Antidepressant Pharmacotherapy Research Articles

Longitudinal invariance of the Patient Health Questionnaire-9 among patients receiving pharmacotherapy for major depressive disorder: A secondary analysis of clinical trial data.

Comparing self-reported symptom scores across time requires longitudinal measurement invariance (LMI), a psychometric property that means the measure is functioning identically across all time points. Despite its prominence as a measure of depression symptom severity in both research and health care, LMI has yet to be firmly established for the Patient Health Questionnaire-9 depression module (PHQ-9), particularly over the course of antidepressant pharmacotherapy. Accordingly, the objective of this study was to assess for LMI of the PHQ-9 during pharmacotherapy for major depressive disorder. This was a secondary analysis of data collected during a randomized controlled trial. A total of 1,944 veterans began antidepressant monotherapy and completed the PHQ-9 six times over 24 weeks of treatment. LMI was assessed using a series of four confirmatory factor analysis models that included all six time points, with estimated parameters increasingly constrained across models to test for different aspects of invariance. Root-mean-square error of approximation of the chi-square difference test values below 0.06 indicated the presence of LMI. Exploratory LMI analyses were also performed for separate sex, age, and race subgroups. Root-mean-square error of approximation of the chi-square difference test showed minimal change in model fits during invariance testing (≤ 0.06 for all steps), supporting full LMI for the PHQ-9. LMI was also supported for all tested veteran subgroups. As such, PHQ-9 sum scores can be compared across extended pharmacotherapy treatment durations. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The association between gray matter volume in the hippocampal subfield and antidepressant efficacy mediated by abnormal dynamic functional connectivity

An abnormality of structures and functions in the hippocampus may have a key role in the pathophysiology of major depressive disorder (MDD). However, it is unclear whether structure factors of the hippocampus effectively impact antidepressant responses by hippocampal functional activity in MDD patients. We collected longitudinal data from 36 MDD patients before and after a 3-month course of antidepressant pharmacotherapy. Additionally, we obtained baseline data from 43 healthy controls matched for sex and age. Using resting-state functional magnetic resonance imaging (rs-fMRI), we estimated the dynamic functional connectivity (dFC) of the hippocampal subregions using a sliding-window method. The gray matter volume was calculated using voxel-based morphometry (VBM). The results indicated that patients with MDD exhibited significantly lower dFC of the left rostral hippocampus (rHipp.L) with the right precentral gyrus, left superior temporal gyrus and left postcentral gyrus compared to healthy controls at baseline. In MDD patients, the dFC of the rHipp.L with right precentral gyrus at baseline was correlated with both the rHipp.L volume and HAMD remission rate, and also mediated the effects of the rHipp.L volume on antidepressant performance. Our findings suggested that the interaction between hippocampal structure and functional activity might affect antidepressant performance, which provided a novel insight into the hippocampus-related neurobiological mechanism of MDD.

Therapies to Treat Depression in Hypothyroid Patients

Abstract Hypothalamic–pituitary–thyroid axis seems to play an important role in the pathogenesis of depression in hypothyroid patients. Studies have shown that hypothyroidism can induce mood changes and major depressive disorders, but what governs the reason for this linkage and the most suitable therapy to manage this condition is not very clear. We aim to investigate the various existing therapies administered for depression due to hypothyroidism and the potential scope of yoga therapy to treat these conditions effectively. A systematic literature search of five databases, namely, EBSCO, SCOPUS, PROQUEST, PubMed, and Elsevier using the keywords in the area of “hypothyroidism, depression, and therapies” was carried out till the period 2023 following the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” guidelines to select the relevant English-language peer-reviewed articles for the study. The objective of this study was to present the work done so far in the field of treating depression in hypothyroidism through therapy techniques. The paper reviews 18 specific empirical studies on various available therapies administered for depression in hypothyroidism and based on the extant literature covers four broad themes: (1) hormone therapy, (2) antidepressant pharmacotherapy, (3) cognitive psychotherapy, and (4) yoga therapy. This review provides a clear need for more yoga therapy studies, as only two yoga studies were found for treating depression in hypothyroidism that have shown significant outcomes.

