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To investigate the safety of COVID-19 vaccination in patients on clozapine as regards plasma clozapine concentration and haematological parameters.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.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.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.

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.pAIM: 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.pMETHOD: Literature research and case studies.pRESULTS: 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.pCONCLUSION: 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.

Presents a case report of a 46-year-old Caucasian nonsmoker, lives at an institution for people with intellectual disabilities He is known to have a severe intellectual disability of unknown cause as well as schizophrenia, for which he takes 200 mg of clozapine twice daily The clozapine trough level at steady state was 553mg/L, the clozapine level/dose (C/D) ratio 1 4, and the clozapine/norclozapine (C/N) ratio 1 7 COVID-19 may be associated with hyper inflammation and extremely severe pneumonia This case illustrates that this can lead to an unexpectedly high increase in the clozapine level, with the danger of intoxication The recommendation to reduce the dosage of clozapine by half is therefore probably not cautious enough Frequent monitoring of the patient for any symptoms of intoxication and monitoring the clozapine levels may help to determine the dose day by day to avoid both underdosing, with the risk of psychotic relapse, and overdosing, with the risk of intoxication Calculating the C/D ratio may help with this (PsycInfo Database Record (c) 2021 APA, all rights reserved)

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

There is no national protocol for the use of light therapy in bipolar depression.br/AIM: The chronotherapy collaboration group of the Foundation for Bipolar Disorders intended to write a protocol for light therapy in bipolar depressive episodes.br/METHOD: Narrative review of several systematic reviews, two clinician's guides and deliberation with the sub-commission Guidelines of the Dutch Ophthalmologic Society.br/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.br/CONCLUSION: There is sufficient evidence to propose light therapy in a bipolar depressive episode with or without seasonal features.

To test whether: (1) psychiatrists will prescribe clozapine more often if they can delegate the monitoring tasks to an advanced nurse practitioner (ANP), (2) clozapine monitoring by an ANP is at least as safe as monitoring by a psychiatrist. Patients from 23 Dutch outpatient teams were assessed for an indication for clozapine. ANPs affiliated to these teams were randomized to Condition A: clozapine monitoring by an ANP, or Condition B: monitoring by the psychiatrist. The safety of monitoring was evaluated by determining whether the weekly neutrophil measurements were performed. Staff and patients were blinded regarding the first hypothesis. Of the 173 patients with an indication for clozapine at baseline, only seven in Condition A and four in Condition B were prescribed clozapine (Odds Ratio = 2.24, 95% CI 0.61–8.21; p = 0.225). These low figures affected the power of this study. When we considered all patients who started with clozapine over the 15-month period (N = 49), the Odds Ratio was 1.90 (95% CI 0.93–3.87; p = 0.078). With regard to the safety of the monitoring of the latter group of patients, 71.2% of the required neutrophil measurements were performed in condition A and 67.3% in condition B (OR = 0.98; CI = 0.16–3.04; p = 0.98). Identifying patients with an indication for clozapine does not automatically lead to improved prescription rates, even when an ANP is available for the monitoring. Clozapine-monitoring performed by an ANP seemed as safe as that by a psychiatrist. Electronic supplementary material The online version of this article (10.1007/s10488-020-01031-4) contains supplementary material, which is available to authorized users.

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.

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.

Objective Several studies show an association between schizophrenia and low levels of vitamin D. To date, there are only few studies about the prevalence of vitamin D deficiency in patients with bipolar disorder. We hypothesized that vitamin D deficiency is less common among patients with bipolar disorder than among patients with schizophrenia or schizoaffective disorder. A second hypothesis is that vitamin D deficiency is more prevalent among patients with schizophrenia, schizoaffective disorder, or bipolar disorders than among the general Dutch population.Most studies have been conducted with hospitalized patients; in this study, we only included outpatients. Methods All outpatients of a center for bipolar disorders and all outpatients of 3 flexible assertive community treatment teams were asked to participate in this cross-sectional study. Results We included 118 patients with bipolar disorder and 202 patients with schizophrenia or schizoaffective disorder. Vitamin D levels were deficient in 30.3% (95% confidence interval, 25.5-35.6) of the cases. The type of psychiatric disorder was not a predictor of vitamin D deficiency. The absolute difference in risk of deficiency between the study population and the Dutch Caucasian population was 23.8% (95% confidence interval, 18.3%-29.3%). Conclusions In this study, vitamin D deficiency was 4.7 times more common among outpatients with bipolar disorder, schizophrenia, or schizoaffective disorder than among the Dutch general population.Given the high prevalence of vitamin D deficiency, we believe that outpatients with bipolar disorder, schizophrenia, or schizoaffective disorder should be considered at risk of having low levels of vitamin D. Annual measurement of vitamin D levels in psychiatric outpatients with these disorders seems to be justified to maintain bone health, muscle strength, and to prevent osteoporosis.

