: AbbVie, Acadia, Alexza, Alkermes, Allergan, Angelini, Astellas, AstraZeneca, Avanir, Axsome, BioXcel, Boehringer Ingelheim, Bristol-Myers Squibb, Cadent Therapeutics, Eisai, Eli Lilly, Forum, Genentech, Impel, Indivior, Intra-Cellular Therapies, Janssen, Jazz, Karuna, Lundbeck, Luye, Lyndra, Medavante-Prophase, Meiji, Merck, Medivation, Mylan, Neurocrine, NeuroRx, Novartis, Noven, Osmotica, Otsuka, Pfizer, Reckitt Benckiser, Relmada, Reviva, Sage, Shire, Sunovion, Takeda, Teva, University of Arizona, Valeant, Vanda, and one-off ad hoc consulting for individuals/entities conducting marketing, commercial, or scientific scoping research. Dr. Freudenreich has the following financial relationship with a commercial interest to disclose (recipient SELF; content area SCHIZOPHRENIA): Alkermes – Research grant (to institution), consultant honoraria (Advisory Board); Avanir – Research grant (to institution); Janssen – Research grant (to institution), consultant honoraria (Advisory Board); Integral - Consultant honoraria; Neurocrine – Consultant honoraria (Advisory Board); Novartis – Consultant honoraria; Otsuka – Research grant (to institution); Roche – Consultant honoraria; Springer Verlag – Royalties (medical writer); Elsevier – Honoraria (medical editing); Global Medical Education – Honoraria (CME speaker and content developer); Medscape – Honoraria (CME speaker); American Psychiatric Association – Consultant honoraria (SMI Adviser); Wolters-Kluwer – Royalties (content developer); UpToDate – Royalties, honoraria (content developer and editor, including for a chapter on clozapine). Dr. Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Axsome, Damitsa, Gedeon Richter, Hikma, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Lundbeck, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of LB Pharma. Dr. Müller reports he has been a co-investigator for two pharmacogenetic studies where genetic test kits were provided as an in-kind contribution by Myriad Neuroscience. He did not receive any payments or any equity, stocks, or options from any pharmacogenetic companies. He is also a co-inventor of two patents assessing risk for antipsychotic-induced weight gain (pending)., (Thieme. All rights reserved.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The Dutch Clozapine Collaboration Group is frequently asked for advice about the management of clozapine-treated patients when infected with or vaccinated against SARS-CoV-2. We provide state of the art information about the risks of SARS-CoV-2 infection for patients on clozapine and we give advice on measures to be taken, especially in regard to the monitoring of clozapine plasma levels, WBC count and differentiation during COVID-19 and after vaccination. We present an overview of relevant editorials, observational studies, and case studies, in which COVID-19 was reported in patients on clozapine. Patients using clozapine may have a higher risk of infection than patients with schizophrenia spectrum disorders (SSD) using other antipsychotics. SARS-CoV-2 infection can result in a dangerous increase of clozapine plasma levels, and granulocytopenia and lymphocytopenia (generally mild and short-term) may also occur, usually not as a result of clozapine treatment. Clozapine intoxication, pneumonia and delirium are the main complications of COVID-19 in patients on clozapine. In order to prevent clozapine intoxication, reduction of the original dose by half is generally recommended in clozapine users who contract COVID-19. When a cytokine storm is suspected in an advanced stage of COVID-19, reduction by three quarters seems more appropriate. If COVID-19 patients on clozapine develop granulocytopenia, SARS-CoV-2, rather than clozapine, should be considered as the cause. Schizophrenia patients in general and clozapine users in particular belong to a high-risk group that warrants early vaccination on a medical indication., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: The Clozapine Plus Working Group is frequently consulted for advice on measures in case of infection with SARSCoV-2 and on vaccination against COVID-19 in patients receiving clozapine.

AIM: Inform about risks of infection with SARS-CoV-2 in patients with severe mental illness (SMI), patients with schizophrenia spectrum disorders (SSD), and patients treated with clozapine. Advise on monitoring of clozapine plasma levels and white blood cell count and differential in COVID-19 and after vaccination, as well as measures to be taken.

METHOD: Literature research and case studies.