Cognitive Outcomes After Antidepressant Pharmacotherapy for Late-Life Depression: A Systematic Review and Meta-Analysis.

The authors evaluated whether treatment of late-life depression (LLD) with antidepressants leads to changes in cognitive function. A systematic review and meta-analysis of prospective studies of antidepressant pharmacotherapy for adults age 50 or older (or mean age of 65 or older) with LLD was conducted. MEDLINE, EMBASE, and PsycInfo were searched through December 31, 2022. The primary outcome was a change on cognitive test scores from baseline to after treatment. Secondary outcomes included the effects of specific medications and the associations between changes in depressive symptoms and cognitive test scores. Participants with bipolar disorder, psychotic depression, dementia, or neurological disease were excluded. Findings from all eligible studies were synthesized at a descriptive level, and a random-effects model was used to pool the results for meta-analysis. Twenty-two studies were included. Thirteen of 19 studies showed an improvement on at least one cognitive test after antidepressant pharmacotherapy, with the most robust evidence for the memory and learning (nine of 16 studies) and processing speed (seven of 10 studies) domains and for sertraline (all five studies). Improvements in depressive symptoms were associated with improvement in cognitive test scores in six of seven relevant studies. The meta-analysis (eight studies; N=493) revealed a statistically significant overall improvement in memory and learning (five studies: effect size=0.254, 95% CI=0.103-0.404, SE=0.077); no statistically significant changes were seen in other cognitive domains. The evaluated risk of publication bias was low. Antidepressant pharmacotherapy of LLD appears to improve certain domains of cognitive function, particularly memory and learning. This effect may be mediated by an improvement in depressive symptoms. Studies comparing individuals receiving pharmacotherapy with untreated control participants are needed.

Utility of pharmacogenetic testing to optimise antidepressant pharmacotherapy in youth: a narrative literature review.

Pharmacogenetics (PGx) is the study and application of how interindividual differences in our genomes can influence drug responses. By evaluating individuals' genetic variability in genes related to drug metabolism, PGx testing has the capabilities to individualise primary care and build a safer drug prescription model than the current "one-size-fits-all" approach. In particular, the use of PGx testing in psychiatry has shown promising evidence in improving drug efficacy as well as reducing toxicity and adverse drug reactions. Despite randomised controlled trials demonstrating an evidence base for its use, there are still numerous barriers impeding its implementation. This review paper will discuss the management of mental health conditions with PGx-guided treatment with a strong focus on youth mental illness. PGx testing in clinical practice, the concerns for its implementation in youth psychiatry, and some of the barriers inhibiting its integration in clinical healthcare will also be discussed. Overall, this paper provides a comprehensive review of the current state of knowledge and application for PGx in psychiatry and summarises the capabilities of genetic information to personalising medicine for the treatment of mental ill-health in youth.

The Relationship of Early Sleep Improvement With Response to Pharmacotherapy in Unipolar Psychotic Depression.

Since insomnia and depression are interrelated, improved sleep early in antidepressant pharmacotherapy may predict a positive treatment outcome. We investigated whether early insomnia improvement (EII) predicted treatment outcome in psychotic depression (PD) and examined if there was an interaction effect between EII and treatment type to assess if findings were treatment-specific. This study is a secondary analysis of a randomized trial comparing 7 weeks treatment with the antidepressants venlafaxine, imipramine and venlafaxine plus the antipsychotic quetiapine in PD ( n = 114). Early insomnia improvement, defined as ≥20% reduced insomnia after 2 weeks, was assessed by the Hamilton Rating Scale for Depression (HAM-D-17). Associations between EII and treatment outcome were examined using logistic regressions. Subsequently, we added interaction terms between EII and treatment type to assess interaction effects. The predictive value of EII was compared with early response on overall depression (≥20% reduced HAM-D-17 score after 2 weeks). EII was associated with response (odds ratio [OR], 7.9; 95% confidence interval [CI], 2.7-23.4; P = <0.001), remission of depression (OR, 6.1; 95% CI, 1.6-22.3; P = 0.009), and remission of psychosis (OR, 4.1; 95% CI, 1.6-10.9; P = 0.004). We found no interaction effects between EII and treatment type on depression outcome. Early insomnia improvement and early response on overall depression had a comparable predictive ability for treatment outcome. Early insomnia improvement was associated with a positive outcome in pharmacotherapy of PD, regardless of the medication type. Future studies are needed to confirm our findings and to examine the generalizability of EII as predictor in treatment of depression.

