Precision medicine is a concept which is recently gaining momentum in all branches of medicine. In particular in psychiatry it is greatly needed given the huge societal costs of psychiatric disorders ...and given the long time needed to observe benefit from treatments and the response variability. The future will be based on biological determinants, however until such an interesting but still futuristic aim will be reached, at present we may only rely on clinical features to guide our individualized prescription which is currently still frequently based on personal opinion and subjective previous experiences. The aim of this review is to offer an overview of the main aspects to take into consideration when prescribing an antidepressant treatment to reach the best precision medicine using clinical information. More than 40 compounds are available for treating depression and a similar amount of compounds for other psychiatric disorders. The process of matching the profile of the patient with all different profiles of available compounds is therefore quite complex. Our everyday prescribing procedure should take into consideration a number of factors such as the knowledge of the profile of available compounds versus the symptomatology profile of the subject, previous efficacy, medical comorbidities, tolerability profile, individual preferences, and family history. While we are waiting more complex algorithms including biological or genetic measures, it is possible to optimize our current prescription practice by using all available information in order to obtain as much as possible an evidence based precision medicine prescription.
A Critical View on New and Future Antidepressants Serretti, Alessandro
Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology,
2024-May-31, Letnik:
22, Številka:
2
Journal Article
Recenzirano
Odprti dostop
For the first time after many decades, many new antidepressants have been approved and many more are under various stages of development and will soon be available in the market. The new drugs ...present a range of new mechanisms of action with benefits in terms of speed of action, tolerability and range of treatable disorders. Neurosteroids have been recently approved and their rapid benefit may extend from postpartum depression to anxious depression and bipolar depression, dextromethorphan and bupropion combination may prove useful in major depression but also in treatment resistant depression, dextromethadone is a possible augmentation in partial antidepressant response, psychedelic drugs have the potential of long lasting benefits after a single administration, though are still experimental treatments. Botulinum has the same advantage of psychedelics of a single administration and its antidepressant effects may last for weeks or more. Further potentially interesting new antidepressant mechanisms include new drug targets, drug repurposing and genetic or epigenetic manipulations. It is therefore important that clinicians are kept up to date with new evidence so that new evidence can be rapidly translated into clinical practice.
The beneficial clinical effects of mindfulness practices are receiving increasing support from empirical studies. However, the functional neural mechanisms underlying these benefits have not been ...thoroughly investigated. Some authors suggest that mindfulness should be described as a ‘top–down’ emotion regulation strategy, while others suggest that mindfulness should be described as a ‘bottom–up’ emotion regulation strategy. Current discrepancies might derive from the many different descriptions and applications of mindfulness. The present review aims to discuss current descriptions of mindfulness and the relationship existing between mindfulness practice and most commonly investigated emotion regulation strategies. Recent results from functional neuro-imaging studies investigating mindfulness training within the context of emotion regulation are presented. We suggest that mindfulness training is associated with ‘top–down’ emotion regulation in short-term practitioners and with ‘bottom–up’ emotion regulation in long-term practitioners. Limitations of current evidence and suggestions for future research on this topic are discussed.
► Mindfulness training (MT) has shown efficacy for many clinical conditions. ► Little is known about the neural correlates supporting the clinical benefits of MT. ► MT could be associated with top–down emotion regulation in short-term practitioners. ► MT could be associated with bottom–up emotion regulation in long-term practitioners. ► Different instructions or mental conditions could influence the neural mechanisms of MT.
