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International audience; Background: Identifying the 30% of adhesive small bowel obstructions (aSBO) for which conservative management will require surgery is essential. The association between the previously described radiological score and failure of the conservative management of aSBO remains to be confirmed in a large prospective multicentric cohort. Our aim was to assess the risk factors of failure of the conservative management of aSBO considering the radiological score.Material and methods: This prospective observational study took place in 15 French centers over 3 months. Consecutive patients experiencing aSBO with no early surgery were included. The six radiological features from the Angers radiological computed tomography (CT) score were noted (beak sign, closed loop, focal or diffuse intraperitoneal liquid, focal or diffuse mesenteric haziness, focal or diffuse mesenteric liquid, and diameter of the most dilated small bowel loop > 40 mm).Results: Two hundred and seventy nine patients with aSBO were screened. Sixty patients (21.5%) underwent early surgery, and 219 (78.5%) had primary conservative management. In the end, 218 patients were included in the analysis of the risk factors for conservative treatment failure. Among them, 162 (74.3%) had had successful management while for 56 (25.7%) management had failed. In multivariate analysis, a history of surgery was not a significant risk factor for the failure of conservative treatment (OR = 0.11; 95%CI = 0-1.23). A previous episode of aSBO was protective against the failure of conservative treatment (OR = 0.36; 95%CI = 0.15-0.85) and an Angers CT score ≥ 5 as the only individual risk factor (OR = 2.39; 95%CI = 1.01-5.69).Conclusion: The radiological score of aSBO is a promising tool in improving the management of aSBO patients. A first episode of aSBO and/or a radiological score ≥5 should lead physicians to consider early surgical management.

La population pédiatrique est considérée comme vulnérable, et la prise en charge de la douleur nociceptive y est parfois complexe mais essentielle. Depuis 2013, la prescription de codéine est restreinte chez les enfants en raison du risque de dépression respiratoire parfois fatale lié à l’activité variable du cytochrome P450 (CYP) 2D6 qui bioactive la codéine en morphine. Les options thérapeutiques approuvées chez l’enfant sont limitées, et pour nombre de prescripteurs, le tramadol est devenu l’alternative de choix à la codéine. Le tramadol est cependant, comme la codéine, un promédicament opioïde qui doit être bioactivé par le CYP2D6. Il est donc également soumis à une importante variabilité de sa réponse et expose les enfants aux mêmes risques de complications respiratoires. La décision de traiter par tramadol doit prendre en compte les comédications, les comorbidités du patient, le type de douleur et les conditions de surveillance. Les soignants et les parents doivent être informés des risques liés à l’administration du tramadol, notamment la variabilité interindividuelle, les risques d’interactions médicamenteuses et les signes de surdosage. Dans les situations de douleurs récurrentes, une approche personnalisée, avec adaptation des doses et sélection du médicament antalgique en fonction de l’activité du CYP2D6, est certainement la méthode la plus sûre. Lorsque l’activité du CYP2D6 n’est pas connue, la prescription de tramadol reste envisageable si le traitement est initié à la dose minimale efficace, titré sous surveillance et administré sous une forme posologique adaptée à l’enfant. Chez l’enfant de moins de 12 ans et en présence de facteurs de risque de dépression respiratoire, la morphine reste une option prudente, puisque son métabolisme ne dépend pas du CYP2D6.

Background and objective Having to deal on a daily routine with prescriptions in adults with intellectual disability (ID), we systematically reviewed the literature on the specificities of pain interventions in that population, focusing on medication and trying to gather practical information on appropriate pain treatments. Given the scarcity of the literature on the topic, we also discussed the pharmacological considerations to be taken into account when prescribing analgesic drugs in that vulnerable population. Databases and data treatment Articles on pain and ID were searched in the Medline and Google scholar electronic databases using the key words "Intellectual Disability," "Developmental Disability" and specific keywords for pharmacological and non-pharmacological pain interventions. Preset outcomes about pharmacological treatment specificity, efficacy and safety were then collected. Results One hundred and fifty-two articles were found and 16 were retained based on our inclusion and exclusion criteria. Of the 16 articles, five were topical reviews. Among the 11 remaining articles, five discussed pharmacological interventions, four considered non-pharmacological interventions and two discussed both. As anticipated, the literature matching our specific outcomes about the pharmacological treatment of pain was scarce and for the most part not designed to answer the questions of specificity, efficacy and safety of pain treatment in adults with ID. Conclusion The specificity of analgesic treatments in adults with ID is a totally unexplored domain. In the absence of clinical guidelines, pharmacological facts-such as inter-individual variability in drug response, pharmacokinetic and pharmacodynamic interactions, frequent co-morbidities and ease of administration-must be systematically integrated, when prescribing in the population of adults with ID. Significance This review synthesizes the state of research on pain interventions in adults with ID and is one of the rare articles addressing the specificities of analgesic prescriptions in this population.