RESULTS: SMI patients and in particular SSD patients have an increased risk of infection with SARS-CoV-2 with more hospitalizations and higher mortality than non-psychiatric patients. Patients using clozapine may be at greater risk of infection. SARS-CoV-2 infection may cause a dangerous increase of clozapine plasma levels and generally mild and short-term granulocytopenia and lymphocytopenia, which are usually not a result of clozapine treatment.

CONCLUSION: In case of COVID-19 extra alertness is required in patients with SMI and especially SSD. In clozapine users, in case of COVID-19, reduction in dose by half to three quarters of the original dose is recommended. When patients develop granulocytopenia, SARS-CoV-2 should be considered as the cause and not immediately clozapine. SMI patients and clozapine users in particular belong to a high risk group with a medical indication for early vaccination.

Background: Behavioural and psychological symptoms of dementia (BPSD) are common and contribute significantly to caregiver burden and institutionalization of the patient. Unfortunately, current guideline-based interventions are sometimes ineffective and BPSD can become extreme., Case Description: A 75-year-old man with dementia was admitted to a psychogeriatric unit because of very severe BPSD in a nursing home. Different kinds of pharmaceutical and psychological interventions had been tried but turned out to be ineffective. Therefore, we started with low dose clozapine which improved his behavior. We reduced the dose twice, whereupon the behavior deteriorated. By reintroducing the proper dose, his behavior became better again., Conclusion: Our case is in accordance with the available literature on Clozapine for BPSD: Six uncontrolled studies have shown a positive effect of clozapine for BPSD, even if other interventions failed. We conclude that clozapine may be tried in cases of serious refractory BPSD when guideline-based interventions are ineffective.

Background: Psychoeducation (PE) for bipolar disorder (BD) has a first-line recommendation for the maintenance treatment phase of BD. Formats vary greatly in the number of sessions, whether offered individually or in a group, and with or without caregivers attending. Due to a large variation in formats in the Netherlands, a new program was developed and implemented in 17 outpatient clinics throughout the country. The current study investigated the feasibility of a newly developed 12-sessions PE group program for patients with BD and their caregivers in routine outpatient practice and additionally explored its effectiveness., Methods: Participants in the study were 108 patients diagnosed with BD, 88 caregivers and 35 course leaders. Feasibility and acceptance of the program were investigated by measures of attendance, and evaluative questionnaires after session 12. Preliminary treatment effects were investigated by pre- and post-measures on mood symptoms, attitudes towards BD and its treatment, levels of self-management, and levels of expressed emotion., Results: There was a high degree of satisfaction with the current program as reported by patients, caregivers, and course leaders. The average attendance was high and 83% of the patients and 75% of the caregivers completed the program. Analyses of treatment effects suggest positive effects on depressive symptoms and self-management in patients, and lower EE as experienced by caregivers., Conclusions: This compact 12-sessions psychoeducation group program showed good feasibility and was well accepted by patients, caregivers, and course leaders. Preliminary effects on measures of self-management, expressed emotions, and depressive symptoms were promising. After its introduction it has been widely implemented in mental health institutions throughout the Netherlands.

Reactions on 'The effectiveness of monoamine oxidase inhibitors in treatment-resistant depressive disorders in clinical practice; a retrospective open-label study'.

Background: There is no national protocol for the use of light therapy in bipolar depression.
AIM: The chronotherapy collaboration group of the Foundation for Bipolar Disorders intended to write a protocol for light therapy in bipolar depressive episodes.
METHOD: Narrative review of several systematic reviews, two clinician's guides and deliberation with the sub-commission Guidelines of the Dutch Ophthalmologic Society.
RESULTS: The following indication was established: depressive episode, with or without seasonal features, in bipolar I or II disorder, including subsyndromal (depressive) seasonal complaints. The list of relative contra-indications (pre-existent retinal illnesses, systemic illnesses with effect on the retina and use of photosensitive medication) was shortened. In this case the medical professional discusses the possibility of an ophthalmologic consultation with the patient. Use of a mood stabilizer/antimanic medication in order to prevent mania or a mixed episode is only necessary in a depressive episode in bipolar I, but not in bipolar II disorder. Standard treatment is 10.000 lux white light during 30 minutes in the morning.
CONCLUSION: There is sufficient evidence to propose light therapy in a bipolar depressive episode with or without seasonal features.