It has been suggested that clozapine has one of the largest diabetic effects of all atypical antipsychotics. To confirm these findings, we examined retrospectively the risk of new-onset diabetes in long-term clozapine treatment compared to treatment with other antipsychotics in a matched control population with schizophrenia or schizoaffective disorder. Ninety-four adult patients with schizophrenia or schizoaffective disorder who had been treated with clozapine for 5 years or longer were matched on age, diagnosis, and sex to 94 patients without any use of clozapine. The groups were followed up for as long as 20 years. The cumulative incidence of new detection of diabetes in the clozapine group was 22.3% (mean follow-up, 12.3 years; absolute risk difference, 6.3%; 95% confidence interval, -4.9% to 17.5%). An additional rigorous analysis of the 83 matched pairs with normal glucose measurement before end point showed a significant risk difference between the 2 groups (21.7% compared with 8.4%) but may have been biased against clozapine. We conclude that definitive evidence showing a clinically significant larger risk for new-onset diabetes after long-term treatment with clozapine in comparison to other antipsychotics is lacking.

BackgroundDysfunction of neuroplasticity due to N-methyl-d-aspartate (NMDA) receptor hypofunction may be a causal factor for memory and executive dysfunctioning in schizophrenia. Deregulation of NMDA transmission in the prefrontal cortex may also explain negative and positive symptoms. Clozapine augmentation with memantine targets altered NMDA receptor-mediated neurotransmission in schizophrenia and showed substantial beneficial effects on several symptom domains in a small proof-of-concept study. We evaluate effects of memantine add-on treatment to clozapine for memory and executive function, and negative and positive symptoms in schizophrenia.MethodClozapine-treated patients with refractory schizophrenia were randomly assigned to 12 weeks of double-blind adjunctive treatment with memantine (n = 26) or placebo (n = 26). Crossover occurred after a 2-week placebo wash-out period. Primary endpoints were change from baseline to 12 weeks treatment and 14 weeks to 26 weeks treatment on memory and executive function using the Cambridge Neuropsychological Test Automated Battery (CANTAB), Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression Severity Scale (CGI-S). Side effects were assessed using the Liverpool University Neuroleptic Side-Effect Rating Scale.ResultsWhen compared with placebo, memantine improved a composite memory score comprising verbal recognition memory and paired associates learning task scores on the CANTAB (effect size = 0.30) and PANSS negative subscale score (effect size = 0.29). Side effects were mild and transient.ConclusionsIn patients with clozapine-treated refractory schizophrenia, memantine addition significantly improved verbal and visual memory and negative symptoms without serious adverse effects. These results justify further investigations on long-term memantine augmentation to clozapine in treatment-resistant schizophrenia.

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.br/AIM: To determine whether some anticonvulsants lower folate and vitamin B12 and raise homocysteine levels.br/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.br/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.br/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.

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.br/AIM: To review the literature on pimavanserin and discuss the position it currently occupies in the Netherlands as a potential treatment for PDP.br/METHOD: Systematic search of the literature.br/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.br/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.

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.br/AIM: To review studies that investigate the potentially protective effects of lithium on cognitive disorders.br/METHOD: We studied English-language and Dutch reports on controlled, clinical trials published up to October 2016.br/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.br/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.

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.

Clozapine is an efficacious antipsychotic drug for patients with treatment-resistant schizophrenia, but does not sufficiently improve these symptoms in a substantial proportion of this population. There is no convincing evidence for the efficacy of any clozapine augmentation strategy. New evidence suggests that glutamate receptors are a candidate target for therapeutic effects in schizophrenia. We present an overview of studies assessing the potential clinical utility of adding glutamatergic agents to clozapine. We conducted 3 metaanalyses of data on positive, negative and overall symptoms of schizophrenia, analysing results from 3 studies on clozapine augmentation with glycine, 6 studies on lamotrigine add-on therapy to clozapine and 4 studies on topiramate addition to clozapine.