The reduction or suspension of psychotropic treatment may be necessary for various medical reasons. This can have serious consequences for patients, including clinical manifestations, both physical and psychological. These manifestations, which are often unpleasant, can compromise care during hospitalization and undermine the therapeutic alliance. Their early detection, readjustment of treatment, when necessary, as well as regular communication with the patient and among specialists are important tips to take into account from caregivers.La diminution ou mise en suspens d’un traitement psychotrope peut être imposée par des raisons médicales diverses. Cela peut avoir d’importantes conséquences pour les patients, notamment des manifestations cliniques, tant physiques que psychologiques. Elles sont souvent désagréables, peuvent compromettre l’adhésion aux soins lors d’une hospitalisation et mettre à mal le lien thérapeutique. Leur détection précoce, le réajustement du traitement quand nécessaire, ainsi que la communication régulière avec le patient et entre spécialistes sont des éléments importants à prendre en compte lors de ces prises en charge.

While morphine is the gold standard treatment for severe nociceptive pain in children, hydromorphone is increasingly prescribed in this population. This review aims to assess available knowledge about hydromorphone and explore the evidence for its safe and effective prescription in children. Hydromorphone is an opioid analgesic similar to morphine structurally and in its pharmacokinetic and pharmacodynamic properties but 5–7 times more potent. Pediatric pharmacokinetic and pharmacodynamic data on hydromorphone are sorely lacking; they are non-existent in children younger than 6 months of age and for oral administration. The current data do not support any advantage of hydromorphone over morphine, both in terms of efficacy and safety in children. Morphine should remain the treatment of choice for moderate and severe nociceptive pain in children and hydromorphone should be reserved as alternative treatment. Because of the important difference in potency, all strategies should be taken to avoid inadvertent administration of hydromorphone when morphine is intended.

Background Antibiomania is a rare but recognized side effect with yet unclear definite pathogenesis although multiple hypotheses have been proposed. The novelty of this case is the suspected pharmacodynamic drug-drug interaction between clarithromycin and amoxicillin-clavulanic acid. Case presentation We present the occurrence of a brief manic episode concerning a 50-year-old man with no psychiatric history, first started on amoxicillin-clavulanic acid therapy and then switched to clarithromycin for left basal pneumonia. Shortly after the antibiotic prescription, he presented psychiatric symptomatology (logorrhea, elevated mood, irritability, increase in physical activity and delusions). The antibiotic was stopped and the patient received lorazepam (2.5 mg p.o.) to treat psychomotor agitation. Approximately 12 h after clarithromycin cessation, amelioration was already observed, supporting the diagnosis of a clarithromycin-induced manic episode. Amoxicillin-clavulanic acid was then reintroduced because of the pneumonia and psychiatric symptoms reemerged. This second antibiotic was also stopped, and 1 week later, the patient was symptom-free. Conclusion The emergence of psychiatric side effects related to antibiotherapy, which is a common treatment, can greatly impact a patient’s quality of life. Early recognition and intervention could substantially influence the administered medical care and recovery. Moreover, given the widespread use of antibiotics including in combination, we thought our case report might be clinically useful as a clinical reminder relevant to the use of antibiotic combinations.

