Optimisation of pharmacotherapy in psychiatry through therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests: focus on antipsychotics.

BACKGROUND: For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialized tools are used. Three tools have been proven useful to personalize drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging. METHODS: In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 50 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET)). RESULTS: Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings. CONCLUSION: All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimize treatment effects, minimize side effects and ultimately reduce the global burden of diseases, personalized drug treatment has not yet become the standard of care in psychiatry.

Use of pharmacological treatment for posttraumatic stress disorder: Analysis of a psychiatric population in Switzerland and comparison with international guidelines.

OBJECTIVES: Several international guidelines for the pharmacological treatment of posttraumatic stress disorder (PTSD) have been published. However, it is unclear whether clinicians use these procedures in their daily practice. We compared the psychopharmacological prescription patterns in a Swiss adult psychiatric center with international clinical guidelines at admission and discharge. METHODS: Retrospective chart review study between 2005 and 2015 of adult patients with PTSD and no other documented psychiatric comorbidity. RESULTS: Fifty-two outpatients and 21 inpatients were included; 47% had at least one psychopharmacological treatment at admission. Among them, 47% had one or several antidepressants, mainly escitalopram (31%, n=5) or citalopram. At discharge, 68% had at least one psychopharmacological treatment. Among them, 76% had at least one antidepressant, mainly escitalopram (34%, n=13) or mirtazapine (21%, n=8). They were compared to the guidelines of the Department of Veterans Affairs and Department of Defense (VA/DoD), showing 19% of the patients treated with antidepressants at admission were in agreement with the guidelines (sertraline, fluoxetine, paroxetine, venlafaxine), and 26% at discharge. In addition, we found prescriptions of benzodiazepines (62% at admission and 50% at discharge), antipsychotics (12% and 22%), Z-drugs (zolpidem, zopiclone: 15 and 40%) and a few pregabalin prescriptions (n=4). CONCLUSIONS: Clinicians in this study frequently prescribed antidepressants to treat PTSD, as recommended. However, most of the antidepressants used were not recommended in the VA/DoD guidelines. Benzodiazepines and Z-drugs remained widely used, although they are not recommended.

Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants.

Objectives: More than 40 drugs are available to treat affective disorders. Individual selection of the optimal drug and dose is required to attain the highest possible efficacy and acceptable tolerability for every patient.Methods: This review, which includes more than 500 articles selected by 30 experts, combines relevant knowledge on studies investigating the pharmacokinetics, pharmacodynamics and pharmacogenetics of 33 antidepressant drugs and of 4 drugs approved for augmentation in cases of insufficient response to antidepressant monotherapy. Such studies typically measure drug concentrations in blood (i.e. therapeutic drug monitoring) and genotype relevant genetic polymorphisms of enzymes, transporters or receptors involved in drug metabolism or mechanism of action. Imaging studies, primarily positron emission tomography that relates drug concentrations in blood and radioligand binding, are considered to quantify target structure occupancy by the antidepressant drugs in vivo. Results: Evidence is given that in vivo imaging, therapeutic drug monitoring and genotyping and/or phenotyping of drug metabolising enzymes should be an integral part in the development of any new antidepressant drug.Conclusions: To guide antidepressant drug therapy in everyday practice, there are multiple indications such as uncertain adherence, polypharmacy, nonresponse and/or adverse reactions under therapeutically recommended doses, where therapeutic drug monitoring and cytochrome P450 genotyping and/or phenotyping should be applied as valid tools of precision medicine.

Reconstruction of cranioplasty using medpor porouspolyethylene implant.

INTRODUCTION: We describe our experience of cranioplasty after a calvarial defect, following an external decompressive craniectomy, with the Medpor® (Stryker®) porous polyethylene implant for cosmetic cranioplasty and reconstruction. METHODS: A retrospective chart review was performed on 23 consecutive patients who underwent cranioplasty at a single institution between January 2013 and January 2016: 9 patients after head injury and 14 patients after vascular event (ruptured aneurysm, intraprenchymal haematoma, malignant cerebrovascular accident). All patients with cranioplasties after oncological resection or infection were excluded. These cranioplasties were performed using porous polyethylene sheet (Medpor®) and contoured with a burr or scissors in the sterile field, and fixed to the calvarial bone with screws. RESULTS: Porous polyethylene sheet (Medpor®) is a proven material used for cranial reconstruction in neurosurgery and maxillofacial surgery with a biocompatibility advantage. The implant can be directly used in an emergency context. The average operating time was 72minutes. An average delay of 527 days (1 year and 5months) with a median of 985 days (43; 4206) occurred between craniectomy and the cranioplasty. There was only one set back implant due to scalp necrosis with infection for a recovery-unit patient. CONCLUSION: Porous polyethylene is an excellent restorative material for the reconstruction of large sized cranial defects and can be also used safely in reconstruction of the cranium. The cosmetic results are good, easy to perform, with a low complication rate.