Understanding and assessing the antidepressant drug-associated risk of bleeding

Antidepressants, in particular selective serotonin reuptake inhibitors (SSRIs), are the most commonly prescribed psychopharmacological drug group. Thus, a precise knowledge of the expected adverse drug reactions is indispensable. The increased risk of bleeding events is well documented, especially in patients treated with SSRIs. However, many other antidepressant drug groups have also been implicated in increasing the risk of bleeding. In the following review, the thrombocytic serotonin system and the respective targets of the different antidepressants are explained. Subsequently, the available literature on bleeding under the respective antidepressant classes or individual substances is presented, using data from meta-analyses whenever possible. In addition to the risk of bleeding in general, individual bleeding entities are also considered, such as gastrointestinal and cerebral hemorrhages. Finally, the effects of other drugs that increase the risk of bleeding (i. e., nonsteroidal anti-inflammatory drugs, platelet aggregation inhibitors and anticoagulants) in combination with antidepressant drugs are discussed. The information presented here is meant to guide practitioner's decision making regarding an appropriate antidepressant pharmacotherapy based on the patient's individual risk constellation.

Towards Novel Potential Molecular Targets for Antidepressant and Antipsychotic Pharmacotherapies.

Depression and schizophrenia are two highly prevalent and severely debilitating neuropsychiatric disorders. Both conventional antidepressant and antipsychotic pharmacotherapies are often inefficient clinically, causing multiple side effects and serious patient compliance problems. Collectively, this calls for the development of novel drug targets for treating depressed and schizophrenic patients. Here, we discuss recent translational advances, research tools and approaches, aiming to facilitate innovative drug discovery in this field. Providing a comprehensive overview of current antidepressants and antipsychotic drugs, we also outline potential novel molecular targets for treating depression and schizophrenia. We also critically evaluate multiple translational challenges and summarize various open questions, in order to foster further integrative cross-discipline research into antidepressant and antipsychotic drug development.

Dissociation Across Cultures: A Transdiagnostic Guide for Clinical Assessment and Management.

The clinical heterogeneity of dissociation constitutes a challenge to the culture-sensitive clinician. Variability in experiencing dissociation, the interplay between acute and chronic conditions, and the predominance of a nosologically interface-type of clinical surface conceal core dissociative symptoms. While the latter (amnesia, depersonalization, derealization, identity confusion, and identity alteration) usually remain underreported, the clinical surface may be dominated by acute (functional neurological symptoms, brief psychosis, an experience of possession, or acute dissociative reaction to a stressful event) or chronic (mood and personality disorders) secondary syndromes. However, these syndromes also constitute gateways in pursuing the clues of core dissociation. Given that culture influences communication between clinician and patient, accurate expression of mental content requires the idiomatic armamentarium describing the experience. The latter is problematic in dealing with phenomena of core dissociation while the secondary representations have a relatively universal character for both clinicians and patients. Nevertheless, this approach requires a transdiagnostic understanding in conceiving this clinical interface. This interface reflects, in fact, complications of dissociative disorders which require to be addressed in the first line. This is either due to the medical and psychiatric urgency (e.g., functional neurological symptoms, brief psychosis) or due to resistance to treatment (e.g., antidepressant pharmacotherapy) which seem to be indicated for the particular condition. This transdiagnostic schema is based on a combined utilization of etic and emic principles in the cultural understanding of psychiatric disorders. Namely, universal medical-psychiatric categories are conceived as tools of communication and mutual understanding rather than being mere appearances or primary disturbances.