Decentration and cognitive restructuring are used in cognitive-behavioural therapy (CBT) with patients suffering from chronic pain and are reinforced by group work. They can also be useful to the general practitioner. Clinical vignettes summarize the role of group CBT in identifying realistic and meaningful activities. They stress decentration and cognitive restructuring as key therapeutic tools in group CBT. Using them with patients suffering from chronic pain is complex and challenging when it comes to allow the patients to overcome the impossibility to function 'as before' while figuring out how to cope 'as for now'.La décentration et la restructuration cognitive sont utilisées dans les thérapies cognitivocomportementales (TCC) chez les patients souffrant de douleurs chroniques et sont renforcées par le travail en groupe. Elles peuvent également être utilisées par les praticiens dans leurs cabinets. Des vignettes cliniques résument leur rôle dans l’identification d’activités réalistes et significatives et posent la décentration et la restructuration cognitive en tant qu’outils d’intérêt pour la TCC de groupe. Leur utilisation avec des patients douloureux chroniques peut permettre aux patients de surmonter l’impossibilité à faire « comme avant » pour s’imaginer parvenir à gérer « comme maintenant ».

Ketamine and its S-enantiomer, esketamine, have shown to be promising molecules for use in psychiatry. Widely investigated for the treatment of drug-resistant depression, they could be used in emergency conditions, due to their rapid onset of action, in two main conditions : 1) psychomotor agitation, and 2) acute suicidal ideation and behavior (suicidal crisis). In particular, intranasal administration offers a non-invasive, safe and very easy to administer option. An effect begins a few hours to a day after intake and lasts for about a week. These molecules present an innovative option for the future and their specific use in psychiatric emergencies.La kétamine et son énantiomère S, l’eskétamine, se sont révélés être des molécules prometteuses pour leur utilisation en psychiatrie. Largement étudiées pour le traitement de la dépression pharmacorésistante, elles pourraient être utilisées dans des conditions d’urgence et, grâce à leur rapidité d’action, dans deux situations : 1) l’agitation psychomotrice, et 2) l’idéation et le comportement suicidaire aigus (crise suicidaire). En particulier, l’administration par voie intranasale offre une option non invasive, sûre et facile à utiliser. On observe un effet quelques heures à un jour après la prise, qui perdure pendant environ une semaine. Ces molécules représentent une option innovatrice pour le futur et pour une utilisation spécifique aux urgences psychiatriques.

ObjectivesAdults with an intellectual disability (AWID) are often polymedicated because of somatic and psychiatric health problems. Besides, they may display challenging behaviours, leading to off-label prescription of psychotropic drugs, without efficacy and with numerous adverse effects. In this context, a prescription/deprescription tool (Tool for Optimising Prescription in Intellectual Disability/TOP-ID) was developed to improve the care of AWID. This paper describes how TOP-ID was designed.DesignFour-step consensus-based process involving a review of the literature, eight semistructured interviews and a two-round Delphi process.SettingSeventeen general practices and university and general hospitals from Belgium, France and Switzerland.ParticipantsEighteen French-speaking physicians from different domains of expertise participated in the Delphi process.Primary and secondary outcome measuresFor the Delphi iteration process, consensus was defined as at least a 65% agreement between the experts.ResultsTwo rounds were needed for the Delphi process. Eighty-one items of the tool were submitted to 18 out of 35 recruited French-speaking experts during the first round. Sixty-nine per cent of the items reached a rate of agreement of 65% or more in that round. Thirteen questions were reformulated and resubmitted for the second Delphi iteration round. All of the statements reached a rate of agreement of 65% or more in the second round.ConclusionTOP-ID is the first prescription–deprescription tool developed specifically for AWIDs in French. It is intended to help prescribers document patient care in order to reduce prescription errors and to improve safety. The next steps of the project include the development of an electronic version of TOP-ID and a utility study.

Behavioral disorders in people with developmental and intellectual disability are frequent but their management is rarely taught. This article is to help primary physicians prescribe drug treatment. We will also discuss the key elements of two of the most commonly used classes of drugs, taking into account the patient's co-morbidities, contraindications and the main side effects.Les troubles du comportement chez la personne en situation de handicap mental sont fréquents, mais leur prise en charge est peu enseignée aux médecins de premier recours. Cet article a pour objectif d’aider à la prescription d’un traitement médicamenteux. Nous discutons des éléments clés des deux classes de médicaments les plus utilisés, en tenant compte des comorbidités du patient, des contre-indications et des principaux effets secondaires.