Local infiltration analgesia with ropivacaine in acute fracture of thoracolumbar junction surgery.

STUDY DESIGN: Retrospective study. INTRODUCTION: Local infiltration analgesia is effective in many surgeries as knee arthroplasty, but the analgesic efficacy of local infiltration analgesia with ropivacaine in trauma spine surgery in T10 to L2 has not been clarified. We conducted a trial to assess the analgesic efficacy of intraoperative local infiltration analgesia (LIA) with ropivacaine. OBJECTIVE: The aim of the present study was to clarify the effect of intraoperative local infiltration analgesia with ropivacaine on postoperative pain for patients undergoing thoracolumbar junction fracture surgery. METHODS: In a retrospective study, in 76 patients undergoing spine surgery for thoracolumbar junction fracture, 20ml of ropivacaine 7.5% (n R group=38) was infiltrated using a systematic technique, or no infiltration was realized (n M group=38). We assessed postoperative pain with Visual Analogue Scale (VAS) and morphine consumption in the 24 first hours. RESULTS: VAS pain score upon awakening and at 2hours postoperatively were significantly lower in the ropivacaine group (P=0.01 and P=0.002). Rescue opioid requirement during the 24 first hours were about 50% lower in the ropivacaine group (P=0.01). No local or systemic side effects were observed. CONCLUSION: Intraoperative LIA with ropivacaine in thoracolumbar junction fracture surgery may have an analgesic effect in postoperative pain control (24hours) with a reduction of VAS and morphine consumption.

CRTC2 polymorphism as a risk factor for the incidence of metabolic syndrome in patients with solid organ transplantation.

Metabolic syndrome after transplantation is a major concern following solid organ transplantation (SOT). The CREB-regulated transcription co-activator 2 (CRTC2) regulates glucose metabolism. The effect of CRTC2 polymorphisms on new-onset diabetes after transplantation (NODAT) was investigated in a discovery sample of SOT recipients (n1=197). Positive results were tested for replication in two samples from the Swiss Transplant Cohort Study (STCS, n2=1294 and n3=759). Obesity and other metabolic traits were also tested. Associations with metabolic traits in population-based samples (n4=46'186, n5=123'865, n6>100,000) were finally analyzed. In the discovery sample, CRTC2 rs8450-AA genotype was associated with NODAT, fasting blood glucose and body mass index (Pcorrected<0.05). CRTC2 rs8450-AA genotype was associated with NODAT in the second STCS replication sample (odd ratio (OR)=2.01, P=0.04). In the combined STCS replication samples, the effect of rs8450-AA genotype on NODAT was observed in patients having received SOT from a deceased donor and treated with tacrolimus (n=395, OR=2.08, P=0.02) and in non-kidney transplant recipients (OR=2.09, P=0.02). Moreover, rs8450-AA genotype was associated with overweight or obesity (n=1215, OR=1.56, P=0.02), new-onset hyperlipidemia (n=1007, OR=1.76, P=0.007), and lower high-density lipoprotein-cholesterol (n=1214, ß=-0.08, P=0.001). In the population-based samples, a proxy of rs8450G>A was significantly associated with several metabolic abnormalities. CRTC2 rs8450G>A appears to have an important role in the high prevalence of metabolic traits observed in patients with SOT. A weak association with metabolic traits was also observed in the population-based samples.

Ectopic bone formation with joint impingement after posterior lumbar fusion with rhBMP-2.

Recombinant human bone morphogenetic protein-2 (rhBMP-2) was recently licensed for local administration during posterior lumbar fusion. In this indication, considerable uncertainty remains about the nature and mechanisms of the many adverse effects of rhBMP-2, such as ectopic bone formation. We report a case of ectopic bone formation with impingement on a facet joint and incapacitating low back pain after minimally invasive transforaminal L5-S1 interbody fusion with local application of rhBMP-2 (InductOs(®)). Revision surgery was eventually performed to alleviate the symptoms by removing the ectopic bone. Caution is in order regarding the use of rhBMP-2 during posterior lumbar fusion. Every effort should be made to minimise the risk of complications.

Spontaneous epidural hematoma due to cervico-thoracic angiolipoma.

Epidural angiolipomas are uncommon benign tumors of the spine. Their clinical presentation is usually a progressive spinal cord compression. We report the case of a 22-year-old patient who presented with an acute paraparesis and a spontaneous epidural hematoma, which revealed a epidural angiolipoma which extended from C7 to T3. The patient underwent a C7-T3 laminectomy, in emergency, with evacuation of the hematoma and extradural complete resection of a fibrous epidural tumor bleeding. The postoperative course was favorable with regression of neurological symptoms. Epidural angiolipomas can be revealed by spontaneous intratumoral hemorrhage without traumatism. The standard treatment is total removal by surgery.