The course of insomnia symptoms during the acute treatment of major depressive disorder: A CAN-BIND-1 report

Despite considerable efforts to study the relationship between insomnia and depression, there is minimal research investigating whether insomnia symptoms change over time during a course of antidepressant pharmacotherapy. This study investigated the course of insomnia symptoms during the acute treatment of major depressive disorder (MDD) using a secondary analysis of data from MDD patients (N = 180) who were treated with open-label escitalopram (10–20 mg/day) for 8-weeks. Montgomery-Asberg Depression Rating Scale without sleep item (modified-MADRS) assessed depression and Self-reported Quick Inventory Depressive Scale (QIDS-SR) measured subjective sleep-onset, mid-nocturnal, and early-morning insomnia throughout 8-weeks of treatment. Pittsburgh Sleep Quality Index (PSQI) was used to assess subjective sleep quality, duration, onset latency, and efficiency throughout 8-weeks of treatment. Remission of depression was defined as modified-MADRS ≤10 at week-8. Mixed model repeated measures (MMRMs) were conducted with remission status as an independent variable and each sleep variable as a dependent variable. MMRMs demonstrated that remitters had significantly lower QIDS-SR sleep-onset and mid-nocturnal insomnia scores as well as a significantly lower PSQI sleep quality score than non-remitters throughout 8-weeks of treatment. Monitoring subjective sleep-onset and mid-nocturnal insomnia during the course of treatment with serotonergic antidepressants may be useful for predicting acute remission of depression.

A nationwide study of initiation of antidepressant pharmacotherapy and the risk of seizures

ObjectiveThe present study aimed to examine whether antidepressant initiation increases the risk of hospitalizations and unplanned outpatient visits for seizures. Research has provided conflicting evidence as to whether antidepressant initiation causes seizures. Because epilepsy and depression are comorbid, this remains an important question, particularly in the care of those already at-risk for seizures. MethodsWe used Swedish-register data, including 658,766 antidepressant initiators and 1:1 age-, region-, and sex-matched non-initiators, ages 12–65. We used filled prescriptions to identify any antidepressant and serotonergic antidepressant and inpatient hospitalizations and unplanned outpatient (to avoid coding routine epilepsy maintenance as a seizure) visits to identify seizures, respectively. We first compared seizure visit incidence between antidepressant-initiators and matched non-users in the year following initiation from 2006 to 2013. To examine seizure risk over months pre- and post-initiation, within-individual analyses compared risk during the month one year prior to initiation with all subsequent months. We examined associations for any antidepressant and serotonergic antidepressants, as well as for any initiator and initiators with a history of seizures. ResultsOur matched-cohort results showed higher incidence of seizure visits among antidepressant users compared with non-users (e.g., adjusted incidence rate ratio [IRR]=3.14, 95% confidence interval [CI]=2.83–3.49). In within-individual analyses, the months after initiation were associated with higher incidence of seizure visits when compared with the month one year prior to initiation (e.g., one month after initiation IRR=1.96, 95%CI=1.64–2.34), but in individuals with a seizure history we observed weaker or no associations in the months after initiation (e.g., two months after initiation IRR=1.12, 95%CI=0.87–1.45). Notably, irrespective of potential seizure history, the months preceding initiation were associated with the greatest risk (e.g., one month before initiation IRR=2.86, 95% CI=2.42–3.38). ConclusionsOur findings suggest that there may be an elevated risk of seizures during antidepressant treatment, though the period of highest risk was before the initiation of antidepressants. Risk for seizure visits was lower among individuals with a history of prior seizures, which may be reassuring for the clinical care of these patients or indicate lack of treatment seeking following seizures. This study highlights the need to consider seizure risk across time; the failure to account for these dynamics may help account for discrepant findings in previous studies.

