Revealing the reporting disparity: VigiBase highlights underreporting of clozapine in other Western European countries compared to the UK.

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.

Risk of clozapine-associated agranulocytosis and mandatory white blood cell monitoring: Can the regulations be relaxed?

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 Clozapine was withdrawn from the market and only reintroduced with strict mandatory white blood cell monitoring as long as treatment lasts and thresholds at which clozapine must be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 × 109/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.

Exploring low clozapine C/D ratios, inverted clozapine-norclozapine ratios and undetectable concentrations as measures of non-adherence in clozapine patients: A literature review and a case series of 17 patients from 3 studies.

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).

Clozapine ultrarapid metabolism during weak induction probably exists but requires careful diagnosis. A literature review, five new cases and a proposed definition.

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.

Escaping the Long Shadow Cast by Agranulocytosis: Reflections on Clozapine Pharmacovigilance Focused on the United Kingdom.

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.

Feasibility and Effect of Increasing Clozapine Plasma Levels in Long-Stay Patients With Treatment-Resistant Schizophrenia.

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.

Clozapine and COVID-19 Vaccination: Effects on blood levels and leukocytes. An observational cohort study.

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.

An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels.

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.

COVID-19: Risks, Complications, and Monitoring in Patients on Clozapine.

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.

A multi-center naturalistic study of a newly designed 12-sessions group psychoeducation program for patients with bipolar disorder and their caregivers.

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.

The chronotherapeutic treatment of bipolar disorders: A systematic review and practice recommendations from the ISBD task force on chronotherapy and chronobiology.

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.

The characteristics of psychotic features in bipolar disorder.

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 (ß = -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 (ß = 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.

Dose reduction of high-dose first-generation antipsychotics or switch to ziprasidone in long-stay patients with schizophrenia: A 1-year double-blind randomized clinical trial.

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.

Treatment for Negative Symptoms in Schizophrenia: A Comprehensive Review.

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.

The treatment of premenstrual syndrome with preparations of Vitex agnus castus: a systematic review and meta-analysis.

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 (I2, 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.

The Effect of Glycopyrrolate on Nocturnal Sialorrhea in Patients Using Clozapine: A Randomized, Crossover, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Nocturnal sialorrhea is one of the most frequent adverse events in clozapine treatment. Symptomatic management of sialorrhea usually consists of off-label treatment with anticholinergic agents. The aim of the current study is to evaluate the efficacy and safety of glycopyrrolate in patients using clozapine that experience sialorrhea. METHODS: In a double-blind randomized crossover trial, patients with nocturnal sialorrhea (n = 32) were randomized to treatment with glycopyrrolate 1 mg or placebo. This double-blinded phase was followed by an optional open label extension phase with glycopyrrolate 2 mg. Exposure periods consisted of 6 consecutive days and were separated with 1 washout week. The primary outcome was clinical improvement of nocturnal sialorrhea assessed by the Patient Global Impression of Improvement (PGI-I). RESULTS: The proportion of patients with a clinical improvement according to PGI-I did not significantly differ between 1 mg and placebo (18.8% vs 6.3%, P = 0.289); however, in patients using glycopyrrolate 2 mg once daily versus placebo, it did (43.5% vs 6.3%, P = 0.039). Glycopyrrolate was not associated with severe adverse events or worsening of cognitive adverse events. CONCLUSIONS: Glycopyrrolate 1 mg was not superior to placebo, whereas 2 mg showed a significant clinical improvement of nocturnal sialorrhea compared with placebo. Glycopyrrolate seemed to be a tolerable anticholinergic agent in the treatment of clozapine-associated sialorrhea.