IntroductionIn a recent placebo-controlled, double blind crossover trial (n = 52), we found significant beneficial effects on memory (d = 0.30) and negative symptoms (d = 0.29) after 12 weeks memantine augmentation in patients with clozapine-refractory schizophrenia.AimsIn this open-label 1 year extension study, we report the long-term effects and tolerability of memantine add-on therapy to clozapine.MethodsCompleters of the first trial who experienced beneficial effects during 12 weeks of memantine treatment received memantine for one year. Primary endpoints were memory and executive function using the Cambridge neuropsychological test automated battery (CANTAB), the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impression Severity Scale (CGI-S).ResultsOf 31 RCT completers who experienced beneficial effects from memantine, 24 received memantine for one year. The small improvement in memory found in the memantine condition in the placebo-controlled trial remained stable in the extension study. Executive function did not improve. After 26 weeks of memantine add-on therapy to clozapine, PANSS negative symptoms (r = 0.53), PANSS positive symptoms (r = 0.50), and PANSS total symptoms (r = 0.54) significantly improved. Even further significant improvement in all these measures was observed between 26 weeks and 52 weeks memantine, with effect sizes varying from 0.39 to 0.51. CGI-S showed a non-significant moderate improvement at 26 weeks (r = 0.36) and 52 weeks (r = 0.34). Memantine was well tolerated without serious adverse effects.ConclusionsIn the one-year extension phase, the favorable effect of adjunctive memantine on memory was sustained and we observed further improvement of positive, negative and overall symptoms of schizophrenia.Disclosure of interestP.F.J.S. reports personal fees from H. Lundbeck A/S, outside the submitted work and he is a board member of the Dutch Clozapine Collaboration Group. L.d.H., has received investigator-led research grants or recompense for presenting his research from Eli Lilly, Bristol-Myers Squibb, Janssen-Cilag and AstraZeneca.

IntroductionIn a recent 26-week placebo-controlled, crossover trial (n = 52) we found significant positive effects on verbal and visual memory, and negative symptoms in clozapine-treated patients with refractory schizophrenia.ObjectivesIn this 1-year extension study, we report the long-term effects and tolerability of memantine add-on therapy to clozapine.AimsTo evaluate the persistence of improvements in cognitive functioning and symptoms of memantine add-on therapy to clozapine in schizophrenia.MethodsCompleters of the first trial who experienced a beneficial effect of memantine after 12 weeks continued memantine for one year. Primary endpoints were change from baseline to 26 weeks treatment and 26 weeks to 52 weeks treatment on memory and executive function using the Cambridge Neuropsychological Test Automated Battery (CANTAB), Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression Severity Scale (CGI-S). Secondary endpoints were change on the Health of the Nation Outcome Scales (HoNOS) and Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS).ResultsOf 32 completers who experienced a beneficial effect of memantine 23 patients continued memantine for one year. Memory improvement was sustained, verbal recognition memory improved even further between t = 26 weeks and t = 52 weeks. Continued treatment with memantine add-on to clozapine was associated with significantly improved PANSS positive, negative and overall score, CGI-S and HoNOS scores.ConclusionsIn the extension phase the positive effect of memantine add-on therapy on verbal memory sustained and positive, negative and overall symptoms of schizophrenia, clinical global status and psychosocial functioning significantly improved. Memantine was well tolerated without serious adverse effects.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Persistent negative symptoms and cognitive impairment are major clinical problems in the treatment of schizophrenia. There is no convincing evidence regarding the efficacy of augmentation of clozapine with a second antipsychotic, ethyl eicosapentaenoic acid (E-EPA), an antidepressant, a mood stabilizer or extract of Ginkgo biloba in clozapine-resistant schizophrenia. We present an overview of studies in which the potential clinical utility of the addition of non-glutamatergic agents to clozapine is assessed. We performed a meta-analysis on the efficacy of both risperidone and aripiprazole compared to placebo. We compared the effects of the addition of a second antipsychotic or an antidepressant to clozapine on positive, negative, overall and affective symptoms of schizophrenia in double-blind placebo-controlled trials.