Antidepressants and quality of life in patients with major depressive disorder - Systematic review and meta-analysis of double-blind, placebo-controlled RCTs.

Quality of Life (QoL) is an important outcome in mental disorders. We investigated whether antidepressant pharmacotherapy improved QoL vs. placebo among patients with MDD. Systematic literature search in CENTRAL, Medline, PubMed Central, and PsycINFO of double-blind, placebo-controlled RCTs. Screening, inclusion, extraction, and risk of bias assessment were conducted independently by two reviewers. We calculated summary standardized mean differences (SMD) with 95%-CIs. We followed Cochrane Collaboration's Handbook of Systematic Reviews and Meta-Analyses and PRISMA guidelines (protocol registration at OSF). We selected 46 RCTs out of 1807 titles and abstracts screened, including 16.171 patients, 9131 on antidepressants and 7040 on placebo, a mean age of 50.9 years, with 64.8% women. Antidepressant drug treatment resulted in a SMD in QoL of 0.22 ([95%-CI: 0.18; 0.26] I2 39%) vs. placebo. SMDs differed by indication: 0.38 ([0.29; 0.46] I2 0%) in maintenance studies, 0.21 ([0.17; 0.25] I2 11%) in acute treatment studies, and 0.11 ([-0.05; 0.26], I2 51%) in studies focussing on patients with a physical condition and major depression. There was no indication of subtstantial small study effects, but 36 RCTs had a high or uncertain risk of bias, particularly maintenance trials. QoL and antidepressive effect sizes were associated (Spearman's rho 0.73, p< 0.001). Antidepressants' effects on QoL are small in primary MDD, and doubtful in secondary major depression and maintenance trials. The strong correlation of QoL and antidepressive effects indicates that the current practice of measuring QoL may not provide sufficient additional insights into the well-being of patients.

Predictive capabilities of the Cloninger Temperament and Character Inventory (TCI) in evaluating the effectiveness of antidepressant pharmacotherapy. Systematic review and meta-analysis

In the pharmacotherapy of depressive disorders, the problem of the predictors of a therapeutic response remains relevant, they may be important in determining treatment tactics. Objective : to determine the predictive power of the Cloninger Temperament and Character Inventory (TCI) in evaluating the results of antidepressant pharmacotherapy in patients with depression (major depressive disorder). Material and methods . PubMed and Google Scholar were searched for articles published between 1990 and November 2021. Only English-language prospective studies, that examined the relationship between pre-treatment TCI personality scores and antidepressant pharmacotherapy efficacy were selected. Results . A total of 18 studies were found (N tot =3122). The most commonly cited statistically significant predictors of therapy effectiveness were: harm avoidance (HA) in 11 studies (N tot =2413), reward dependence in 6 (N tot =1941), cooperativeness (CO) in 6 (N tot =1259). In only two studies (N tot =234), personality parameters were not associated with treatment efficacy. In 10 studies (N tot =1065) baseline values of personality characteristics were indicated, which made it possible to include them in the meta-analysis. HA (z=4.06; p&lt;0.0001; I 2 =49%) and CO (z=2.71; p=0.007; I 2 =66%) were associated – in a statistically significant way – with the likelihood of achieving a response to antidepressant pharmacotherapy. Conclusion . Personality dimensions from the TCI questionnaire are predictors of the effectiveness of antidepressant pharmacotherapy

CPViz: Visualizing clinical pathways represented in higher-order networks

To improve clinical care practice, it is important to understand the variability of clinical pathways executed in different contexts (e.g., pathways in different geographical locations, demographics, and phenotypic groups). A common way of representing clinical pathways is through network-based representations that capture trajectories of treatment steps. However, first-order networks, which are based on the Markovian property and the de facto standard model to represent transitions between steps, often fail to capture real trajectories. This paper introduces a visual analytic tool to explore and compare pathways represented in higher-order networks. Because each higher node in the network is a subtrajectory (i.e., partial or full history of treatment steps), the tool can display true sequences of treatment steps and compute the similarity of the two networks in a space of higher-order nodes. The tool also highlights areas in which the two networks are similar and dissimilar and how a certain subtrajectory is realized differently in different pathways. The paper demonstrates the tool's usefulness by applying it to multiple antidepressant pharmacotherapy pathways for veterans diagnosed with major depressive disorder and by illustrating heterogeneity in prescription patterns across pathways.