Aims: To systematically review the literature on the efficacy and tolerability of the major chronotherapeutic treatments of bipolar disorders (BD)-bright light therapy (LT), dark therapy (DT), treatments utilizing sleep deprivation (SD), melatonergic agonists (MA), interpersonal social rhythm therapy (IPSRT), and cognitive behavioral therapy adapted for BD (CBTI-BP)-and propose treatment recommendations based on a synthesis of the evidence., Methods: PRISMA-based systematic review of the literature., Results: The acute antidepressant (AD) efficacy of LT was supported by several open-label studies, three randomized controlled trials (RCTs), and one pseudorandomized controlled trial. SD showed rapid, acute AD response rates of 43.9%, 59.3%, and 59.4% in eight case series, 11 uncontrolled, studies, and one RCT, respectively. Adjunctive DT obtained significant, rapid anti-manic results in one RCT and one controlled study. The seven studies on MA yielded very limited data on acute antidepressant activity, conflicting evidence of both antimanic and maintenance efficacy, and support from two case series of improved sleep in both acute and euthymic states. IPSRT monotherapy for bipolar II depression had acute response rates of 41%, 67%, and 67.4% in two open studies and one RCT, respectively; as adjunctive therapy for bipolar depression in one RCT, and efficacy in reducing relapse in two RCTs. Among euthymic BD subjects with insomnia, a single RCT found CBTI-BP effective in delaying manic relapse and improving sleep. Chronotherapies were generally safe and well-tolerated., Conclusions: The outcome literature on the adjunctive use of chronotherapeutic treatments for BP is variable, with evidence bases that differ in size, study quality, level of evidence, and non-standardized treatment protocols. Evidence-informed practice recommendations are offered., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: In a large and comprehensively assessed sample of patients with bipolar disorder type I (BDI), we investigated the prevalence of psychotic features and their relationship with life course, demographic, clinical, and cognitive characteristics. We hypothesized that groups of psychotic symptoms (Schneiderian, mood incongruent, thought disorder, delusions, and hallucinations) have distinct relations to risk factors., Methods: In a cross-sectional study of 1342 BDI patients, comprehensive demographical and clinical characteristics were assessed using the Structured Clinical Interview for DSM-IV (SCID-I) interview. In addition, levels of childhood maltreatment and intelligence quotient (IQ) were assessed. The relationships between these characteristics and psychotic symptoms were analyzed using multiple general linear models., Results: A lifetime history of psychotic symptoms was present in 73.8% of BDI patients and included delusions in 68.9% of patients and hallucinations in 42.6%. Patients with psychotic symptoms showed a significant younger age of disease onset (β = -0.09, t = -3.38, p = 0.001) and a higher number of hospitalizations for manic episodes (F11 338 = 56.53, p < 0.001). Total IQ was comparable between groups. Patients with hallucinations had significant higher levels of childhood maltreatment (β = 0.09, t = 3.04, p = 0.002)., Conclusions: In this large cohort of BDI patients, the vast majority of patients had experienced psychotic symptoms. Psychotic symptoms in BDI were associated with an earlier disease onset and more frequent hospitalizations particularly for manic episodes. The study emphasizes the strength of the relation between childhood maltreatment and hallucinations but did not identify distinct subgroups based on psychotic features and instead reported of a large heterogeneity of psychotic symptoms in BD.

Long-stay patients with severe schizophrenia are frequently treated with high doses of first-generation antipsychotics (FGA). Dose reduction or switching to ziprasidone may reduce the severity of negative symptoms and side effects. We investigated in a randomized double-blind trial whether a dose-reduction strategy to achieve an adequate dose of a FGA (5 mg/day haloperidol equivalents, n = 24) or switching to ziprasidone (160 mg/day, n = 24) in treatment resistant patients would decrease negative symptoms after 1 year of treatment. We found that negative symptoms did not change significantly in either condition. Positive symptoms, excited symptoms, and emotional distress worsened over time with ziprasidone, resulting in a significant difference between conditions in favour of FGA dose reduction. Relapse and treatment failure, defined as a prolonged or repeated relapse, occurred more often with ziprasidone than with FGA (45.8% versus 20.8%, and 25.0% versus 16.7%, respectively). Treatment with ziprasidone was superior for extrapyramidal symptoms. Our study establishes that lowering high FGA doses to an equivalent of 5 mg/day haloperidol or switching to ziprasidone is feasible in the vast majority of patients but does not improve negative or other symptoms. Neither FGA dose reduction nor switching to ziprasidone is an adequate alternative to clozapine for long-stay patients with severe treatment resistant schizophrenia., (Copyright © 2018 Elsevier B.V. and ECNP. All rights reserved.)