The use over the last 50 years of antidepressants having both serotonergic and noradrenergic properties, as the first line for the management of neuropathic pain or chronic pain syndromes, is based on a twofold rationale: on the one hand, a plausible analgesic mechanism of action independent of the effect on mood, on the other hand, efficacy data in humans and animals. Their prescription should be part of a multimodal approach to pain. The dose to reach the analgesic effect, which on average occurs within four weeks after the initiation of treatment, is sometimes lower than the dose required to achieve the antidepressant effect. The choice of antidepressant will rely on the profile of adverse effects and other expected secondary benefits in the case of comorbidities.L’utilisation depuis 50 ans d’antidépresseurs ayant à la fois une action sérotoninergique et noradrénergique comme première ligne pour la prise en charge de douleurs neuropathiques ou de syndromes douloureux chroniques est basée sur les deux raisons suivantes : d’une part, un mécanisme d’action antalgique plausible et indépendant de l’effet thymique, d’autre part, des données d’efficacité chez l’humain et l’animal. Leur prescription doit s’inscrire dans une approche multimodale de la douleur. La dose nécessaire pour atteindre l’effet antalgique, qui survient en moyenne dans les 4 semaines après l’introduction du traitement, est parfois moins importante que celle qui permet d’obtenir l’effet antidépresseur. Le choix de la molécule se fera en fonction du profil d’effets indésirables et d’autres bénéfices secondaires éventuels attendus.

Suicide is a common cause of death in Switzerland. It often occurs during a period of crisis marked by a disruption of the subject's intrapsychic, interpersonal or social balance. The management of this crisis is crucial and essentially psychotherapeutic. Drug therapy may be necessary for the management of acute symptoms or for the prevention of long-term suicidal risk. Benzodiazepines and atypical antipsychotics are often used for acute symptoms such as anxiety or sleep disorders while other molecules are recognized in reducing long-term suicidal risk. Some disorders, such as borderline personality disorder, account for more frequent suicidal behaviors. The pharmacological management of these specific situations is discussed.Le suicide est une cause de mortalité fréquente en Suisse. Il survient souvent durant une période de crise marquée par une perturbation de l’équilibre intrapsychique, interpersonnel ou social du sujet. La prise en charge de cette crise est cruciale et essentiellement psychothérapeutique. Un traitement médicamenteux peut s’avérer nécessaire pour la gestion des symptômes aigus ou la prévention du risque suicidaire à long terme. Les benzodiazépines et les antipsychotiques atypiques sont souvent utilisés pour les symptômes aigus comme l’anxiété ou les troubles du sommeil. D’autres molécules sont reconnues dans la diminution du risque suicidaire à long terme. Certains troubles, comme le trouble borderline, rendent compte de comportements suicidaires plus fréquents. La prise en charge pharmacologique de ces situations spécifiques est discutée.

Since the endocannabinoid system is involved in immune function, the effect of cannabinoid intake on infectious conditions is questioned for several years and is of particular interest in the COVID 19 pandemia. Some data suggest that the immunomodulatory effect of cannabinoids may affect the course and severity of SARS-CoV-2 infection. Given the large number of cannabinoids consumers in the community, this commentary presents the current knowledge on the potential impact of cannabinoids and endocannabinoids on bacterial and viral infection courses namely SARS-CoV-2 disease. Practical recommendations, which can be drawn from the literature, are given.

International audience; Background & aims: Liver adenomatosis (LA) is characterized by the presence of at least 10 hepatocellular adenomas (HCAs), but the natural history of this rare liver disorder remains unclear. Thus, we aimed to reappraise the natural history and the risk of complications in a cohort of patients with at least 10 HCAs.Methods: We analyzed the natural history of 40 patients with LA, excluding glycogen storage disorders, in a monocentric cohort. Pathological examination was performed, with immunostaining and molecular biology carried out on surgical specimens or liver biopsies.Results: Forty patients (36 female) were included with a median follow-up of 10.6 (1.9-26.1) years. Six (15%) patients had familial LA, all with germline HNF1A mutations. Median age at diagnosis was 39 (9-55) years. Thirty-three (94%) women had a history of oral contraception, and 29 (81%) women had a pregnancy before LA diagnosis. Overall, thirty-seven (93%) patients underwent surgery at diagnosis. Classification of HCAs showed 46% of patients with HNF1A-mutated HCA, 31% with inflammatory HCA, 3% with sonic hedgehog HCA, 8% with unclassified HCA. Only 15% of the patients demonstrated a "mixed LA" with different HCA subtypes. Hepatic complications were identified in 7 patients: 1 patient (3%) died from recurrent hepatocellular carcinoma after liver transplantation; 6 (15%) had hemorrhages, of which 5 occurred at diagnosis, with 1 fatal case during pregnancy, and 2 occurred in male patients with familial LA. Four patients (10%) had repeated liver resections. Finally, 4 (10%) patients developed extrahepatic malignancies during follow-up.Conclusions: The diversity in HCA subtypes, as well as the occurrence of bleeding and malignant transformation during long-term follow-up, underline the heterogeneous nature of LA, justifying close and specific management. In patients with germline HNF1A mutation, familial LA occurred equally frequently in males and females, with a higher rate of bleeding in male patients.Lay summary: Liver adenomatosis is a rare disease characterized by the presence of 10 or more hepatocellular adenomas that may rarely be of genetic origin. Patients with liver adenomatosis have multiple adenomas of different subtypes, with a risk of bleeding and malignant transformation that justify a specific management and follow-up.

