Relevance of pharmacogenetic analyses and therapeutic drug monitoring of antidepressants for an individualized treatment of peripartum psychopathology.

OBJECTIVE: Psychiatric disorders burden the peripartum period, often requiring psychopharmacological treatment, including antidepressants. Efficacy and tolerability of antidepressants are influenced by the physiological changes of the peripartum and individual metabolic profiles, which in turn can be modified by pregnancy. The objective of this study is to assess the relationship between antidepressants' pharmacokinetic profiles during pregnancy and individual metabolic profiles, along with the efficacy of the treatment. METHODS: In total 87 outpatients with diagnoses of bipolar disorder, major depression, anxiety, obsessive-compulsive disorder and post-traumatic stress disorder who required antidepressant treatment during pregnancy were recruited. Genotyping analysis of hepatic cytochrome P450 (CYPs) individual isoforms was performed. Antidepressants' blood concentrations and psychometric assessments were collected at five time points. Antidepressants' cord blood concentrations were assessed at birth. RESULTS: Sertraline showed greater stability in plasma concentrations and a lower placental penetrance index. Most of the antidepressants' concentrations below the therapeutic range were found in women with an extensive/ultrarapid metabolic profile. Antidepressants mainly metabolized by CYP2C19 were less frequently below the therapeutic range compared with antidepressants metabolized by CYP2D6. CONCLUSIONS: Pregnancy modulates cytochrome activity and drugs' pharmacokinetics. Genotyping analysis of CYPs isoforms and therapeutic drug monitoring might be used to guide clinicians in a well-tolerated treatment of psychiatric symptoms in pregnant women.

Staging models applied in a sample of patients with bipolar disorder: Results from a retrospective cohort study.

BACKGROUND: Bipolar Disorder (BD) is a life-long illness with compelling evidence of progression. Although different staging models have been proposed to evaluate its course, clinical data remain limited. The aim of the present study was to retrospectively assess applicability of available staging approaches and their pattern of progression in a sample of bipolar patients. METHODS: In a naturalistic sample of 100 BD patients, retrospective assessment of clinical stages was performed at four time points over 10 years, according to four staging models. Staging progression with potential associations between stages and unfavourable illness characteristics were analyzed. RESULTS: A pattern of stage worsening emerged for each model, with a significant increase at every time point. Greater stage increases emerged in patients with lower educational level, age at first elevated episode ≤35 years, duration of illness ≤25 years, and duration of untreated illness ≤5 years. Lower stage values were associated with BD II, no psychiatric hospitalization, depressive onset and predominant polarity, ≤three lifetime episodes, age at first mood stabilizer >40 years, duration of illness ≤25 years, and engaged/employed status. Higher stage values were associated with lower age at first elevated episode and mood stabilizing treatment instead. LIMITATIONS: Naturalistic and retrospective design, recruitment at a 2nd level specialistic clinic. CONCLUSIONS: Reported findings support the progressive nature of BD and the application of staging models for early intervention, suggesting a conceptualization of a standardized approach to better characterize patients, predict their clinical course, and deliver tailored treatment options.

Breastfeeding in Phenylketonuria: Changing Modalities, Changing Perspectives.

Phenylketonuria (PKU) management aims to control phenylalanine (Phe) intakes. In newborns and infants this implies possible titration of Human milk (HM) with supplementation of Phe-free formula. HM benefits, better if prolonged, are well known in healthy populations, suggesting it may be used in PKU patients. Despite that, the current literature does not define recommendations on how best perform it in such a population. The main purpose of this study was to evaluate nutrition approaches in newborns and infants affected by PKU and to define if differences can influence the duration of breastfeeding. Data from 42 PKU infants were reviewed. Of these, 67% were breastfed with the use of three different approaches. The type of approach used impacted the duration of breastfeeding, which was longer when using a pre-measured amount of Phe-free formula administered prior to HM. This is the first study to suggest a specific method for breastfeeding in PKU. Considering widely known breastfeeding benefits, both for patients and their mothers, our data should encourage adequate awareness on how to choose correct breastfeeding modalities.

Personality traits and efficacy of anti-CGRP monoclonal antibodies in migraine prevention.

