Depression is increasingly conceptualized as a disorder of impaired synaptic plasticity and excitation–inhibition imbalance within corticolimbic circuits. Two rapid-acting therapeutic classes, NMDA receptor modulators (ketamine, esketamine) and neuroactive-steroid GABA-A positive allosteric modulators (brexanolone, zuranolone), offer complementary approaches to restore circuit function. Clinically, intravenous ketamine and intranasal esketamine show superiority over placebo and active comparators in treatment-resistant depression (TRD), with esketamine supported for continuationphase relapse prevention and, in the United States, is approved both as adjunctive therapy and as monotherapy in adults with TRD. Evidence of efficacy extends to bipolar depression with careful mood-stabilizer coverage. Both agents reduce suicidal ideation within hours to days, although effects on suicidal behavior have not been demonstrated. Safety profiles include dissociation and hemodynamic changes; concerns with prolonged or high-cumulative exposure include cystitis and misuse liability. Neurosteroid GABA-A modulators are effective in post partum depression with some preliminary evidence in major depression, particularly in combination with antidepressants, while adverse events are mainly dose-dependent sedation. Brexanolone requires monitored infusion, whereas zuranolone enables a 14-day outpatient course. Patient selection should integrate diagnosis, comorbidity, concomitant medications (e.g. benzodiazepines), logistics, and perinatal goals. Robust efficacy/tolerability predictors remain limited, though early symptomatic change is clinically informative. In conclusion, NMDA receptor modulators and neuroactive-steroid GABA-A positive allosteric modulators have improved the treatment for mood disorders and accelerated a transition to mechanism-driven care.

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.

Anhedonia is a core symptom of depression and of several psychiatric disorders. Anhedonia has however expanded from its original definition to encompass a spectrum of reward processing deficits that received much interest in the last decades. It is a relevant risk factor for possible suicidal behaviors, and that it may operate as an independent risk factor for suicidality apart from the episode severity. Anhedonia has also been linked to inflammation with a possible reciprocal deleterious effect on depression. Its neurophysiological bases mainly include alterations in striatal and prefrontal areas, with dopamine being the most involved neurotransmitter. Anhedonia is thought to have a significant genetic component and polygenic risk scores are a possible tool for predicting an individual’s risk for developing anhedonia.Traditional antidepressants, such as selective serotonin reuptake inhibitors, showed a limited benefit on anhedonia, also considering their potential pro-anhedonic effect in some subjects. Other treatments may be more effective in treating anhedonia, such as agomelatine, vortioxetine, ketamine and transcranial magnetic stimulation. Psychotherapy is also widely supported, with cognitive-behavioral therapy and behavioral activation both showing benefit. In conclusion, a large body of evidence suggests that anhedonia is, at least partially, independent from depression, therefore it needs careful assessment and targeted treatment.

Major depressive disorders are ranked as the single largest contributor to non-fatal health loss and biomarkers could largely improve our routine clinical activity by predicting disease course and guiding treatment. However there is still a dearth of valid biomarkers in the field of psychiatry. The initial assumption that a single biomarker can capture the myriad of complex processes proved to be naive. The purpose of this paper is to critically review the field and to illustrate the possible practical application for routine clinical care. Biomarkers derived from DNA analysis are the ones that have received the most attention. Other potential candidates include circulating transcription products, proteins, and inflammatory markers. DNA polygenic risk scores proved to be useful in other fields of medicine and preliminary results suggest that they could be useful both as risk and diagnostic biomarkers also in depression and for the choice of treatment. A number of other possible fluid biomarkers are currently under investigation for diagnosis, outcome prediction, staging, and stratification of interventions, however research is still needed before they can be used for routine clinical care. When available, clinicians may be able to receive a lab report with detailed information about disease risk, outcome prediction, and specific indications about preferred treatments.

Objective: We report the results of pharmacogenomics-based antidepressant treatment (PGXt) results in treating treatment-resistant major depressive disorder (TRD) patients in real practice. Methods: Nine patients were prescribed NeuropharmagenⓇ for selection of antidepressants for individual patient and their clinical outcomes were followed. Results: After treatment by PGXt results from current antidepressants, substantial reduction of depressive symptoms was observed at some point and maintained during observation period in six patients. Conclusion Our case series potentially shows the clinical utility and benefit of PGXt for treatment of TRD patients.