Gabapentinoids and opioids have in common that they are used in medicine in the treatment of pain, and by addicts in recreational use. In recent years, in the context of the "opioid epidemics", gabapentinoids, which had a reputation for low risk of abuse, have been increasingly prescribed. This was accompanied by increasingly frequent abuses, the patients most at risk being those suffering from opiate addiction. However, gabapentinoids increase the risks associated with opioids or other sedatives, due to a synergy of central depressant effects. This leads to reconsider the framework of their prescription and the management of chronic pain.

Purpose Sinusoidal obstruction syndrome (SOS) is a likely side effect of colorectal liver metastases (CRLM) chemotherapy. This study aimed to assess computed tomography scan (CT-scan) performance for SOS diagnosis for patients receiving neoadjuvant chemotherapy (NC) prior to CRLM surgery, comparing obtained results with pathological gold standard. Methods Preoperative CT-scans of 67 patients who had received a NC prior to liver resection for CRLM from 2011 to 2016 were retrospectively analysed. Positive diagnosis and severity of SOS were established after consensual review of the slides by three pathologists. Preoperative CT-scans were separately interpreted by two radiologists and evocative signs of SOS were sought, defined according to a literature review and operators experience. In order to identify SOS predictors, univariate analysis and multivariate logistic regression were used to study CT-scan signs and pathological results correlation. Results Twenty-nine patient (43%) had an SOS, 22 (33%) were low-grade and 7 (10%) were high-grade. All patient had received a median of 6 cures (3–27) containing Oxaliplatin for 53 (79%) of them. In univariate analysis, hepatic heterogeneity (p Conclusion CT-scan can detect suggestive signs of SOS in patients receiving chemotherapy for CRLM. By integrating clinical and biological information into CT-scan data, it may be fruitful to create a positive diagnostic and severity score for chemotherapy-induced SOS.

Background Solitary plasmacytoma of the liver is a very rare and aggressive form of plasma cell dyscrasia. To the best of our knowledge, very few cases have been reported without systemic disease. We reported a rare case of hepatic solitary plasmacytoma that successfully responded to fractionated stereotactic radiotherapy. Case presentation A 64-year-old white French man had monoclonal gammopathy of the immune globulin G lambda type; he developed a cholestasis and cytolysis with the discovery of a subscapular nodule. A biopsy showed plasma cells and, for several reasons, the decision was made to use the fractionated stereotactic radiotherapy strategy. After 20 months, he is asymptomatic and the immune globulin G component has completely disappeared. Conclusion We suggest considering Cyberknife® radiosurgery as an option for the treatment of hepatic solitary plasmacytoma.