BACKGROUND: Anti-CGRP monoclonal antibodies (CGRPmAbs) enlarged migraine prevention options. They work targetedly, safely, and efficiently in many patients. Inexplicably, a proportion of patients show scarce improvement. OBJECTIVE: To identify the possible role of personality traits, determined with the Personality Inventory for DSM5 (PID5), on the efficacy of CGRPmAbs on migraine. METHODS: We evaluated 3 parameters: monthly headache days (MHD), monthly painkillers intake (MPI), and MIDAS. For each parameter, patients were classified as: (A) non-responders (reduction < 3 0% vs. baseline); (B) partial responders (30-49% reduction); (C) full responders (reduction > 50%). RESULTS: Ninety-seven patients treated with CGRP-mAbs were included (33 galcanezumab, 13 fremanezumab, 51 erenumab). Considering attack reduction (MHD), 53 (54.6%) were full responders, 13 (13.4%) partial responders, and 31 (32%) non-responders. Considering MPI, 61 (62.9%) were full responders, 11 (11.3%) partial responders, and 24 (24.7%) non-responders. Concerning MIDAS, 53 (53%) were full responders, 17 (17.5%) partial responders, and 21 (21.6%) were non-responders. All the 97 patients were tested with the PID5. In terms of MHDs, non-responders, in comparison with responders, showed a significant excess of disinhibition, especially in relation with the anhedonia and depressivity facets. Concerning MPI, non-responders showed increased depressivity and distractibility. MIDAS non-responders had significantly higher scores in the antagonism domain and submissiveness facet. DISCUSSION: Non-responders seem to have different personality traits in comparison to responders, with a higher tendency toward depressed mood and difficulty to feel pleasure previously found in migraineurs vs. non-migraineurs: the more strict certain traits are, the more difficult to treat the migraine could be.

A 6-month follow-up study on response and relapse rates following an acute trial of repetitive transcranial magnetic stimulation in patients with major depression.

BACKGROUND: Little is known about the post-acute effects of repetitive transcranial magnetic stimulation (rTMS) in patients with major depression. The present study focused on the 6-month follow-up of a sample of patients with major depression, after the completion of an acute 4 weeks rTMS trial, with the aim of evaluating response (in terms of sustained and late response) and relapse rates. METHODS: Following the completion of an acute trial of rTMS (T0-T4), 31 drug-resistant depressed patients (bipolar or unipolar) entered a naturalistic follow-up period of 6 months, with three timepoints (T5, T6, and T7) during which they were assessed with the Hamilton Depression Rating Scale and the Young Mania Rating Scale. RESULTS: Results showed that in the 6 months following an acute transcranial magnetic stimulation (TMS) trial, a higher rate of late responders was observed among previously acute TMS nonresponders (63.64%, 7 out of 11) compared to the rate of relapse among those who had acutely responded to TMS (10%, 2 out of 20). In addition, an overall high rate of maintained response (90%) was observed. CONCLUSION: Present findings seem to support the possibility of obtaining a clinical response also after the end of an acute TMS trial in patients with major depression. The concomitant low rate of relapse observed at the end of follow-up along with a high rate of maintained response provides further support to the post-acute efficacy of TMS. Nonetheless, further controlled studies, with larger samples and longer follow-up observation, are needed to confirm the reported results.

Managing Problematic Usage of the Internet and Related Disorders in an Era of Diagnostic Transition: An Updated Review.

INTRODUCTION: Problematic Usage of the Internet (PUI) refers to a broad and likely heterogeneous group of Internet-related conditions associated with behavioural disturbances and functional impairment. METHODS: Within PUI several conditions have been reported, including Gaming Disorder, Shopping Addiction, Cyberchondria, Gambling Disorder, Cyberpornography Addiction and Cyberbullying. While increasing reports in the field try to define the epidemiologic and clinical boundaries of these conditions, the rapid and continuous evolution of Internet related behaviours as well as their problematic/pathological expressions are often difficult to diagnose, assess, approach with treatment interventions and follow-up. RESULTS: In addition, some of the PUI-related conditions show characteristics of addiction to the Internet as a preferential tool to engage in specific behaviours, while some others exclusively manifest on the Internet, making it necessary to find distinct assessment and treatment pathways. CONCLUSION: The inclusion of Internet Gaming Disorder in Section III by the DSM-5 and the recognition of Gaming Disorder by the ICD-11 opened the way for a systematic clinical investigation of this and other PUI-related conditions, particularly in terms of preventive and therapeutic strategies. The present article is aimed at offering an updated clinical overview on the main expressions of PUI, focussing on the latest acquisitions in this evolving field.

Correlation between pharmacokinetics and pharmacogenetics of Selective Serotonin Reuptake Inhibitors and Selective Serotonin and Noradrenaline Reuptake Inhibitors and maternal and neonatal outcomes: Results from a naturalistic study in patients with affective disorders.