We discuss the relevance of the glutamate hypothesis in explaining cognitive disturbances and negative symptoms in schizophrenia. 4 lines of evidence support the hypothesis that glutamate deregulation, mainly through dysfunction of the N-methyl-D-aspartate (NMDA) receptor, is an important underlying mechanism of schizophrenia. Glutamate pathways are promising sites for intervention. Glutamate agonists combined with non-clozapine antipsychotics and glutamate antagonists augmented to clozapine show interesting clinical benefits in refractory schizophrenia. We illustrate how unique properties of the NMDA receptor antagonist memantine in addition to clozapine, may cause improvement of positive, negative and cognitive symptoms of schizophrenia.

Getuige publicaties in wetenschappelijke tijdschriften en lekenpers krijgen natuurgeneeswijzen steeds meer belangstelling.1 Tegenwoordig vragen depressieve patienten soms naar behandeling met sint-janskruid (Hypericum perforatum L.). In Duitsland is dit middel (met 25 procent) marktleider onder de antidepressiva en overtreft het de ssri's* (* = zie uitleg aan het einde van dit artikel) ruimschoots. Sommige preparaten, bijvoorbeeld Jarsin (300), worden ook door de Duitse ziekenfondsen vergoed. In Nederland en Belgie is de ervaring echter tot nog toe beperkt. Toch is sint-janskruid in verschillende preparaten vrij verkrijgbaar bij apotheken, drogisterijen en natuurvoedingswinkels (zie tabel 1). Soms blijken ook Nederlandse ziekenfondsen bereid deze te vergoeden. Deze bijdrage geeft in kort bestek een overzicht van de uitkomsten van dubbelblind, gerandomiseerd onderzoek naar de werkzaamheid van sint-janskruid bij de behandeling van depressie. We gaan in op vragen als: Voor welke groepen patienten heeft sint-janskruid een bewezen werkzaamheid en wat zijn de bijwerkingen?

Many patients eligible to receive clozapine do not receive it, either because they are concerned about or have previously experienced adverse effects, or because of a reluctance to undergoing mandatory blood monitoring. This chapter will combine research evidence and practical clinical experience to offer advice on improving the acceptability and tolerability of clozapine. It will cover common but troublesome problems such as hypersalivation and sedation, as well as the approach to re-challenging patients who have previously experienced suspected blood dyscrasias or cardiovascular complications of clozapine.

The addition of fluvoxamine to clozapine induces a rise of plasma concentrations of clozapine. This enables the prescription of a lower number of clozapine tablets, yet it attains sufficient clozapine plasma concentrations, and facilitates treatment adherence.Providing practical advice for the practical implementation of the addition of fluvoxamine to clozapine.A review of the literature with Ovid Medline and the presentation of a case series (N=7).Addition of 25 or 50 mg fluvoxamine induces a mean rise of plasma concentrations of clozapine with a factor 2-3, probably even higher with the addition of 100 mg. However, the range of this factor varies considerably between individuals. The use of clozapine and fluvoxamine at the same time possibly has a favourable impact on the metabolic side-effects of clozapine.Addition of fluvoxamine to clozapine can lead to a dangerous rise of clozapine plasma concentrations. However, it can also be used to prescribe a lower number of clozapine tablets and to facilitate treatment adherence. A sufficient safety margin should be taken and regular control of clozapine plasma concentrations is mandatory.

Tumors of the cerebral hemispheres comprise a big variety of histologic tumor types. Therefore, in the literature usually only specific subgroups such as benign gliomas and temporal lobe tumors are reported. In this study we report on 44 tumors of the cerebral hemispheres, including 9 angiomas. Apart from the treatment results concerning event free survival, the neurological and neuropsychological outcome of the patients were assessed. A peculiarity in the hemispheric tumors is their association with focal epilepsies. In 94% of our patient series, epileptic seizures had been the first tumor associated symptom and approximately 62% developed focal epilepsy. Seizure types, their association with tumor location and histology, the success of tumor therapy in concern of the epilepsy and the significance of the electroencephalogram in the follow up care of these patients were assessed separately.

