To minimise infection during COVID-19, the clozapine haematological monitoring interval was extended from 4-weekly to 12-weekly intervals in South London and Maudsley NHS Foundation Trust.

To investigate the impact of this temporary policy change on clinical and safety outcomes.

All patients who received clozapine treatment with extended (12-weekly) monitoring in a large London National Health Service trust were included in a 1-year mirror-image study. A comparison group was selected with standard monitoring. The proportion of participants with mild to severe neutropenia and the proportion of participants attending the emergency department for clozapine-induced severe neutropenia treatment during the follow-up period were compared. Psychiatric hospital admission rates, clozapine dose and concomitant psychotropic medication in the 1 year before and the 1 year after extended monitoring were compared. All-cause clozapine discontinuation at 1-year follow-up was examined.

Of 569 participants, 459 received clozapine with extended monitoring and 110 controls continued as normal. The total person-years were 458 in the intervention group and 109 in the control group, with a median follow-up time of 1 year in both groups. During follow-up, two participants (0.4%) recorded mild to moderate neutropenia in the intervention group and one (0.9%) in the control group. There was no difference in the incidence of haematological events between the two groups (IRR = 0.48, 95% CI 0.02–28.15, P = 0.29). All neutropenia cases in the intervention group were mild, co-occurring during COVID-19 infection. The median number of admissions per patient during the pre-mirror period remained unchanged (0, IQR = 0) during the post-mirror period. There was one death in the control group, secondary to COVID-19 infection.

There was no evidence that the incidence of severe neutropenia was increased in those receiving extended monitoring.

Sexual dysfunction is a frequent adverse drug reaction (ADR) of antidepressants that considerably affects quality of life and adherence to therapy. We previously investigated the potential underlying neurofunctional mechanisms by neuroimaging methods and revealed a dampening of the dopaminergic mesolimbic-mesocortical reward system along with decreased sexual functioning under serotonergic antidepressants compared to placebo.

Within a combined pharmacoepidemiologic and pharmacodynamic approach, we examined the association between serotonin transporter (SERT) affinity of various antidepressants and corresponding alterations in sexual desire as ADR.

Using disproportionality analyses, reporting odds ratios (RORs) were calculated for reports indicating decreased sexual desire as ADR under the antidepressants. The data were extracted from the WHO global database of individual case safety reports VigiBase and several MedDRA terms were grouped for “Sexual Desire Disorders”. For the pharmacodynamic assessment, we calculated Pearson correlation coefficients between SERT affinity and corresponding RORs

16 signals were detected for “Sexual Desire Disorders”. We observed a statistically significant (r (20) =. 65, p = 0.001) association between SERT affinity and decreased sexual desire. Higher SERT affinity was associated with higher risk of sexual desire.

While sexual dysfunctions under serotonergic medication were previously described, we now elaborated that in particular attenuated sexual desire as ADR is associated with SERT affinity of the antidepressant. These results strengthen our previously described neurofunctional model regarding sexual dysfunction under antidepressant medication and indicate that the specific SERT affinity of the antidepressant drug should be considered in clinical practice to minimize the risk of this ADR.

No significant relationships.

Drug-induced liver injury is one of the leading causes for acute liver failure and drug withdrawal after marketing approval. One important risk factor is the extent of exposure of the hepatocytes to a substance, either by high doses or by long-term medication. In many psychiatric diseases, like schizophrenia long-term use of drugs is common. However, systematic data on the hepatotoxic potential of antipsychotics is scarce.

To perform an explorative analysis of pharmacovigilance data on the risk of hepatotoxicity related to the use of antipsychotics.

We conducted an explorative case/non-case study based on data from VigiBase for 30 antipsychotics marketed in the European Union. Reporting odds ratios were calculated for antipsychotics associated with the SMQ “Drug related hepatic disorders - comprehensive search” and the SMQ “Drug related hepatic disorders - severe events only”.

We found several associations of antipsychotics with drug-induced liver injury including associations with severe events. 17/30 antipsychotics were associated with “Drug related hepatic disorders - comprehensive search”, and for 10/30 substances were associated with severe hepatic events.

Several antipsychotics are associated with the risk for hepatotoxic side effects, even severe ones. Further research is warranted on patient and substance-dependent risk factors.