Background Rebound cholinergic syndrome is a rare, but well known unwanted phenomenon occurring after abrupt clozapine discontinuation. There have been previous reported cases of cholinergic rebound in the literature; however, these reports described cholinergic rebound following cessation of high doses of clozapine in patients diagnosed with schizophrenia. Here, we report a case of rebound cholinergic syndrome and catatonia in a male patient three days after abrupt discontinuation of 50 mg of clozapine prescribed for type I bipolar affective disorder. Case presentation A 66-year old male of Spanish origin, treated for type I bipolar affective disorder for 15 years and for Crohn disease, was brought to the emergency department because of a sudden onset of mutism, dysphagia and trismus. He was described catatonic and presented hypertension, tachycardia and tachypnea. His body temperature was normal and the laboratory tests were unremarkable at presentation. A head CT and an EEG were in the normal range. While reviewing his history, it appeared the he was on clozapine 50 mg a day, first introduced 2 months ago, during a previous hospitalization for a manic episode resistant to other mood stabilizers. For an unknown reason, the patient’s psychiatrist stopped clozapine three days before the admission and replaced it by risperidone 5 mg and quetiapine 200 mg daily. A cholinergic rebound syndrome was then evoked. The patient’s ability to speak recovered dramatically and fast after the intravenous administration of 2.5 mg of biperiden supporting the diagnosis. Risperidone and quetiapine were also stopped. The patient fully recovered in 20 days after the reintroduction of 50 mg of clozapine and 2.5 mg of biperiden daily. Conclusions This case report underscores that cholinergic rebound syndrome may occur in patients suffering from bipolar affective disorders, being on clozapine as a mood stabilizer. The low dose clozapine does not preclude severe manifestations of the phenomenon. Progressive tapering should therefore be adopted in any case.

Ein 61-jähriger Patient mit alkoholbezogener Störung (ABS) wurde mit Verdacht auf Schlafapnoe-Syndrom (SAS) überwiesen. Er hatte im Vorjahr drei Verkehrsunfälle, die auf Schläfrigkeit zurückgeführt wurden; diese Unfälle ereigneten sich kurz nach Beginn einer hochdosierten Behandlung mit Baclofen (2 × täglich 100 mg), einem Wirkstoff, der zunehmend im ABS-Management eingesetzt wird. Die Polysomnographie ergab ein schweres zentrales SAS (CSAS) mit einem Apnoe-Hypopnoe-Index (AHI) von 81,6/h. Baclofen wurde als mögliche Ursache des CSAS benannt. Nach seiner Absetzung erfolgte eine zweite Polysomnographie, die das Ausbleiben zentraler Apnoen und eine Verschiebung hin zu schwerem obstruktivem SAS (AHI 43,9/h) ergab, weshalb eine CPAP-Therapie (kontinuierliche Überdruckbeatmung) eingeleitet wurde. Schließlich wurde eine dritte Polysomnographie unter CPAP durchgeführt, nachdem der Patient die Einnahme von Baclofen (50 mg 2 × täglich) wiederaufgenommen hatte, woraufhin das CSAS (AHI 42,1/h) wieder auftrat. Dieser Fallbericht veranschaulicht die schädliche Wirkung von Baclofen auf die Atemphysiologie im Schlaf. Da das Medikament in der Regel hochdosiert einer Patientenpopulation verschrieben wird, die potenziell noch andere Substanzen konsumiert, die den Atemantrieb hemmen, ist diese mögliche Nebenwirkung von größter Bedeutung. Wenn die Anwendung von Baclofen bei Patienten mit ABS in Betracht gezogen wird, ist das Potenzial für schlafbezogene Atmungsstörungen abzuwägen und der Patient sorgfältig zu überwachen.

Meme si les evidences sont minces, il est frequent et parfois legitime en pratique d’avoir recours aux opioides chez un patient qui a mal, dont la qualite de vie et la fonction sont alteres par la douleur et qui ne repond pas aux antalgiques non opioides.

Auch wenn die Evidenz dafur dunn ist, ist es in der Praxis eine haufige und in manchen Fallen legitime Vorgehensweise, Opioide bei Schmerzpatienten einzusetzen, deren Lebensqualitat und Funktionsfahigkeit durch die Schmerzen eingeschrankt sind und die auf Nicht-Opioid-Analgetika nicht ansprechen.