Psychosocial interventions to improve adherence in depressed and anxious older adults prescribed antidepressant pharmacotherapy: a scoping review.

Medication nonadherence in depressed and anxious older adults is prevalent and associated with non-response to antidepressant pharmacotherapy. Evidence-based options to improve medication adherence are limited in this population. To review the state of the literature on the types and efficacy of psychosocial interventions for improving antidepressant pharmacotherapy adherence in depressed and anxious older adults. We conducted a scoping review according to PRISMA-ScR guidelines. PubMed/Medline and article references starting in 1980 up to 28 February 2023 were reviewed. Of the 710 records screened, 4 psychosocial interventions were included in the review. All studies included depressed older adults, and none included anxious older adults. Samples included racial and ethnic minorities and were primarily women. The psychosocial interventions consisted mainly of psychoeducation with usual care as the control comparison. Measures of antidepressant adherence included self-reported adherence or pill counting. Three of the four randomized controlled trials improved medication adherence rates and reduced depression symptom burden. Effective interventions exist for improving antidepressant medication adherence in depressed older adults. Improved adherence can reduce depression symptom burden. The lack of interventions for anxious older adults highlights the need to develop and deliver interventions for anxious older adults prescribed antidepressant pharmacotherapy.

Economic burden and antidepressant treatment patterns among patients with major depressive disorder in the United States.

BACKGROUND: The prevalence of major depressive disorder (MDD) continues to rise year over year, resulting in significant economic implications. However, when patients are treated with contemporary standard-of-care antidepressant pharmacotherapies, a suboptimal response is often attained, resulting in frequent treatment changes. OBJECTIVE: To compare health care resource utilization (HCRU) and all-cause medical and pharmacy costs between commercially insured patients with an MDD diagnosis and matched non-MDD patients and explore treatment patterns among patients with MDD initiating antidepressant pharmacotherapy. METHODS: This was a retrospective, observational analysis of IBM MarketScan US commercial claims data. Adults aged 18 years and older with continuous enrollment 12 or more months before and after the patient's first MDD diagnosis from 2017 to 2018 were included in the analysis. HCRU and all-cause medical and pharmacy costs were compared among patients with MDD and a 1:1 exact-matched cohort of non-MDD patients during the same period (Objective 1). Treatment patterns (persistence, discontinuation, switch, combination, and augmentation) were analyzed for patients with MDD starting first-line antidepressant monotherapy for up to 12 months following their antidepressant initiation index date (Objective 2). Time to first treatment change or discontinuation was calculated and treatment patterns were graphically displayed in Sankey diagrams. RESULTS: 625,272 patients with MDD were matched 1:1 to a cohort of non-MDD patients in Objective 1. Patients with MDD had statistically significantly greater all-cause medical (20.4 vs 9.4; P < 0.0001), outpatient (19.5 vs 9.0; P < 0.0001), emergency department (0.51 vs 0.23; P < 0.0001), inpatient (0.35 vs 0.11; P < 0.0001), and any mental health-related (7.7 vs 0.58; P < 0.0001) visits compared with non-MDD patients. Mean all-cause medical costs were $6,809 (P < 0.0001) higher among patients with MDD than among patients without MDD ($13,183 vs $6,374, respectively). In Objective 2, 44,485 patients with MDD who received antidepressant monotherapy as their first-line MDD treatment were examined. Among the first treatment patterns observed following initiation, 19.3% of patients persisted with their first-line therapy, 56.2% discontinued antidepressant therapy, 24.5% experienced a treatment change (switching, adding a second antidepressant, or augmenting their existing therapy). The median days until first treatment change were 65 days for those discontinuing and 47 days for those switching antidepressants. Among the 24.5% of patients with a treatment change, 50.0% experienced another change in therapy within 30 days. CONCLUSIONS: The HCRU and costs accrued for patients with MDD is significantly greater than those for non-MDD patients. A large proportion of patients with MDD experienced treatment changes shortly after initiating their first-line antidepressant therapy. The results of this study highlight the need for reevaluation of the current MDD treatment paradigm. DISCLOSURES: Drs Zhu and Namjoshi are employees of Biogen Inc. and may hold stock. Dr Ferries and Ms Suthoff are employees of Sage Therapeutics, Inc., and may hold stock and/or stock options. Dr Bera has no potential conflicts of interest to disclose. This research was funded by Sage Therapeutics and Biogen. Manuscript editorial services were provided by Boston Strategic Partners, Inc., funded by Sage Therapeutics and Biogen. This work was supported by Sage Therapeutics, Inc., and Biogen. The authors had full editorial control of the manuscript and provided final approval on all content.

