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.

Non-overweight depressed patients who respond to antidepressant treatment have a higher risk of later metabolic syndrome: findings from the METADAP cohort.

BACKGROUND: Major depressive disorder (MDD) is a complex disorder with a significant public health burden. Depression remission is often associated with weight gain, a major risk factor for metabolic syndrome (MetS). The primary objective of our study was to assess prospectively the impact of response to antidepressant treatment on developing MetS in a sample of MDD patients with a current major depressive episode (MDE) and who are newly initiating their treatment. METHODS: In the 6-month prospective METADAP cohort, non-overweight patients, body mass index <25 kg/m2, with MDD and a current MDE were assessed for treatment response after 3 months of treatment, and incidence of MetS after 3 and 6 months of treatment. Outcome variables were MetS, number of MetS criteria, and each MetS criterion (high waist circumference, high blood pressure, high triglyceridemia, low high-density lipoprotein-cholesterolemia, and high fasting plasma glucose). RESULTS: In total, 98/169 patients (58%) responded to treatment after 3 months. A total of 2.7% (1/38) developed MetS out of which 12.7% (10/79) (p value < 0.001) had responded to treatment after 3 months. The fixed-effect regression models showed that those who responded to treatment after 3 months of follow-up had an 8.6 times higher odds of developing MetS (odds ratio = 8.58, 95% confidence interval 3.89-18.93, p value < 0.001). CONCLUSION: Compared to non-responders, non-overweight patients who responded to treatment after 3 months of antidepressant treatment had a significantly higher risk of developing MetS during the 6 months of treatment. Psychiatrists and nurses should closely monitor the metabolic profile of their patients, especially those who respond to treatment.

Prolonged impact of the COVID-19 pandemic on self-harm hospitalizations in France: A nationwide retrospective observational study.

BACKGROUND: The first wave of the COVID-19 pandemic in France was associated with a reduced number of hospitalizations for self-harm, with the exception of older people. The on-going pandemic may have both sustained and delayed effects. METHODS: Data were extracted from the French national hospital database (PMSI), a nationwide exhaustive database. The number of self-harm hospitalizations (ICD-10 codes X60-84) between September 1, 2020 and August 31, 2021 (N = 85,679) was compared to 2019 (N = 88,782) using Poisson regression models. RESULTS: There was a decrease in the total number of self-harm hospitalizations during the studied period versus 2019 (-3.5%; Relative Risk [RR] [95% Confidence Intervals] = 0.97 [0.96-0.97]; p < 0.0001). However, sex and age effects were identified. While adults aged 30-59-years-old showed a decrease (monthly decreases: -12.6 to -15.0%), we found an increase in adolescent girls (+27.7%, RR = 1.28 [1.25-1.31]; p < 0.0001), notably since January 2021. Moreover, the numbers were similar to 2019 in adolescent boys, in youths aged 20-29 years, and in people aged 70 and more. Hospitalizations in intensive care units decreased (-6.7%, RR = 0.93 [0.91-0.96]; p < 0.0001) and deaths at hospital following self-harm remained stable (+0.6%, Hazard Ratio = 0.99 [0.91-1.08], p = 0.79). CONCLUSIONS: During this second stage, the number of self-harm hospitalizations remained at a lower level than in the prepandemic period. However, significant variations over time, age, and sex were observed. Young people (notably adolescent girls) appear to have particularly suffered from the persistence of the pandemic, while older people did not show any decrease since the beginning. Vigilance and continuing prevention are warranted.

[Advance directives in perinatal psychiatry: A parenting aid for women with bipolar disorder?] / Directives anticipées en psychiatrie périnatale : une aide à la parentalité pour les femmes ayant un trouble bipolaire ?

Advance directives in psychiatry (ADP) allow patients to anticipate their requests for care. Their purpose is to promote the acceptation of care, prevent relapses and maintain the autonomy of people with severe and persistent disorders such as bipolar disorder (BD). The risk of relapse is particularly high during the perinatal period. ADPs could be a tool to facilitate care pathway and so maintain mood stability for women with BD during the perinatal period and provide good conditions for child development.

Nitric Oxide Synthase activity in major depressive episodes before and after antidepressant treatment: Results of a large case-control treatment study.