The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens.

Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3(-/-) mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3(-/-) mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse.

Tokuhashi score and other prognostic factors in 260 patients with surgery for vertebral metastases.

BACKGROUND: Metastatic disease of the spine is an increasingly common public health problem. Surgery should be an integral component of the overall cancer treatment plan and, importantly, must neither delay not jeopardize any of the other components. The prognosis governs the choice of the surgical strategy. Tokuhashi et al. developed a prognostic score in 1990, then revised it in 2000 and 2005. Here, our objective was to evaluate the performance of the Tokuhashi score in a cohort of 260 patients and to look for other variables that might improve preoperative outcome prediction. MATERIAL AND METHOD: We retrospectively established a single-centre cohort of 260 patients who underwent spinal metastasis surgery between 1998 and 2008. For each patient, the following data were collected prospectively: socio-demographic features, history of the malignancy, variables needed to determine the Tokuhashi score, and treatments used. SAS 9.0 software was chosen for the statistical analysis. Variables were described as mean ± SD, overall survival was estimated using the Kaplan-Meier method, and survivals in subgroups were compared by the log-rank test. To assess agreement between survival predicted by the Tokuhashi score and observed survival, we computed Cohen's kappa and interpreted the results according to Landis and Koch. RESULTS: There were 143 females and 117 males with a mean age of 59 years and overall median survival of 10 months. Median observed survivals in the three Tokuhashi score categories (< 6, 6-12, and > 12 months predicted survival) were 5, 10, and 36 months, respectively. These survival times differed significantly (P < 0.0001). Cohen's kappa indicated moderate agreement between predicted and observed survivals. Other factors associated with significant survival differences were time from cancer diagnosis to metastasis diagnosis (synchronous, < 2 years, 2-5 years, or > 5 years; P < 0.0001) and age (< 70 years or ≥ 70 years, P = 0.0053). CONCLUSION: Our cohort study supports the validity and reproducibility of the Tokuhashi score. Our finding that shorter time to metastasis diagnosis and age ≥ 70 years were also significantly associated with survival in our population invites further efforts to improve and update the Tokuhashi score.

Advantages and limitations of endoscopic endonasal odontoidectomy. A series of nine cases.

INTRODUCTION: Transoral odontoidectomy is the treatment of choice in cases of anterior bulbo-medullary compression. The development of endoscopic procedures has made it possible to perform odontoidectomy via a minimally invasive endoscopic endonasal approach. We discuss the feasibility, advantages, and limitations of this surgical approach. MATERIALS AND METHODS: We report a two-center retrospective series of patients who underwent endoscopic endonasal odontoidectomy between September 2011 and February 2013. Preoperative characteristics, intraoperative data, clinical course, and postoperative complications were studied. The patients were followed for a minimum of 6 months. Cervico-occipital posterior fusion was performed during the same hospital stay in cases of preoperative instability. RESULTS: Nine patients underwent decompressive odontoidectomy, for rheumatoid pannus in five cases and basilar impression in four cases. All had progressive neurological symptoms. Seven patients also underwent posterior fusion. In six patients, the C1 anterior arch was preserved. Decompression was achieved satisfactorily in all nine cases. The patients were able to resume oral feeding the day after the intervention. No patient required tracheostomy. We observed no dural fistulae or infectious complications. One patient died 2 months after the intervention of a pulmonary embolism. All patients improved in terms of their preoperative neurological status. CONCLUSION: This short series shows the feasibility of the endoscopic endonasal approach for resection of the dens. This approach allows optimal viewing when using angulated instrumentation and seems to result in low morbidity. In some cases, this approach makes it possible to preserve the C1 anterior arch, thus limiting the risk of cranial settling. LEVEL: IV retrospective study.

Can valproic acid be an inducer of clozapine metabolism?

INTRODUCTION: Prior clozapine studies indicated no effects, mild inhibition or induction of valproic acid (VPA) on clozapine metabolism. The hypotheses that (i) VPA is a net inducer of clozapine metabolism, and (ii) smoking modifies this inductive effect were tested in a therapeutic drug monitoring study. METHODS: After excluding strong inhibitors and inducers, 353 steady-state total clozapine (clozapine plus norclozapine) concentrations provided by 151 patients were analyzed using a random intercept linear model. RESULTS: VPA appeared to be an inducer of clozapine metabolism since total plasma clozapine concentrations in subjects taking VPA were significantly lower (27% lower; 95% confidence interval, 14-39%) after controlling for confounding variables including smoking (35% lower, 28-56%). DISCUSSION: Prospective studies are needed to definitively establish that VPA may (i) be an inducer of clozapine metabolism when induction prevails over competitive inhibition, and (ii) be an inducer even in smokers who are under the influence of smoking inductive effects on clozapine metabolism.