No significant relationships.

Clozapine-induced gastrointestinal hypomotility (CIGH) affects some 75% of patients treated with clozapine.

To document the incidence of potentially harmful CIGH in the UK.

We studied spontaneous UK pharmacovigilance reports recorded as clozapine-related gastrointestinal adverse drug reactions, 1992–2017.

There were 527 patients reported with potentially harmful CIGH; 33% (n = 172) died. Deaths averaged 1 per year 1992–1999, 5 per year 2000–2009 and 15 per year 2010–2017. Those who died were older (median 52 years v. 49 years) and had been prescribed clozapine for longer than those who recovered (median 11.3 years v. 4.8 years), but there was no difference in prescribed dose. Within the first 4 years of clozapine treatment, there were 169 reports of CIGH, of which 3% (n = 5) were fatal. At 10–14 years there were 63 reports of CIGH, of which 25% (n = 16) were fatal. Among the deaths, males were younger (median 51, range 22–89 v. median 57, range 24–89 years) with higher clozapine doses (median 450, range 100–900 v. median 300, range 12.5–800 mg/d) than females. In non-fatal CIGH, surgery was the most frequent outcome (n = 92). The procedures included appendectomy, ileostomy, total/partial colectomy, colostomy/stoma and proctosigmoidectomy. Clozapine dosage was reduced in 6 patients, stopped and restarted in 23, ‘continued’ in 6 and discontinued permanently in at least 76 patients.

The risk of serious morbidity/mortality from CIGH is substantial. The need to actively monitor bowel function and give laxatives to patients treated with clozapine is clear.

The approval of the esketamine nasal spray for treatment-resistant depression in March 2019 by the Food and Drug Administration (FDA), and few months later by the European Medicine Agency, triggered a vivid debate and many concerns, mainly because of the lack of convincing evidence on its efficacy and safety, based on the development programs, approval trials and few post-marketing trials.

We aimed to detect and characterize safety signals for esketamine, by analyzing relevant adverse events (AEs) reports in the FDA Adverse Event Reporting System (FAERS) database (March 2019-March 2020).

We performed disproportionality analysis through the case/non-case approach: reporting odds ratios (ROR) and information components (IC) with 95% confidence intervals (95%CI) were estimated for esketamine-related AEs with at least four counts. We compared serious and non-serious AEs using non-parametrical tests.

The FAERS database registered 962 reports of esketamine-related AEs in one year. Signals (i.e., statistically significant disproportionality) were detected for several AEs, such as dissociation, sedation, feeling drunk, suicidal ideation and completed suicide. Signals for suicidal ideation, but not suicide attempt and completed suicide, remained significant when comparing esketamine to venlafaxine. The comparison of patients with serious vs. non-serious esketamine AEs revealed that females, patients receiving antidepressant polypharmacy, co-medication with antipsychotics, mood stabilizers, benzodiazepines or somatic medications were more likely to suffer from serious AEs.

This real-world pharmacovigilance analysis detected signals of serious unexpected esketamine-related AEs, thus reinforcing current worries regarding esketamine safety/acceptability. Further real-world studies are urgently needed to unravel the safety profile of esketamine.

No significant relationships.

The only non-legal reference in Lord Cullen's Review of fatal accident inquiry (FAI) Legislation in Scotland (2009) was my audit of FAIs into 97 deaths in prison custody in Scotland, 1999–2003: recommending that waiting time from prisoner death to end of FAI should be less than 1 year for 90% of FAIs, and epidemiological rules for FAIs to have a written determination versus formal findings.

Audit of FAIs into 83 deaths in Scottish prison custody in the period 2010–2013.

Assessement of waiting times from prisoner death to end of FAI; dissemination of written determinations; self-inflicted death rate per 1000 prisoner-years; cause of natural deaths; and yellow card submissions. Detailed cross-checking was nec37essary between Scottish Prison Service and courts’ websites and the Scottish Fatalities Investigation Unit.