Objective: The genetic background of mood disorders is gradually emerging through the use of large multicenter samples but a detailed phenotyping is complementary in elucidating the role of modulating variants. Methods: In the present paper we focused on the possible modulatory effects of ARC gene variants on two independent mood disorder samples of European (n = 246 bipolar disorder) and Korean (n = 132 bipolar disorder; n = 242 major depressive disorder [MDD]) ancestry. Results: No result survived Bonferroni correction, however we evidenced promising trend toward possible association between ARC gene variants and mood disorder phenotypes. In particular, we evidenced weak correlations of ARC single nucleotide polymorphisms with depressive symptoms severity (evaluated through Hamilton depression rating scale scores) in the MDD Korean (rs7465272) and European (rs11167152) samples. Additionally rs10110456 was found to be related to Family History, while rs7465272 was related to suicide risk in the Korean sample. Finally, rs7465272 was associated with body mass index in the European sample. Conclusion Overall, ARC gene variants may have a partial role in modulatory effect on treatment efficacy or phenotypes of mood disorders. Further studies, on larger samples may provide a better understanding on the role of ARC gene variants in the symptom severity and treatment outcomes in patients with mood disorders.

Pharmacogenetic testing is a useful and increasingly widespread tool to assist in antidepressant prescription. More than ten antidepressants (including tricyclics, selective serotonin reuptake inhibitors and venlafaxine) have already genetic biomarkers of response/side effects in clinical guidelines and drug labels. These are represented by functional genetic variants in genes coding for cytochrome enzymes (CYP2D6 and CYP2C19). Depending on the predicted metabolic activity, guidelines provide recommendations on drug choice and dosing. Despite not conclusive, the current evidence suggests that testing can be useful in patients who did not respond or tolerate at least one previous pharmacotherapy. However, the current recommendations are based on pharmacokinetic genes only (CYP450 enzymes), while pharmacodynamic genes (modulating antidepressant mechanisms of action in the brain) are still being studied because of their greater complexity. This may be captured by polygenic risk scores, which reflect the cumulative contribution of many genetic variants to a trait, and they may provide future clinical applications of pharmacogenetics. A more extensive use of genotyping in clinical practice may lead to improvement in treatment outcomes thanks to personalized treatments, but possible ethical issues and disparities should be taken into account and prevented.

Objective: Genetic variations in the gene encoding zinc finger protein 804A gene (ZNF804A) have been associated with major depression and bipolar disorder. In this work we focused on the potential influence of ZNF804A variations on the risk of developing specific sub-phenotypes as well as the individual response to available treatments. Methods: We used two samples of different ethnic origin: a Korean sample, composed by 242 patients diagnosed with major depression and 132 patients diagnosed with bipolar disorder and 326 healthy controls; an Italian sample composed 151 major depression subjects, 189 bipolar disorder subjects and 38 outpatients diagnosed for a primary anxiety disorder. Results: Our analyses reported an association of rs1344706 with psychotic phenotype in the cross-diagnostic pooled sample (geno p = 4.15 × 10−4, allelic p = 1.06 × 10−4). In the cross-diagnosis Italian sample but not in the Korean one, rs7597593 was involved with depressive symptoms improvement after treatment (geno p = 0.025, allelic p = 0.007). Conclusion The present study evidenced the role of ZNF804A alterations in symptoms improvement after treatment. Both manic and depressive symptoms seem to be modulated by ZNF804A, though the latter was observed in the bipolar pooled sample only. The role of this factor is likely related to synaptic development and maintenance; however, further analyses will be needed to better understand the molecular mechanics involved with ZNF804A.

Depression is the single largest contributor to non-fatal health loss and affects 322 million people globally. The clinical heterogeneity of this disorder shows biological correlates and it makes the personalization of antidepressant prescription an important pillar of treatment. There is increasing evidence of genetic overlap between depression, other psychiatric and non-psychiatric disorders, which varies across depression subtypes. Therefore, the first step of clinical evaluation should include a careful assessment of psychopathology and physical health, not limited to previously diagnosed disorders. In part of the patients indeed the pathogenesis of depression may be strictly linked to inflammatory and metabolic abnormalities, and the treatment should target these as much as the depressive symptoms themselves. When the evaluation of the symptom and drug tolerability profile, the concomitant biochemical abnormalities and physical conditions is not enough and at least one pharmacotherapy failed, the genotyping of variants in CYP2D6 /CYP2C19 (cytochromes responsible for antidepressant metabolism) should be considered. Individuals with altered metabolism through one of these enzymes may benefit from some antidepressants rather than others or need dose adjustments.Finally, if available, the polygenic predisposition towards cardio-metabolic disorders can be integrated with non-genetic risk factors to tune the identification of patients who should avoid medications associated with this type of side effects.A sufficient knowledge of the polygenic risk of complex medical and psychiatric conditions is becoming relevant as this information can be obtained through direct-to-consumer genetic tests and in the future it may provided by national health care systems.