The report of clozapine-induced late leukopenia by Latif et al. [1] adds to the body of literature on this rare but important subject [2–5]. We would like to comment on this case report and draw attention to the differences between guidelines on this subject. In line with the two most influential international guidelines, the European Medicines Agency (EMEA) [6] and the Food and drug Administration (FDA) [7], clozapine was withdrawn when the white blood count (WBC) was 2.80 9 10/l, below the accepted threshold of 3.0 9 10/l. Interestingly, while the EMEA states that clozapine must be stopped and never prescribed again when the white blood count (WBC) is \3.0 9 10/l or the neutrophil count (NTC) is\1.5 9 10/ l, the FDA leaves the possibility open for a rechallenge with clozapine if the WBC remains [2.0 9 10/l and the NTC [1.0 9 10/l. The risk of serious complications during close monitoring is limited: an NTC of 1.0–1.5 9 10/l is not accompanied by an increased risk of infection, and the risk is only slightly increased when the NTC is 0.5–1.0 9 10/l; however, infections are common when the NTC is 0.2–0.5 9 10/l and almost inevitable when the NTC drops below 0.2 9 10/l [8]. The patient described in the case report had only moderate leukopenia and mild neutropenia. Moreover, low NTC is not always a sign of a malign process and can present as ‘‘pseudo-neutropenia’’ or benign neutropenia. Pseudo-neutropenia has several causes, varying from a laboratory fault, extreme use of neutrophils due to a viral infection, diurnal variation (low NTC in the morning, higher NTC in the afternoon), and ethnicity (NTC levels are low in individuals of African or Yemenite Jewish descent). Although the case report does not provide sufficient information to determine whether these factors were taken into account, we assume they were. The more prevalent benign neutropenias are characterised by a rapid recovery of cell numbers (NTC and WBC) after discontinuation of clozapine therapy. The condition is readily reversible without residual symptoms. In contrast, a malign process is more severe, with a continuous decrease in NTC and WBC even after discontinuation of clozapine, as a result of the depletion of leukocyte precursors in the bone marrow by an as yet unknown process associated with clozapine therapy; it takes time for the bone marrow to recover. We were unable to decide which type of neutropenia was present from the information available in this case. The authors are members of the board of the Netherlands Clozapine Collaboration Group.

Objective: Clozapine is the preferred option for treatment-resistant schizophrenia. However, since 1975, clozapine has been known to cause agranulocytosis. In the clozapine screening guidelines, white blood cell count is mandatory. In the past 20 years, after its reintroduction, 3 other serious side effects, namely, diabetic ketoacidosis, gastrointestinal hypomotility, and myocarditis have been documented but have so far failed to be incorporated in the screening guidelines. The objective of this review is to determine whether an update of the screening guidelines for serious side effects with clozapine is evidence based.Data Sources: The English-language literature, available via MEDLINE or PubMed, on the incidence of 4 clozapine-related side effects, using clozapine, agranulocytosis, diabetic ketoacidosis, and gastrointestinal hypomotility as keywords, that have been published over the period 1976-2010, was collected.Study Selection: 16 studies that provided incidence rates or data from which these rates could be calculated were included.Data Extraction: We compared 1-year incidence rates, mortality rates in the whole study population and in the affected cases. When rates reflected longer periods of observation, the given rate was recalculated to obtain a 1-year incidence rate.Results: The incidence of clozapine-induced agranulocytosis varies between 3.8 parts per thousand-8.0 parts per thousand. The mortality rate is 0.1 parts per thousand-0.3 parts per thousand, and the case-fatality rate is 2.2 parts per thousand-4.2 parts per thousand. In diabetic ketoacidosis, the incidence was calculated at 1.2 parts per thousand-3.1 parts per thousand, and the case-fatality rate was 20%-31%. In gastrointestinal hypomotility, the incidence was 4 parts per thousand-8 parts per thousand, and the case-fatality rate was 15%-27.5%. The discrepancy in incidence rates between Australia (7 parts per thousand-34 parts per thousand) and the rest of the world (0.07 parts per thousand-0.6 parts per thousand) impairs a general approach of this side effect.Conclusions: In 2 of the 3 studied side effects, diabetic ketoacidosis and gastrointestinal hypomotility, reduction of mortality to the level of agranulocytosis is both necessary and feasible. In order to obtain this outcome, the screening guidelines need to be modified; early detection of treatment-emergent hyperglycemia, that might-via diabetes mellitus-develop into diabetic ketoacidosis, requires obligatory monthly measurement of fasting plasma glucose. To prevent gastrohypomotility, and complications therefrom, the clinician should be required to choose between either weekly monitoring or standard coprescription of laxatives for prevention. The reported incidence of myocarditis (high in Australia, low in the rest of the world) is too divergent to allow for an overall recommendation outside Australia. J Clin Psychiatry 2012;73(10):1307-1312 (c) Copyright 2012 Physicians Postgraduate Press, Inc.