BACKGROUND Patients with epilepsy who use anticonvulsants frequently show low levels of folate and vitamin B12 and high levels of homocysteine. Patients with bipolar disorder use some anticonvulsants as mood stabilisers.
AIM: To determine whether some anticonvulsants lower folate and vitamin B12 and raise homocysteine levels.
METHOD: Systematic literature search to determine the relation between the anticonvulsants valproic acid, carbamazepine, lamotrigine and topiramate on the one hand and blood levels of folate, vitamin B12 and homocysteine on the other hand.
RESULTS: The vast majority of studies in adults and children showed a correlation between use of anticonvulsant carbamazepine and decrease of the folate level. Hardly any of the studies that examined the effect of valproic acid on folate levels found a correlation. There was next to no evidence of a correlation between the use of carbamazepine and a low vitamin B12 level in adults or children. In adults and children the use of valproic acid was found to correlate with a higher vitamin B12 level. Nearly all studies found an increase in homocysteine in adults and children using carbamazepine. Among the users of valproic acid, it was only children who showed a clear association with a rise in homocysteine level. The results for adults were contradictory. We were unable to make any clear statement about topiramate or lamotrigine because there have been very few publications about these anticonvulsants.
CONCLUSION: In adults and children with epilepsy use of carbamazepine is associated with a decrease of folate, valproic acid with a rise in the vitamin B12 level, and carbamazepine with an increase in homocysteine. Valproic acid showed only in children an association with the rise of the homocysteine level. Psychiatrists may find it advisable to control the levels of folate and homocysteine in adults and children who are taking carbamazepine and to measure homocysteine level in children taking valproic acid.

Negative symptoms (such as amotivation and diminished expression) associated with schizophrenia are a major health concern. Adequate treatment would mean important progress with respect to quality of life and participation in society. Distinguishing primary from secondary negative symptoms may inform treatment options. Primary negative symptoms are part of schizophrenia. Well-known sources of secondary negative symptoms are psychotic symptoms, disorganisation, anxiety, depression, chronic abuse of illicit drugs and alcohol, an overly high dosage of antipsychotic medication, social deprivation, lack of stimulation and hospitalisation. We present an overview of reviews and meta-analyses of double-blind, controlled randomised trials, in which the efficacy of pharmacological and non-pharmacological interventions for negative symptoms was assessed. Unfortunately, there have been very few clinical trials focusing on primary negative symptoms and selecting chronically ill patients with predominant persistent negative symptoms. An important limitation in many of these studies is the failure to adequately control for potential sources of secondary negative symptoms. At present, there is no convincing evidence regarding efficacy for any treatment of predominant persistent primary negative symptoms. However, for several interventions there is short-term evidence of efficacy for negative symptoms. This evidence has mainly been obtained from studies in chronically ill patients with residual symptoms and studies with a heterogeneous study population of patients in both the acute and chronic phase. Unfortunately, reliable information regarding the distinction between primary and secondary negative symptoms is lacking. Currently, early treatment of psychosis, add-on therapy with aripiprazole, antidepressants or topiramate, music therapy and exercise have been found to be useful for unspecified negative symptoms. These interventions can be considered carefully in a shared decision-making process with patients, and are promising enough to be examined in large, well-designed long-term studies focusing on primary negative symptoms. Future research should be aimed at potential therapeutic interventions for primary negative symptoms since there is a lack of research in this field.