This retrospective study evaluates the link between an adverse drug reaction (ADR) or a non-response to treatment and cytochromes P450 (CYP), P-glycoprotein (P-gp) or catechol-O-methyltransferase (COMT) activity in patients taking analgesic drugs for chronic pain. Patients referred to a pain center for an ADR or a non-response to an analgesic drug between January 2005 and November 2014 were included. The genotype and/or phenotype was obtained for assessment of the CYPs, P-gp or COMT activities. The relation between the event and the result of the genotype and/or phenotype was evaluated using a semi-quantitative scale. Our analysis included 243 individual genotypic and/or phenotypic explorations. Genotypes/phenotypes were mainly assessed because of an ADR (n = 145, 59.7%), and the majority of clinical situations were observed with prodrug opioids (n = 148, 60.9%). The probability of a link between an ADR or a non-response and the genotypic/phenotypic status of the patient was evaluated as intermediate to high in 40% and 28.2% of all cases, respectively. The drugs in which the probability of an association was the strongest were the prodrug opioids, with an intermediate to high link in 45.6% of the cases for occurrence of ADRs and 36.0% of the cases for non-response. This study shows that the genotypic and phenotypic approach is useful to understand ADRs or therapeutic resistance to a usual therapeutic dosage, and can be part of the evaluation of chronic pain patients.

Antidepressants are widely administered to chronic pain patients, but there is large interindividual variability in their efficacy and adverse effect rates that may be attributed to genetic factors. Studies have attempted to determine the impact of genetic polymorphisms in enzymes and transporters that are involved in antidepressant pharmacokinetics, for example, cytochrome P450 and P-gp. The impacts of genetic polymorphisms in the targets of antidepressants, such as the serotonin receptor or transporter, the noradrenaline transporter and the COMT and monoamine oxydase enzymes, have also been described. This manuscript discusses the current knowledge of the influence of genetic factors on the plasma concentrations, efficacy and adverse effects of the major antidepressants used in pain management.

Drug-induced liver injury (DILI) represents a complex clinical problem, both in terms of diagnosis and of therapeutic approach. When the suspected treatment is a psychotropic drug, the role of the liaison psychiatrist is not limited to the re-adaptation of the drug treatment. In this article, with a clinical case as an example, we will discuss the issues to deal with facing a perturbation of liver enzymes in a patient on psychotropic treatment. The risk and benefit assessment of a therapeutic window, as well as the overall care of the patient at the general hospital will be detailed.Les atteintes hépatiques d’origine médicamenteuse représentent une problématique clinique complexe tant sur le plan du diagnostic que sur celui de l’approche thérapeutique. Quand le médicament suspecté est un traitement psychotrope, le rôle du psychiatre de liaison ne se limite pas à la réadaptation du traitement médicamenteux. Dans cet article, et à partir d’un cas clinique adapté, nous aborderons la conduite à tenir face à une perturbation des enzymes hépatiques chez un patient sous traitement psychotrope. L’évaluation du rapport risque-bénéfice d’une fenêtre thérapeutique, ainsi que la prise en charge globale du patient à l’hôpital général seront discutées.

OBJECTIVE Drug-metabolizing enzymes (DMEs), such as cytochrome P450 (CYP) enzymes, and transporters have emerged as major determinants of variability in drug metabolism and response. This study investigated the association between CYP and P-glycoprotein activities and plasma antidepressant concentration in an outpatient clinical setting. Secondary outcomes were antidepressant efficacy and tolerance. We also describe phenotypes in patients treated with antidepressants and evaluate the tolerance of a minimally invasive phenotyping approach. METHODS From January 2015 to August 2015, 64 patients on a stable antidepressant regimen underwent a simultaneous assessment of steady-state antidepressant concentration and DME (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A) and P-glycoprotein transporter activity using a cocktail phenotyping approach. Psychiatric diagnoses were in accordance with DSM-5. RESULTS We observed a high proportion of subjects (> 20%) with reduced activity of CYP2C19, CYP2D6, CYP3A4, and P-glycoprotein. As expected, higher CYP activity for major metabolic pathways was associated with lower concentration of the parent compound (CYP2C19 and escitalopram, P = .025; CYP2D6 and fluoxetine, P < .001; CYP2C19 and sertraline, P = .001), higher concentration of the metabolite (CYP2D6 and O-desmethylvenlafaxine, P = .007), and higher metabolite-to-parent drug ratio (CYP2C19 and escitalopram, P = .03; CYP2D6 and fluoxetine, P < .001; CYP2C19 and sertraline, P = .048; CYP2B6 and sertraline, P = .006). Phenotyping also highlighted the relevance of a minor metabolic pathway for venlafaxine (CYP3A4). Insufficient response and adverse reactions to antidepressants were not significantly associated with plasma antidepressant concentration, DME, or P-glycoprotein activity. Tolerance of the phenotypic test in ambulatory settings was found to be excellent. CONCLUSIONS The phenotypic assessment of DMEs and a transporter is a valuable, well-tolerated method to explore the interindividual variability in drug disposition in clinical settings. The method is able to account for the inhibitory activity of antidepressants themselves and for polymedication, which is frequent in this population of refractory depressed patients. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02438072.