OBJECTIVE: Some studies have linked the use of selective serotonin reuptake inhibitors and selective serotonin and noradrenaline reuptake inhibitors (SSRIs/SNRIs) to the risk of perinatal complications. This study explored the relationship between pharmacokinetics and pharmacogenetics, SSRIs/SNRIs tolerability and effectiveness and maternal and newborn outcomes. METHODS: Fifty-five pregnant women with Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) diagnoses of affective disorders, treated with SSRIs/SNRIs, were recruited and, during the third trimester, their blood samples were collected for pharmacokinetic and pharmacogenetic analyses. Plasma levels and metabolic phenotypes were then related to different obstetrical and maternal outcomes. RESULTS: The pharmacokinetic data were more stable for Sertraline, Citalopram, and Escitalopram compared to other molecules (p = 0.009). The occurrence of postnatal adaptation syndrome onset was associated with higher plasma levels for Sertraline (median at delivery: 16.7 vs. 10.5 ng/ml), but not for fluoxetine and venlafaxine. Finally, the subgroup within range plasma concentrations had less blood loss than the below range subgroup (p = 0.030). CONCLUSIONS: Plasma levels of Sertraline, Citalopram and Escitalopram were more frequently in range in late pregnancy when compared to other drugs. Drug plasma concentrations do not strictly correlate with worse perinatal outcomes, but with possible differences between the different drugs.

Crossing Borders Between Frontotemporal Dementia and Psychiatric Disorders: An Updated Overview.

Frontotemporal dementia (FTD) includes a group of neurocognitive syndromes, clinically characterized by altered behaviors, impairment of language proficiency, and altered executive functioning. FTD is one of the most frequently observed forms of dementia in the elderly population and the most common in presenile age. As for other subtypes of dementia, FTD incidence is constantly on the rise due to the steadily increasing age of the population, and its recognition is now becoming a determinant for clinicians. FTD and psychiatric disorders can overlap in terms of clinical presentations by sharing a common genetic predisposition and neuropathological mechanism in some cases. Nonetheless, this association is often unclear and underestimated. Since its first reports, research into FTD has constantly grown, with the identification of recent findings related to its neuropathology, genetic, clinical, and therapeutic issues. Literature is thriving on this topic, with numerous research articles published in recent years. In the present review, we aimed to provide an updated description of the clinical manifestations that link and potentially confound the diagnosis of FTD and psychiatric disorders in order to improve their differential diagnosis and early detection. In particular, we systematically reviewed the literature, considering articles specifically focused on the behavioral variant FTD, published after 2015 on the PubMed database.

Postpartum Bleeding in Pregnant Women Receiving SSRIs/SNRIs: New Insights From a Descriptive Observational Study and an Analysis of Data from the FAERS Database.

PURPOSE: To date, the available data on the relationship between the use of selective serotonin reuptake inhibitors (SSRIs) or the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine and postpartum hemorrhage (PPH) are conflicting and have not been extensively investigated, especially in terms of plasma drug concentrations. We performed data mining of antidepressant-induced PPH reported to the US Food and Drug Administration's Adverse Event Reporting System database, to assess the strength of the potential association between antidepressant pharmacotherapy and PPH in pregnant women. Concurrently, we carried out a descriptive observational population (pregnant women) analysis of the correlation between the plasma concentrations of SSRIs/SNRIs used during pregnancy and the extent of bleeding at delivery. METHODS: A disproportionality analysis of individual case study reports of PPH associated with SSRIs or venlafaxine in pregnant women was performed. Reporting odds ratio was used as a measure of disproportionality analysis. Pregnant women treated with an SSRI or SNRI (venlafaxine) for depressive or anxiety disorder and who consented to plasma drug concentration monitoring at the time of delivery were recruited. Plasma drug concentration assay was performed according to validated LC-MS/MS. Based on plasma drug concentrations, patients were classified into 1 of 2 groups, in therapeutic range or below therapeutic range for the drug administered, in accordance with the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie guideline, and correlations with blood loss were identified, with PPH defined as a blood loss of >500 mL. FINDINGS: Only 43 Individual Case Safety Reports (ICSRs) reported at least one SSRIs or venlafaxine as suspect drug in 14 years (database analyses). Forty-three women were enrolled in the study population (observational study). In 24 patients (55.8%) the plasma drug concentration was below the therapeutic threshold. Unexpectedly, the mean blood loss in the below-range group was significantly higher than that in the in-range group. PPH occurred in 30% of women: in 9.3% and in 20.7% of patients in the in-range and below-range groups, respectively. IMPLICATIONS: Although preliminary, these data indicate a rather good tolerability profile of SSRIs/SNRIs regarding postpartum bleeding. Moreover, they suggest that keeping the plasma levels of SSRIs/SNRIs low as a precautionary measure does not reduce postpartum bleeding, which was higher in the below-range group. The findings from this study suggest that the use of therapeutic drug monitoring in pregnancy, a period in which multiple variables affect drug metabolism, may allow for better treatment customization, with subsequent advantages in terms of tolerability and efficacy of treatment.