[Psychiatry]. / Psychiatrie.

Contemporary psychiatry uses a variety of complementary approaches which enrich one another. In this paper, we describe the development of a brief psychodynamic approach for hospitalized patients with major depression, as well as the recent commercialization of an atypical neuroleptic depot medication. In addition, we discuss electro-convulsotherapy which, despite it has been widely and understandably condemned on the basis of its abusive and non medical application in certain political contexts, deserves objective assessment on the basis of scientific data stemming from recent research suggesting it is in some contexts a valuable tool.

Anterior minimally invasive extrapleural retroperitoneal approach to the thoraco-lumbar junction of the spine.

BACKGROUND: The anterior approach to the thoraco-lumbar junction of the spine allows therapeutic interventions on post-traumatic, infectious, and neoplastic vertebral lesions from T11 to L2 combining spinal cord decompression, corporectomy, and vertebral body fusion. However, this approach also has a reputation for damaging the intervening anatomic structures (lungs, peritoneum, and diaphragm). The objective of this study was to show that both nervous structure decompression and anterior vertebral reconstruction can be achieved via an anterior minimally invasive extrapleural retroperitoneal (AMIER) approach. MATERIAL: We describe each of the steps of the AMIER approach to the thoraco-lumbar junction of the spine. RESULTS: The AMIER approach ensures excellent exposure that allows full decompression and satisfactory anterior anatomic reconstruction. The main difficulties and complications relate to the lungs, and a painstaking and rigorous technique limits the complications compared to conventional thoraco-phreno-lumbotomy.

[Migration of a ventriculoperitoneal shunt in the liver: A rare complication]. / La perforation hépatique d'un cathéter de dérivation ventriculo-péritonéale : une complication rare.

We report on a case of migration inside the liver of the distal end of a ventriculoperitoneal shunt catheter in an adult patient. A simple laparotomy permitted the surgical removal with no haemorrhagic complication. We discuss the other cases reported in the literature and we outline the need to perform an abdominal CT scan in patients carrying a VP shunt with digestive symptoms.

[Spontaneous resorption of thoracic calcified disc herniation: Report of two cases and review of the literature]. / Résorption spontanée de hernies discales thoraciques calcifiées : à propos de deux cas et revue de la littérature.

We report on two cases of spontaneous resorption of a calcified thoracic hernia. This phenomenom is widely recognised in lumbar and cervical hernia, but is exceptional at the thoracic level. The potential mechanisms underlying this resorption are discussed trough a review of the literature. We think this could be another argument for a "wait and watch" period before a surgical decision in the patients who have few symptoms.

Adherence to antidepressant treatment: what the doctor thinks and what the patient says.

Adherence to antidepressant treatment has been shown to range from 30 to 70%. The aim of this study was to compare the patient's self-report of adherence with the doctors' estimation of adherence and therapeutic alliance in 104 outpatients with mood and/or anxiety disorder treated with antidepressants. The adherence scores estimated by the patients and the doctors were significantly different, the doctors underestimating adherence in 29% of cases and overestimating it in 31% of cases compared to the patients' evaluation. Adherence measured by drug plasma concentration, despite being higher than expected from previously published reports, was in line with the patients' self-reported score but not the doctors' estimation. Finally, the patients' and the doctors' Helping Alliance scores were not related to adherence self-report.

[Management of WHO grade II and II meningiomas: retrospective study of surgical series of 36 cases at a single institution]. / Prise en charge des méningiomes OMS grade II et III : étude rétrospective monocentrique d'une série chirurgicale de 36 cas.

INTRODUCTION: Atypical and malignant meningiomas are a rare disease whose histological definition is still recent. Their management is not consensual. The aim of this study was to review the outcome, prognostic factors and the role of complementary therapies. PATIENTS AND METHODS: Between 1999 and 2007, 36 patients with atypical or malignant meningiomas were managed in our hospital. All surgical specimens were reviewed according to the 2007 WHO classification system. The sex ratio was 1.25 male, the median age was 59 years. The median follow-up was 55 months. Thirty meningiomas were atypical and six were malignant. RESULTS: Five and 10 years overall survival rate are respectively 72 and 41%, whereas 5 and 10 years progression free survival rate are 61 and 23%. We only identify female sex, age over 70 years and Karnofsky status under 70% as negative prognostic factors. CONCLUSION: Atypical and malignant meningiomas are difficult to manage and have high recurrence and poor survival rates. The prognostic of OMS II meningiomas is heterogeneous. Adjuvant radiation therapy is recommended in case of malignant menigioma or in case of atypical meningioma if incomplete surgical excision is performed.