It is well known that the standard doses of a given drug may not have equivalent effects in all patients. To date, the management of depression remains mainly empirical and often poorly evaluated. The development of a personalized medicine in psychiatry may reduce treatment failure, intolerance or resistance, and hence the burden and costs of mood depressive disorders. The Geneva Cocktail Phenotypic approach presents several advantages including the “in vivo” measure of different cytochromes and transporter P-gp activities, their simultaneous determination in a single test, avoiding the influence of variability over time on phenotyping results, the administration of low dose substrates, a limited sampling strategy with an analytical method developed on DBS analysis. The goal of this project is to explore the relationship between the activity of drug-metabolizing enzymes (DME), assessed by a phenotypic approach, and the concentrations of Venlafaxine (VLX) + O-demethyl-venlafaxine (ODV), the efficacy and tolerance of VLX. This study is a multicentre prospective non-randomized open trial. Eligible patients present a major depressive episode, MADRS over or equal to 20, treatment with VLX regardless of the dose during at least 4 weeks. The Phenotype Visit includes VLX and ODV concentration measurement. Following the oral absorption of low doses of omeprazole, midazolam, dextromethorphan, and fexofenadine, drug metabolizing enzymes activity is assessed by specific metabolite/probe concentration ratios from a sample taken 2 h after cocktail administration for CYP2C19, CYP3A4, CYP2D6; and by the determination of the limited area under the curve from the capillary blood samples taken 2–3 and 6 h after cocktail administration for CYP2C19 and P-gp. Two follow-up visits will take place between 25 and 40 days and 50–70 days after inclusion. They include assessment of efficacy, tolerance and observance. Eleven french centres are involved in recruitment, expected to be completed within approximately 2 years with 205 patients. Metabolic ratios are determined in Geneva, Switzerland. By showing an association between drug metabolism and VLX concentrations, efficacy and tolerance, there is a hope that testing drug metabolism pathways with a phenotypical approach would help physicians in selecting and dosing antidepressants. The MARVEL study will provide an important contribution to increasing the knowledge of VLX variability and in optimizing the use of methods of personalized therapy in psychiatric settings. ClinicalTrials.gov NCT02590185 (10/27/2015). This study is currently recruiting participants.

Positive allosteric modulators of GABAA receptors (GAMs) acting at specific subtypes of GABAA receptors effectively restore compromised spinal pain control in rodents. Studies addressing a similar antihyperalgesic effect in humans are sparse and are hampered by sedative effects of nonselective GAMs available for use in humans. We present results from a randomized controlled double-blind crossover study in 25 healthy volunteers, which addressed potential antihyperalgesic actions of clobazam (CBZ) and clonazepam (CLN) at mildly sedating equianticonvulsive doses. Clobazam was chosen because of its relatively low sedative properties and CLN because of its use in neuropathic pain. Tolterodine (TLT) was used as an active placebo. The primary outcome parameter was a change in the area of cutaneous UVB irradiation-induced secondary hyperalgesia (ASH), which was monitored for 8 hours after drug application. Sedative effects were assessed in parallel to antihyperalgesia. Compared with TLT, recovery from hyperalgesia was significantly faster in the CBZ and CLN groups (P = 0.009). At the time point of maximum effect, the rate of recovery from hyperalgesia was accelerated by CBZ and CLN, relative to placebo by 15.7% (95% confidence interval [CI] 0.8-30.5), P = 0.040, and 28.6% (95% CI 4.5-52.6), P = 0.022, respectively. Active compounds induced stronger sedation than placebo, but these differences disappeared 8 hours after drug application. We demonstrate here that GAMs effectively reduce central sensitization in healthy volunteers. These results provide proof-of-principle evidence supporting efficacy of GAMs as antihyperalgesic agents in humans and should stimulate further research on compounds with improved subtype specificity.