BACKGROUND: Nitric oxide synthase (NOS) activity, an enzyme potentially involved in the major depressive episodes (MDE), could be indirectly measured by the L-Citrulline/L-Arginine ratio (L-Cit/L-Arg). The aim of this study was: (1) to compare the NOS activity of patients with a MDE to that of healthy controls (HC); (2) to assess its change after antidepressant treatment. METHODS: A total of 460 patients with a current MDE in a context of major depressive disorder (MDD) were compared to 895 HC for NOS activity (L-Cit/L-Arg plasma ratio). L-Arg and L-Cit plasma levels were measured using a MS-based liquid chromatography method. Depressed patients were assessed at baseline, and after 3 and 6 months of antidepressant treatment for depression severity and clinical response. RESULTS: Depressed patients had a lower NOS activity than HC at baseline [0.31 ± 0.09 v. 0.38 ± 0.12; 95% confidence interval (CI) -0.084 to -0.062, p < 0.0001]. Lower NOS activity at baseline predicted a higher response rate [odds ratio (OR) = 29.20; 95% CI 1.58-536.37; p = 0.023]. NOS activity in depressed patients increased significantly up to 0.34 ± 0.08 after antidepressant treatment (Est = 0.0034; 95% CI 0.0002-0.0067; p = 0.03). CONCLUSIONS: Depressed patients have a decreased NOS activity that improves after antidepressant treatment and predicts drug response. NOS activity may be a promising biomarker for MDE in a context of MDD.

Reviving through human hippocampal newborn neurons.

Recent contradictory data has renewed discussion regarding the existence of adult hippocampal neurogenesis (AHN) in humans, i.e., the continued production of new neurons in the brain after birth. The present review revisits the debate of AHN in humans from a historical point of view in the face of contradictory evidence, analyzing the methods employed to investigate this phenomenon. Thus, to date, of the 57 studies performed in humans that we reviewed, 84% (48) concluded in favor of the presence of newborn neurons in the human adult hippocampus. Besides quality of the tissue (such as postmortem intervals below 26hours as well as tissue conservation and fixation), considerations for assessing and quantify AHN in the human brain require the use of stereology and toxicological analyses of clinical data of the patient.

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.

Relationship between achieved personalized glycaemic targets and monitoring of clinical events in elderly diabetic patients.

AIM: Recent guidelines for the management of type 2 diabetes (T2DM) in the elderly recommend adjusting the therapeutic target (HbA1c) according to the patient's health. Our study aimed to explore the association between achieving the recommended personalized HbA1c target and the occurrence of major clinical events under real-life conditions. METHODS: The T2DM S.AGES cohort was a prospective multicentre study into which 213 general practitioners recruited 983 non-institutionalized T2DM patients aged>65 years. The recommended personalized HbA1c targets were<7%, <8% and <9% for healthy, ill and very ill patients, respectively. Major clinical events (death from any cause, major vascular events and/or hospitalization) were recorded during the 3-year follow-up. Mixed-effects logistic regression models were used for the analyses. RESULTS: Of the 747 patients analyzed at baseline, 551 (76.8%) were at their recommended personalized HbA1c target. During follow-up, 391 patients (52.3%) experienced a major clinical event. Of the patients who did not achieve their personalized HbA1c target (compared with those who did), the risk (OR) of a major clinical event was 0.95 (95% CI: 0.69-1.31; P=0.76). The risk of death, major vascular event and hospitalization were 0.88 (95% CI: 0.40-1.94; P=0.75), 1.14 (95% CI: 0.7-1.83; P=0.59) and 0.84 (95% CI: 0.60-1.18; P=0.32), respectively. CONCLUSION: Over a 3-year follow-up period, our results showed no difference in risk of a major clinical event among patients, regardless of whether or not they achieved their personalized recommended HbA1c target. These results need to be confirmed before implementing a more permissive strategy for treating T2DM in elderly patients.

PPAR-γ Agonists for the Treatment of Major Depression: A Review.

Introduction: Selective agonists of the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-γ) are used for the treatment of type 2 diabetes. We reviewed their efficacy and safety for the treatment of major depression and the association of their potential antidepressant effects with changes in biomarkers of metabolism and inflammation. Methods: From 8 studies, 4 open-label trials, and 4 randomized controlled trials (RCT) (3 vs. placebo and 1 vs. metformin), 448 patients with major depression were included, of which 209 patients received PPAR-γ agonists (pioglitazone or rosiglitazone) for 6-12 weeks, either alone or in add-on therapy to conventional treatments. Results: PPAR-γ agonists have antidepressant effects in the 4 open-label studies and in 3 out of 4 RCT. No major adverse event was reported. Improvement in depression scores was associated with improvement in 3 biomarkers of insulin resistance (homeostatic model assessment [HOMA-IR], oral glucose tolerance test, and fasting plasma glucose) and 1 biomarker of inflammation (interleukin-6) among 21 biomarkers studied. Conclusion: PPAR-γ agonists may have antidepressant properties, which need to be assessed in further studies of major depressive episodes.