A bipolar disorder is a mood disorder characterized by recurrent occurrences of manic, depressive or mixed episodes, separated by shorter or longer relatively symptom-free periods. In the Netherlands, the incidence of bipolar disorders is 1.9%. Bipolar disorders are usually treated with a combination of psycho-education, self-management and pharmacotherapy. Both the bipolar disorder and the drugs for treating this disorder have negative effects on oral health. Patients have, among other things, an increased risk of caries, xerostomia, taste abnormalities and bruxism. Extensive instruction in oral hygiene, supported frequently by professional oral health care, is therefore essential. Considering the possible interaction among different kinds of drugs, NSAIDs should only be prescribed after consulting the patient's psychiatrist.

In the last five years seven independently financed studies comparing first and second generation antipsychotics (FGAS and SGAS) have been published. Most of these studies were conducted among patients attending regular psychiatric practices. The results show that very few or no advantages are to be gained from using SGAS rather than FGAS. In general, the clinical effectiveness is not increased, but the side-effects are different. The effectiveness studies in fact definitely justify the selection of FGAS (particularly those of low and medium potency) if a change in medication is indicated.

Bipolar disorderis underdiagnosed. On average there is a delay of about 12 years between the onset of symptoms and a correct diagnosis of the disorder. This delay may lead to inadequate treatment. The Mood Disorder Questionnaire (MDQ) is a screening instrument to improve the detection ofbipolar disorder. Research has shown that the English version of this self-administered questionnaire has sufficient reliability and validity. A Dutch version of the MDQ (MDQ-NL) is now available. The MDQ-NL is not time-consuming for both patient and investigator and is well suited for screening. A positive test should be followed by assessment of the patient by a psychiatrist. Application of the MDQ-NL will lead to better recognition and treatment of bipolar disorder in the Netherlands.

Background: Clozapine is the gold standard in treatment of treatment-resistant psychotic patients. We know little about the effects of compulsory treatment in patients unwilling to accept the necessary treatment.Aims: To assess the effectiveness, tolerability and safety of compulsory treatment with clozapine (CTC).Method: A cohort of 17 consecutive patients given compulsory treatment with clozapine were rated retrospectively by their treating psychiatrists on the basis of their case notes.Results: CGI-S decreased significantly over tithe until last observation after a mean of more than 15 months. No patient deteriorated as measured by CGI-1. At last observation as many as ten of the 11 patients still on clozapine were classified as much to very much improved. The degree of custodial restriction at last observation showed improvement in 11 patients and no change in six. No serious adverse events were observed.Conclusion: A trial of compulsory treatment with clozapine showed this treatment to be feasible, effective, safe and well tolerated. (c) 2007 Elsevier Inc. All rights reserved.

Unter einer Asphyxie wird heute der Sauerstoffmangel lebenswichtiger Organe verstanden; eine Asphyxie kann intrauterin oder auch postnatal durch pulmonale und kardiozirkulatorische Insuffizienz auftreten. Im Verlauf der Asphyxie konnen sich Funktionsstorungen aller Organe (Niere, Herz, Leber, Darm, Lunge), in schweren Fillen kann sich ein Multiorganversagen mit hypoxisch-ischimi-scher Enzephalopathie entwickeln (s. Kap. 52).

Definition. Unter Enzephalitis versteht man eine Entzundung des Hirnparenchyms. Sie kann durch eine virale Infektion bedingt sein und lasst sich dann in 4 Gruppen unterteilen (Tab. 205.1).