Of 83 FAIs into deaths in Scottish prison custody, 2010–2013, 37 (45%) were long-awaited (ongoing >2 years after the prisoner's death); 16 (19%, 95% CI 11–28%) beyond 3 years. Of 37 long-awaited FAIs, 27 made written determinations but only 12 of these (44%) were published. Self-inflicted deaths numbered 36: 1.1 per 1000 prisoner-years (95% CI 0.75–1.48). Of 47 deaths from natural causes, cardiovascular disease accounted for 23 (49%, 95% CI 34–63%); liver disease was implicated in 10 of 47. To support pharmacovigilance, submissions were made to Medicines and Healthcare Regulatory Agency for eight deaths (10%, 95% CI 4–19%).

FAIs into prisoner deaths in Scotland are too long-awaited given that four (5%) identified precautions that could have prevented death.

Le traitement de l’alcoolo-dépendance représente un enjeu majeur de santé publique en France. Le baclofène, myorelaxant d’action centrale, agoniste du récepteur GABA-B, dispose depuis 1974 d’une AMM pour le traitement de la spasticité musculaire. Devant une utilisation croissante du baclofène hors-AMM dans le traitement de l’alcoolo-dépendance, l’ANSM a organisé dès 2011 un suivi national de pharmacovigilance. Le RCP a été mis à jour le 27/11/13, introduisant de nouvelles précautions d’emploi, dont les troubles psychiatriques sévères, pouvant favoriser des dépressions majeures avec suicides et une sévérité accrue des effets indésirables. Une RTU, octroyée le 14/03/2014 par l’ANSM, permet désormais la prescription de baclofène dans deux indications spécifiées, après échec des autres traitements disponibles.

Rapporter les effets indésirables liés au baclofène dans le traitement de l’alcoolo-dépendance, conformément aux recommandations de l’ANSM, à travers l’étude de trois cas d’hypomanie, survenus à de faibles doses, chez des patients ayant des comorbidités psychiatriques, et tenter, au regard de la littérature, une approche analytique de ces données.

Ces épisodes, obligeant l’arrêt du traitement, ont évolué vers une guérison sans séquelle. Un seul cas est survenu dans le cadre de la RTU, objet d’une déclaration d’effet indésirable : le signalement d’hypomanie au CRPV a été considéré comme effet indésirable grave, non mentionné dans le RCP. La présence constante d’un antidépresseur interroge sur les interactions : leur utilisation concomitante, signalée comme association à prendre en compte, devrait-elle être déconseillée, par risque de virage hypomaniaque ?

Ces observations cliniques renforcent la question de l’efficacité du baclofène dans le traitement de l’alcoolo-dépendance en présence de pathologies psychiatriques associées par risque important d’effets indésirables graves. Le protocole de suivi de la RTU offre un cadre sécurisant et prometteur dans le système de pharmacovigilance. Les résultats d’études randomisées sont attendus prochainement.

Clozapine is mainly used in patients with treatment-resistant schizophrenia and may lead to potentially severe haematologic adverse events, such as agranulocytosis. Whether clozapine might be associated with haematologic malignancies is unknown. We aimed to assess the association between haematologic malignancies and clozapine using Vigibase®, the WHO pharmacovigilance database.

We performed a disproportionality analysis to compute reporting odds-ratio adjusted for age, sex and concurrent reporting of antineoplastic/immunomodulating agents (aROR) for clozapine and structurally related drugs (loxapine, olanzapine and quetiapine) compared with other antipsychotic drugs. Cases were malignant lymphoma and leukaemia reports. Non-cases were all other reports including at least one antipsychotic report.

Of the 140 226 clozapine-associated reports, 493 were malignant lymphoma cases, and 275 were leukaemia cases. Clozapine was significantly associated with malignant lymphoma (aROR 9.14, 95% CI 7.75–10.77) and leukaemia (aROR 3.54, 95% CI 2.97–4.22). Patients suffering from those haematologic malignancies were significantly younger in the clozapine treatment group than patients treated with other medicines (p < 0.001). The median time to onset (available for 212 cases) was 5.1 years (IQR 2.2–9.9) for malignant lymphoma and 2.5 years (IQR 0.6–7.4) for leukaemia. The aROR by quartile of dose of clozapine in patients with haematologic malignancies suggested a dose-dependent association.

Clozapine was significantly associated with a pharmacovigilance signal of haematologic malignancies. The risk-benefit balance of clozapine should be carefully assessed in patients with risk factors of haematologic malignancies. Clozapine should be used at the lowest effective posology.