[Vortioxetine: a new antidepressant to treat depressive episodes]. / La vortioxétine : un nouvel antidépresseur pour traiter les épisodes dépressifs caractérisés.

Vortioxetine is a new antidepressant, which mechanism of action is multimodal, targeting the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT3, 5-HT7 receptors and the serotonin transporter (5-HTT). Its efficacy and safety were assessed in fourteen studies including more than 3700 patients with a major depressive episode and treated with vortioxetine. In short-term studies (8 weeks), vortioxetine is more efficacious than placebo in decreasing depressive symptoms as measured by the MADRS total score, response rate (vortioxetine: 53.2% vs placebo: 35.2%) and remission rate (vortioxetine: 29.2% vs placebo: 19.3%). In a long-term study (52 weeks), vortioxetine is also superior to placebo in preventing relapses and recurrences. Moreover, in second line treatment, after failure of a first line selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrin reuptake inhibitor (SNRI), vortioxetine is superior to agomelatine in improving depressive symptoms and achieving response and remission. Furthermore, the positive effects of vortioxetine on improvement of cognitive symptoms of major depressive episodes are particularly well established in several clinical trials. The tolerability profile of vortioxetine is favourable. The recommended daily posology of vortioxetine is 10mg/d. Vortioxetine is a new antidepressant drug with a multimodal mechanism of action, well-documented efficacy and safety profiles.

An increase in joy after two weeks is more specific of later antidepressant response than a decrease in sadness.

BACKGROUND: Early improvement in positive emotions-more than decreases in negative emotions-was highly predictive of treatment response in an ecologically valid prospective manner. This result needs replication with simpler assessments to determine whether it can be translated into clinical practice. METHODS: 2049 adult depressed outpatients receiving agomelatine were assessed at inclusion, week 2, and week 6 using the clinician-rated Quick Inventory of Depressive Symptomatology, Sheehan Disability Scale, Clinical Global Impression scale, and Multidimensional Assessment of Thymic States (MATHYS), an auto-questionnaire rating the frequency of emotions, including sadness and joy, over the previous week. RESULTS: Joy and sadness had a relatively low correlation coefficient at baseline (r=-0.277), joy (r=-0.160) being less correlated with clinical severity than sadness (r=0.317). An increase in joy at week 2 had higher specificity (85.04%) and positive predictive value (70.55%) for treatment response than decreased sadness (57.92% and 66.04%, respectively), and the global capacity of the former to predict remission, either clinical (Yule Q coefficient, 39.96%) or functional (44.35%), was even better compared to the prediction of clinical response (37.38%). LIMITATIONS: MATHYS retrospectively assesses emotions, with five possible ratings only, relying on self-rated frequencies. With only a 6-week follow-up, conclusions are limited to short-term aspects of clinical and functional remission. CONCLUSIONS: Early improvement in joy during the first 2 weeks of treatment is strongly specific for treatment response and remission. The frequency of joy captures the predictivity and may deserve further study regarding inclusion in depressive rating scales.

Therapeutic management in ambulatory elderly patients with atrial fibrillation: the S.AGES cohort.

UNLABELLED: Few epidemiologic studies have specifically focused on very old community dwelling population with atrial fibrillation (AF). The objectives of the AF-S.AGES cohort were to describe real-life therapeutic management of non-institutionalized elderly patients with AF according to age groups, i.e., 65-79 and ≥ 80 and to determine the main factors associated with anticoagulant treatment in both groups. METHODS: Observational study (N=1072) aged ≥ 65 years old, recruited by general practitioners. Characteristics of the sample were first evaluated in the overall sample and according to age (< 80 or ≥ 80 years) and to use of anticoagulant treatment at inclusion. Logistic models were used to analyze the determinants of anticoagulant prescription among age groups. RESULTS: Mean age was 78.0 (SD=6.5) years and 42% were ≥ 80 years. Nineteen percent had paroxysmal AF, 15% persistent, 56% permanent and 10% unknown type, 77% were treated with vitamin K antagonists (VKA), 17% with antiplatelet therapy with no differences between age groups. Rate-control drugs were more frequently used than rhythm-control drugs (55% vs. 37%, p < 0.001). VKA use was associated with permanent AF, younger age and cancer in patients ≥ 80 years old and with permanent AF and preserved functional autonomy in patients < 80 years old. Hemorrhagic scores were independently associated with non-use of VKA whereas thromboembolic scores were not associated with VKA use. CONCLUSIONS: In this elderly AF outpatient population, use of anticoagulant therapy was higher even after 80 years than in previous studies suggesting that recent international guidelines are better implemented in the elderly population.