Perspectives on the success rate of current antidepressant pharmacotherapy

ABSTRACT Introduction There has been growing debate about the effectiveness of traditional antidepressants for the treatment of depression, and whether the clinical trials literature overstates the value of existing agents. Antidepressant efficacy is limited by suboptimal remission rates, lack of robust efficacy across diverse depressed subgroups, slow onset, and challenges managing tolerability. Clinicians can better navigate uncertainties in this area by recognizing patient-specific clinical and prognostic factors that influence the likelihood of antidepressant drug response. Areas covered The author summarizes pertinent literature regarding drug-placebo differences in antidepressant outcome as well as patient-specific factors that influence antidepressant drug responsivity across subtypes of depressive disorders. Expert opinion Standardized effect sizes for most monoaminergic antidepressants are relatively modest. At least one-third of treatment response derives from nonspecific (yet substantial) placebo effects, limiting the ability to compare antidepressant medication effects to that of ‘no treatment.’ Patients with high baseline depressive symptom severity are less likely to respond to placebo but may be more responsive to antidepressant pharmacotherapy than is the case in mild forms of depression. Patient satisfaction with antidepressant response must take into consideration not only efficacy for reducing symptoms but also drug tolerability/acceptability and tangible improvement in functional outcome and quality of life.

Network science approach elucidates integrative genomic-metabolomic signature of antidepressant response and lifetime history of attempted suicide in adults with major depressive disorder.

Background: Individuals with major depressive disorder (MDD) and a lifetime history of attempted suicide demonstrate lower antidepressant response rates than those without a prior suicide attempt. Identifying biomarkers of antidepressant response and lifetime history of attempted suicide may help augment pharmacotherapy selection and improve the objectivity of suicide risk assessments. Towards this goal, this study sought to use network science approaches to establish a multi-omics (genomic and metabolomic) signature of antidepressant response and lifetime history of attempted suicide in adults with MDD. Methods: Single nucleotide variants (SNVs) which associated with suicide attempt(s) in the literature were identified and then integrated with a) p180-assayed metabolites collected prior to antidepressant pharmacotherapy and b) a binary measure of antidepressant response at 8 weeks of treatment using penalized regression-based networks in 245 ‘Pharmacogenomics Research Network Antidepressant Medication Study (PGRN-AMPS)’ and 103 ‘Combining Medications to Enhance Depression Outcomes (CO-MED)’ patients with major depressive disorder. This approach enabled characterization and comparison of biological profiles and associated antidepressant treatment outcomes of those with (N = 46) and without (N = 302) a self-reported lifetime history of suicide attempt. Results: 351 SNVs were associated with suicide attempt(s) in the literature. Intronic SNVs in the circadian genes CLOCK and ARNTL (encoding the CLOCK:BMAL1 heterodimer) were amongst the top network analysis features to differentiate patients with and without a prior suicide attempt. CLOCK and ARNTL differed in their correlations with plasma phosphatidylcholines, kynurenine, amino acids, and carnitines between groups. CLOCK and ARNTL-associated phosphatidylcholines showed a positive correlation with antidepressant response in individuals without a prior suicide attempt which was not observed in the group with a prior suicide attempt. Conclusion: Results provide evidence for a disturbance between CLOCK:BMAL1 circadian processes and circulating phosphatidylcholines, kynurenine, amino acids, and carnitines in individuals with MDD who have attempted suicide. This disturbance may provide mechanistic insights for differential antidepressant pharmacotherapy outcomes between patients with MDD with versus without a lifetime history of attempted suicide. Future investigations of CLOCK:BMAL1 metabolic regulation in the context of suicide attempts may help move towards biologically-augmented pharmacotherapy selection and stratification of suicide risk for subgroups of patients with MDD and a lifetime history of attempted suicide.