131 Kinder, die als Neugeborene mit Verdacht auf eine Erkrankung oder zumindest Mitbeteiligung des Zentralnervensystems bei uns auf-genommen und nach einem bestimmten neurologischen Befundbogen untersucht wurden, haben wir bis zu einem Alter von 18 Monaten in ihrer Entwicklung verfolgt. Wir haben zu ermitteln versucht, welche neurologischen Befunde mit groser Sicherheit auf eine schlechte Prognose quo-ad vitam oder Sanationen hinweisen. 1. 40,5% der Kinder waren bei der Nachuntersuchung gesund, 26,7% hatten geringgradige Storungen der motorischen Entwicklung, 32,8% hatten neurologische Residualsyndrome oder waren an ihrer Erkrankung verstorben. 2. Prognostisch besonders ungunstige Erkrankungen der Neugeborenenperiode waren in dieser Reihenfolge zunehmend: Geburtstrauma (abnorme Geburt und Asphyxie), Misbildungen, schwere Erkrankungen von Herz und Lunge, Encephalitiden. 3. Eine sorgfaltige, unter Umstanden mehrfache und speziell auf die Neugeborenenperiode abgestellte neurologische Untersuchung erlaubt schon in den erten Lebenstagen schwer und dauerhaft geschadigte Kinder zu erkennen. 4. Alle Neugeborenen ohne eindeutige neurologische Ausfalle haben sich in unserer Untersuchungsreihe normal entwickelt. 5. Kinder mit bestimmten neurologischen Syndromen oder Syndromkombinationen in der Neugeborenenperiode (Hemisyndrome, Hypertonie und Apathie, Krampfe und Apathie oder Skeletmuskeldystonie) hatten bis auf seltene und noch unsichere Ausnahmen nach 1 bis 2 Jahren eine infantile Cerebralparese.

Objective: To provide information for physicians and patients on which to base a decision as to whether to stop mandatory blood testing. Data Sources: Articles on drug-induced blood dyscrasias were identified by searches of MEDLINE (1966—September 2005) and review of their bibliographies. Novartis was asked to provide additional data on clozapine, leukopenia, agranulocytosis, and suicidality. Study Selection and Data Extraction: Data on the chance of clozapine-induced leukopenia and agranulocytosis were combined with data about possible fatality and compared with the risks associated with other medications and with life in general. Data Synthesis: The chance of clozapine-induced leukopenia or agranulocytosis decreases exponentially over time. In the US, the chance in the second 6 months of treatment is 0.70/1000 patient-years and, after the first year, 0.39/1000 patient-years. The case fatality rate of clozapine-induced agranulocytosis is estimated as 4.2–16%, depending on whether a granulocyte colony-stimulating factor is used. Nevertheless, treatment with clozapine reduces overall mortality, probably because it reduces suicidality. Conclusions: After at least 6 months' treatment with clozapine, the mortality involved in stopping white blood cell monitoring is about the same as the mortality associated with other medications, such as mianserin or phenylbutazone, and with life in general (traffic or occupational accident). If the patient has been well informed and wishes to stop the monitoring, it is a medically justifiable option to do so and is preferable to stopping treatment with clozapine since this drug reduces overall mortality.

Clozapine is the gold standard and 'last resort' in treatment of refractory schizophrenia. It is important to know whether a trial with clozapine is adequate or not. Six studies show a significantly higher response rate at clozapine plasma trough levels above a therapeutic threshold of 350-400 micro g/L. The absolute risk reduction is about 40%. An additional study found best results with plasma levels between 300 and 700 micro g/L, and one (probably too small) study could not detect a significantly different response rate for 350-450 micro g/L in comparison to 200-300 micro g/L. In addition, two extension studies showed conversion from nonresponders to responders if plasma levels increased above the threshold. Investigations on time to response in treatment with clozapine are often hampered by not controlling for time until plateau of dose titration or clozapine concentration. One of the better studies found 34 responders within 8 weeks after the last dose escalation. The remaining 16 non-responding patients did not change their status during a mean follow-up of 75 weeks. A second 1 year trial found a superior differential response rate for clozapine in comparison to haloperidol only during the first 6 weeks. A third study combined regular clozapine plasma level assays with assessment of response status. At the time of response 17 out of 19 responders showed clozapine concentrations above 350 micro g/L. The nine non-responders remained below this threshold throughout the rest of the year. These results favour an approach of raising the clozapine plasma level in treatment-refractory schizophrenic patients who do not respond to an initial low-to-medium dose treatment with clozapine. Some patients, especially young male smokers, will need dosages higher than 900 mg/day. Addition of low-dose fluvoxamine while closely monitoring clozapine levels can help decrease the high number of necessary pills. An adequate trial with clozapine should last at least 8 weeks on a plasma trough level above 350-400 micro g/L.