Response to CYP2D6 substrate antidepressants is predicted by a CYP2D6 composite phenotype based on genotype and comedications with CYP2D6 inhibitors.

The cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of most antidepressants. Comedication with a potent CYP2D6 inhibitor can convert patients with extensive metabolizer (EM) or ultra-rapid metabolizer (UM) genotypes into poor metabolizer (PM) phenotypes. Since comedication is frequent in depressed patients treated with antidepressants, we investigated the effect of the CYP2D6 composite phenotype on antidepressant efficacy, taking into account both the CYP2D6 genotype and comedication with CYP2D6 inhibitors. 87 Caucasian in patients with a major depressive episode were prospectively treated with flexible doses of antidepressant monotherapy as well as comedications and genotyped for the major CYP2D6 alleles (CYP2D6*3 rs35742686, *4 rs3892097, *5 del, *6 rs5030655, and *2xN). They were classified for CYP2D6 composite phenotype and assessed for antidepressant response after 4 weeks. In terms of genotypes (g), 6 subjects were UMg, 6 PMg, and 75 EMg. Ten patients were coprescribed a CYP2D6 inhibitor, resulting in the following composite phenotypes (cp): 5 UMcp, 16 PMcp, and 66 EMcp. Whereas none of the CYP2D6 genotypes were significantly associated with antidepressant response, UMcp had a lower antidepressant response than PMcp or EMcp (respectively: 39.0 ± 17.9, 50.0 ± 26.0, and 61.6 ± 23.4, p = 0.02). Despite small sample size, this study suggests that a CYP2D6 composite phenotype, taking into account both genotype and comedications with CYP2D6 inhibitors, could predict CYP2D6 substrate antidepressants response. Thus, to optimize antidepressant response, CYP2D6 genotype could be performed and comedications with CYP2D6 inhibitors should be avoided, when prescribing CYP2D6 substrate antidepressants.

The therapeutic management of chronic pain in ambulatory care patients aged 65 and over in France: the S.AGES Cohort. Baseline data.

OBJECTIVE: The main objective of the S.AGES (Elderly Subjects) cohort study is to describe the current therapeutic strategy for chronic pain in non-institutionalised elderly patients in France. METHODS: In this prospective cohort study, non-institutionalised patients aged 65 years and over with chronic pain were recruited by general practitioners (GP) across France. All medicinal and non- medicinal prescriptions were recorded at inclusion and will be followed up over 3 years via an eCRF. Data recorded at baseline are presented in this paper. RESULTS: Two hundred and sixty GPs enrolled 1379 evaluable patients between June 3rd, 2009 and June 3rd, 2011. Pain was mainly of a mechanical nature, due to osteoarthritis or common back pain. 80% of the patients had moderate or severe pain. More than a third of patients were treated with a step 1 analgesic (mainly paracetamol), and approximately 30% received a step 2 analgesic (23% dextropropoxyphene and 40.3% tramadol/paracetamol combination). Only 3% received step 3 analgesics; this rate remained low even in patients with severe pain. The proportion of patients treated with an antiepileptic was higher in case of neuropathic pain. More than 25% of patients did not receive any analgesic medication. CONCLUSION: The baseline S.AGES study results exhibit a well-balanced therapeutic management of chronic pain by GPs for ambulatory elderly patients. Clinicaltrials.org NCT01065909.

[Recommendations for therapeutic monitoring of antidepressants]. / Dosage plasmatique des medicaments antidépresseurs.

Therapeutic drug monitoring (TDM), combined in certain situations with pharmacogenetic tests of metabolism, has proven a valuable tool for psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, nonresponse at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. This article is an adaptation of guidelines recently issued by the AGNP-TDM group (Hiemke et al., www. agnp.de), but its content focuses mainly on the TDM of antidepressants. Finally, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process.