Abstract Up to one third of patients adequately treated for Major Depressive Disorder (MDD) do not respond to multiple interventions. Many studies investigated predictors in MDD outcome, but no study ...focused on predictors of non-response or non-remission to antidepressants in subjects with treatment resistant depression (TRD). The present study aimed to evaluate possible socio-demographic and clinical predictors of non-response and non-remission in MDD patients who failed to benefit from at least one antidepressant trial. A total of 51 papers were included. A number of severity indicators, such as longer duration of depressive episode, moderate-high suicidal risk, anxious comorbidity, higher number of hospitalizations and higher dosage of ADs, were associated with non-response as well as age. Interestingly, severity of illness, as well as comorbid personality disorders and anxiety symptoms, had also a predictive value in non-remission with the addition of marital status. Considering limitations, selected studies were observational or randomized non controlled/controlled trials and different TRD definitions and outcome measures were used. Overall, predictors of outcome were similar to MDD, but specific socio-demographic and clinical factors should be considered in clinical practice to formulate a more focused treatment in TRD patients.
The choice of the most appropriate psychoactive medication for each of our patients is always a challenge. We can use more than 100 psychoactive drugs in the treatment of mood disorders, which can be ...prescribed either alone or in combination. Response and tolerability problems are common, and much trial and error is often needed before achieving a satisfactory outcome. Precision medicine is therefore needed for tailoring treatment to optimize outcome. Pharmacological, clinical, and demographic factors are important and informative, but biological factors may further inform and refine prediction. Twenty years after the first reports of gene variants modulating antidepressant response, we are now confronted with the prospect of routine clinical pharmacogenetic applications in the treatment of depression. The scientific community is divided into two camps: those who are enthusiastic and those who are skeptical. Although it appears clear that the benefit of existing tools is still not completely defined, at least in the case of central nervous system gene variants, this is not the case for metabolic gene variants, which is generally accepted. Cumulative scores encompassing many variants across the entire genome will soon predict psychiatric disorder liability and outcome. At present, precision medicine in mood disorders may be implemented using clinical and pharmacokinetic factors. In the near future, a genome‐wide composite genetic score in conjunction with clinical factors within each patient is the most promising approach for developing a more effective way to target treatment for patients suffering from mood disorders.
Present and future steps for precision medicine in mood disorder.
The pharmacogenetics of antidepressants has been not only a challenging but also frustrating research field since its birth in the 1990s. Indeed, great expectations followed the first evidence of ...familiar aggregation of antidepressant response. Despite the progress from candidate gene studies to genome-wide association studies (GWAS), results fell out the expectations and they were often inconsistent. Anyway, the cumulative evidence supports the involvement of some genes and molecular pathways in antidepressant efficacy. The best single genes are
SLC6A4
,
HTR2A
,
BDNF
,
GNB3
,
FKBP5
,
ABCB1
, and cytochrome P450 genes (
CYP2D6
and
CYP2C19
). Molecular pathways involved in inflammation and neuroplasticity show the greatest support. The first studies evaluating benefits of genotype-guided antidepressant treatments provided encouraging results and confirmed the relevance of
SLC6A4
,
HTR2A
,
ABCB1
, and cytochrome P450 genes. Further progress in genotyping and data analysis would allow to move forward and complete the understanding of antidepressant pharmacogenetics and its translation into clinical applications.
Treatment-resistant depression (TRD) is a major contributor to the disability caused by major depressive disorder (MDD). Primary care electronic health records provide an easily accessible approach ...to investigate TRD clinical and genetic characteristics. MDD defined from primary care records in UK Biobank (UKB) and EXCEED studies was compared with other measures of depression and tested for association with MDD polygenic risk score (PRS). Using prescribing records, TRD was defined from at least two switches between antidepressant drugs, each prescribed for at least 6 weeks. Clinical-demographic characteristics, SNP-based heritability (h
) and genetic overlap with psychiatric and non-psychiatric traits were compared in TRD and non-TRD MDD cases. In 230,096 and 8926 UKB and EXCEED participants with primary care data, respectively, the prevalence of MDD was 8.7% and 14.2%, of which 13.2% and 13.5% was TRD, respectively. In both cohorts, MDD defined from primary care records was strongly associated with MDD PRS, and in UKB it showed overlap of 71-88% with other MDD definitions. In UKB, TRD vs healthy controls and non-TRD vs healthy controls h
was comparable (0.25 SE = 0.04 and 0.19 SE = 0.02, respectively). TRD vs non-TRD was positively associated with the PRS of attention deficit hyperactivity disorder, with lower socio-economic status, obesity, higher neuroticism and other unfavourable clinical characteristics. This study demonstrated that MDD and TRD can be reliably defined using primary care records and provides the first large scale population assessment of the genetic, clinical and demographic characteristics of TRD.