Background: Premenstrual syndrome is characterized by the cyclic occurrence of physical, behavioral and psychological symptoms during the luteal phase of the menstrual cycle disappearing within a few days of the onset of menstruation. Generally symptoms are mild, but 5-8% of women suffer from severe PMS. Apart from conventional drugs, like serotonin reuptake inhibitors and oral contraceptives, complementary and alternative medicines such as Vitex agnus castus are used by many women experiencing PMS., Objective: Our objective was to determine the efficacy, tolerability, and acceptability of Vitex agnus castus preparations for treatment of premenstrual syndrome., Study Design: All journals in the Ovid software from inception through January 2016 were searched, including the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and PsycINFO. Gray literature was searched by Google Scholar and manufacturers of Vitex agnus castus preparations were contacted for information about unpublished trials. We included randomized controlled trials with Vitex agnus castus in women with premenstrual syndrome and/or premenstrual dysphoric disorder with a minimal duration of 2 menstrual cycles. The eligibility of the manuscripts was assessed by 2 reviewers independently. The data abstracted included characteristics of the study design, characteristics of the patient population, intervention details, type of comparator, method of diagnosis, and outcome measures. We adhered to the PRISMA guidelines., Results: We found 17 randomized controlled trials of Vitex agnus castus in the treatment of premenstrual syndrome. Fourteen of these could be included in the quantitative analysis. Thirteen of 14 studies with placebo, dietary supplements, or herbal preparations as controls reported positive effects of Vitex agnus castus on total premenstrual syndrome symptoms. Unfortunately most of the trials are associated with a high risk of bias. The pooled effect of Vitex agnus castus in placebo-controlled trials was large (Hedges g, -1.21; 95% confidence interval, -1.53 to -0.88), but heterogeneity was extremely high (I 2 , 91%). We were unable to single out factors that could explain this heterogeneity satisfactorily. The funnel plot and Egger tests suggest the presence of publication bias., Conclusion: Although meta-analysis shows a large pooled effect of Vitex agnus castus in placebo-controlled trials, the high risk of bias, high heterogeneity, and risk of publication bias of the included studies preclude a definitive conclusion. The pooled treatment effects should be viewed as merely explorative and, at best, overestimating the real treatment effect of Vitex agnus castus for premenstrual syndrome symptoms. There is a clear need for high-quality trials of appropriate size examining the effect of standardized extracts of Vitex agnus castus in comparison to placebo, selective serotonin reuptake inhibitors, and oral contraceptives to establish relative efficacy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Clozapine is an effective drug for treating psychosis in Parkinson's disease (PDP) and is registered as such in the Netherlands. However, clozapine can have adverse effects, including agranulocytosis. The new drug pimavanserin was recently registered in the United States for the treatment of PDP.
AIM: To review the literature on pimavanserin and discuss the position it currently occupies in the Netherlands as a potential treatment for PDP.
METHOD: Systematic search of the literature.
RESULTS: We found reports on four randomised controlled trials (RCTs), one review and six articles about the pharmacokinetics and pharmacodynamics of pimavanserin. Pimavanserin is an effective treatment for PDP, and, like clozapine, it has very few negative effects on motor skills. However, all of the RCTs were funded by the manufacturer of pimavanserin and the trials were conducted in a very selective patient population. This means that results cannot be generalised. Long-term results are not yet available. In earlier trials clozapine was shown to have a greater and faster antipsychotic effect. Many clinicians and psychiatrists have a great deal of experience with this drug. Another important point is that no-one has yet conducted a trial comparing clozapine and pimavanserin.
CONCLUSION: Given that the current second drug of choice, namely quetiapine, has not been found to be effective for PDP, we are of the opinion that - if pimavanserin is registered in the Netherlands - pimavanserin could be used when the current drug of choice, clozapine, is not completely effective or is poorly tolerated. For patients who have cognitive impairments in addition to psychosis, we advise testing the patient's reaction to a cholinesterase inhibitor before starting the patient on a course of antipsychotics.

Background: Lithium is associated with adverse effects on cognitive functioning. However, there are published trials that have investigated the protective effects of lithium in cognitive decline.
AIM: To review studies that investigate the potentially protective effects of lithium on cognitive disorders.
METHOD: We studied English-language and Dutch reports on controlled, clinical trials published up to October 2016.
RESULTS: We found four relevant articles. Two studies indicated that cognitive functioning remained more stable when patients were given lithium than when they were given a placebo. One study, however, could not detect any difference between the effects of lithium and the effects of placebos. The fourth study, which examined patients' ability to tolerate lithium, could not find any difference in the cognitive functioning of patients.
CONCLUSION: The reported results indicate that the cognitive functioning of patients with pre-stage Alzheimer's disease remains more stable after patients have taken lithium than after they have taken a placebo.