Is it worth assessing progress as early as week 2 to adapt antidepressive treatment strategy? Results from a study on agomelatine and a global meta-analysis.

CONTEXT: A delay of 4-8weeks before modifying the prescribed antidepressant treatment is usually proposed when incomplete treatment response is observed. A number of studies nevertheless proposed that the lack of early improvement (usually 20% decrease of severity at week 2) is predictive of the absence of subsequent treatment response, potentially saving weeks of inadequate treatment, but with no information for non-interventional studies devoted to outpatients. METHOD: Two thousand nine hundred and thirty-eight outpatients with major depressive disorder were included in a multicentre, non-interventional study, assessing at inclusion, week 2 and week 6, mood (QIDS-C, CGI, PGI and VAS) sleep (LSEQ) and functionality (SDS). All metrics at week 2 were tested for their capacity to predict response (and then remission) at week 6, all patients being treated by agomelatine. A meta-analysis of all studies (n=12) assessing the predictive role of improvement at week 2 was also performed, assessing specific effect size of published studies and the weight of the different parameters they used. RESULTS: The QIDS-C and the CGI-I were the only instruments with an area under the curve over 0.7, with different cut-offs for treatment response and remission. A decrease of more than five points at the QIDS-C had the highest positive predictive value for treatment response, and a CGI-I over three had the highest negative predictive value, which would favour relying on the clinicians for warning (too high CGI-I), and on instruments for confidence (favourable decrease of the QIDS-C). The meta-analysis of all studies also detected a large effect size of early improvement, stressing how rating week 2 severity could be beneficial in clinical practice. CONCLUSIONS: Previous reports stressing the interest of an assessment at week 2 were reinforced by the present results, which also defined more accurately what could be the most appropriate cut-offs, and how combining these early results could be more effective.

Carbamazepine directly inhibits adipocyte differentiation through activation of the ERK 1/2 pathway.

BACKGROUND AND PURPOSE: Carbamazepine (CBZ), known for its anti-epileptic, analgesic and mood-stabilizing properties, is also known to induce weight gain but the pathophysiology of this adverse effect is still largely unknown. We tested the hypothesis that CBZ could have a direct effect on adipocyte development and metabolism. EXPERIMENTAL RESEARCH: We studied the effects of CBZ on morphological biochemical and molecular markers of adipogenesis, using several pre-adipocyte murine cell lines (3T3-L1, 3T3-F442A and T37i cells) and primary cultures of human pre-adipocytes. To delineate the mechanisms underlying the effect of CBZ, clonal expansion of pre-adipocytes, pro-adipogenic transcription factors, glucose uptake and lipolysis were also examined. KEY RESULTS: CBZ strongly inhibited pre-adipocyte differentiation and triglyceride accumulation in a time- and dose-dependent manner in all models. Pleiotropic mechanisms were at the basis of the inhibitory effects of CBZ on adipogenesis and cell lipid accumulation. They included suppression of both clonal expansion and major adipogenic transcription factors such as PPAR-γ and CCAAT/enhancer binding protein-α, activation of basal lipolysis and decrease in insulin-stimulated glucose transport. CONCLUSIONS AND IMPLICATIONS: The effect of CBZ on adipogenesis involves activation of the ERK1/2 pathway. Our results show that CBZ acts directly on pre-adipocytes and adipocytes to alter adipose tissue development and metabolism.

Treatment response in major depression: effects of personality dysfunction and prior depression.

BACKGROUND: The impact of personality dysfunction on the outcome of treatment for depression remains debated. AIMS: To examine the relationship between the number of prior depressive episodes, personality dysfunction and treatment response for depression. METHOD: In a large sample (n = 8229) of adult out-patients with a major depressive episode (DSM-IV), personality dysfunction was assessed using the Standardised Assessment of Personality - Abbreviated Scale (SAPAS). Potential predictors of treatment response at 6 weeks were examined via structural equation modelling. RESULTS: The amount of personality dysfunction and number of prior episodes of depression were both associated with poor response to treatment. Once personality dysfunction was controlled for, the number of prior episodes of depression was not associated with treatment response. CONCLUSIONS: Personality dysfunction is associated with impaired short-term response to antidepressant treatment in major depression. The apparent detrimental effect of prior depression on treatment response may be accounted for by pre-existing personality dysfunction.