Bipolar disorder (BD) shows one of the strongest genetic predispositions among psychiatric disorders and the identification of reliable genetic predictors of treatment response could significantly ...improve the prognosis of the disease.
The present study investigated genetic predictors of long-term treatment–outcome in 723 patients with BD type I from the STEP-BD (Systematic Treatment Enhancement Program for Bipolar Disorder) genome-wide dataset. BD I patients with >6months of follow-up and without any treatment restriction (reflecting a natural setting scenario) were included. Phenotypes were the total and depressive episode rates and the occurrence of one or more (hypo)manic/mixed episodes during follow-up. Quality control of genome-wide data was performed according to standard criteria and linear/logistic regression models were used as appropriate under an additive hypothesis. Top genes were further analyzed through a pathway analysis.
Genes previously involved in the susceptibility to BD (DFNB31, SORCS2, NRXN1, CNTNAP2, GRIN2A, GRM4, GRIN2B), antidepressant action (DEPTOR, CHRNA7, NRXN1), and mood stabilizer or antipsychotic action (NTRK2, CHRNA7, NRXN1) may affect long-term treatment outcome of BD. Promising findings without previous strong evidence were TRAF3IP2-AS1, NFYC, RNLS, KCNJ2, RASGRF1, NTF3 genes. Pathway analysis supported particularly the involvement of molecules mediating the positive regulation of MAPK cascade and learning/memory processes.
Further studies focused on the outlined genes may be helpful to provide validated markers of BD treatment outcome.
•Genetic markers of long-term treatment outcome could improve the prognosis of bipolar disorder.•Single SNPs and molecular pathways were analyzed in a genome-wide association study.•TRAF3IP2-AS1, RNLS, DFNB31, NFYC and DEPTOR genes were predictors of total episode rate.•The DFNB31 gene was strongly associated with the risk of depressive recurrence.•Top pathways mediate the regulation of MAPK cascade and learning/memory processes.
The empirical approach to drug choice and dosing in depression often results into inadequate response and side effects. Pharmacogenetic (PGx) testing appears a promising way to implement personalized ...treatments.
A systematic review was performed to identify available PGx tests, compare the genes they include with clinical guidelines and drug labels, and assess the quality of published clinical studies.
~40 commercial PGx tests are available and potential benefits were estimated for nine of them by clinical studies. The most part of studies are observational (9/21) or non-randomized case-control trials that compared standard care with PGx-guided treatment (6/21), six randomized controlled trials (RCTs) are available. The only genes included in all the available PGx tests and with recommendations in current clinical guidelines and drug labels are CYP2D6 and CYP2C19. There is heterogeneity among outcome measures across studies (response, remission, improvement, health care utilization, medication tolerability), as well as in trial design. Relatively weak clinical benefits were reported by RCTs and higher clinical benefits by non-RCTs, but the last group showed greater risk of bias. Lack of patient and rater's blindness, retrospective design and possible confounders (concomitant medications and medical diseases, lack of wash out prior to inclusion, no assessment of compliance etc.) were the main issues. Estimations of cost savings provided heterogeneous findings.
Variants in CYP2D6 and CYP2C19 have already adequate support for clinical application. The development of future PGx tests should include best practices for clinical evidence development and for health economic assessment.
•Pharmacogenetic (PGx) testing may provide personalized treatments for depression.•Dozens of PGx testing kits are commercialized and they include different variant panels.•Effectiveness and particularly cost/utility of PGx testing are still unclear.•The highest level of evidence was provided for CYP2C19 and CYP2D6 genes.•Best practices for experimental evidence development and economic assessment should be applied.
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