Telomerase enzyme activity in patients with major depressive disorder: A pre and post-treatment study

BackgroundTelomerase is a cellular enzyme that prevents telomere shortening and promoting viability. The literature has reported shortened telomere length in patients with major depressive disorder (MDD). Methods35 patients with diagnosis of major depressive disorder (MDD) fulfilling DMS-5 criteria in the age range of 18–60 years, treatment-naïve after assessing the severity on HAM-D and HAM-A and 35 age and sex matched healthy controls were included in the study. Baseline peripheral blood monocytes (PBMC) telomerase enzyme was assessed in cases and controls and repeated in cases of MDD at 8th week after intervention with escitalopram for 8 weeks. ResultsPretreatment telomerase activity (TA) was elevated in cases as compared to controls and it was also significantly correlated to the severity of depression (p = 0.00). There was a significant positive difference in telomerase activity between non-responders (higher TA) and responders at baseline (p = 0.001) and 8th week (p = 0.012). The TA did not vary significantly amidst pretreatment and post-treatment, although it was slightly lower in the post-treatment group. LimitationsThe study has few limitations in the form of small sample size, shorter duration of follow-up, and leucocyte telomeres length (LTL) was not assessed. ConclusionThe index study concludes that TA is higher in drug naïve patients with MDD than age and sex matched healthy control. The non-responders had significantly higher TA as compared to responders at baseline and post-treatment which indicates TA as a potential biomarker in the underlying biological mechanism of MDD and in response to antidepressant pharmacotherapy.

Lateralized subgenual ACC metabolic connectivity patterns in refractory melancholic depression: does it matter?

Although treatment resistance to antidepressant pharmacotherapy is quite common, the phenomenon of refractory major depressive disorder (rMDD) is not well understood. Nevertheless, the metabolic activity of the subgenual anterior cingulate cortex (sgACC) has been put forward as a possible metabolic biomarker of clinical prediction and response, albeit sgACC lateralization differences in functional connectivity have not yet been extensively examined. Also not in the refractory depressed state. To examine sgACC lateralization differences in metabolic connectivity, we recruited 43 right-handed antidepressant-free unipolar melancholic rMDD patients and 32 right-handed healthy controls to participate in this 18FDG PET study and developed a searchlight-based interregional covariance connectivity approach. Compared to non-depressed individuals, sgACC covariance analysis showed stronger metabolic connections with frontolimbic brain regions known to be affected in the depressed state. Furthermore, whereas the left sgACC showed stronger metabolic connections with ventromedial prefrontal cortical regions, implicated in anhedonia, suicidal ideation, and self-referential processes, the right sgACC showed significantly stronger metabolic connections with posterior hippocampal and cerebellar regions, respectively specialized in memory and social processing. Overall, our results substantiate earlier research that the sgACC is a metabolic key player when clinically depressed and that distinct lateralized sgACC metabolic connectivity patterns are present.