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Anhedonia, a complex symptom rooted in deficits across reward processes, is primarily linked to depression and schizophrenia but transcends diagnostic boundaries across various mental disorders. Its presence correlates with poorer clinical outcomes, including an increased risk of suicide and diminished response to treatment. The neurobiological underpinnings of anhedonia remain incompletely understood despite advancements in biomarkers and imaging that contribute to deeper insights. Ketamine, known for its rapid-acting antidepressant properties, appears to possess antianhedonic effects through a mechanism of action not fully elucidated. This effect appears to be independent of its antidepressant properties. Explorations into alternative antianhedonic treatments have been underway, yet lingering questions persist, underscoring the imperative need for ongoing research to advance the field. [ABSTRACT FROM AUTHOR]

There is an urgent need to identify interventions to reduce suicidality. We investigated the antisuicidal effects of intravenous (IV) ketamine and intranasal (IN) esketamine among patients with treatment-resistant depression (TRD) in a historical cohort study. The Quick Inventory of Depressive Symptomatology self-report (QIDS-SR) question 12 was used to measure suicidal ideation (SI). Cox proportional hazards models were used to evaluate associations between the number of treatments to response and baseline SI (yes, Q12 > 0 versus no, Q12 = 0), adjusting for covariates and modified baseline QIDS-SR score. We evaluated associations between the number of treatments to a 50 % reduction in SI score between IV and IN treatment. Fifty-two adults (62.5 % female, median age 49.1 years) received IV ketamine (71 %, n = 37) or IN esketamine (29 %, n = 15). Eighty-one percent of patients reported SI at baseline. Among those with baseline SI, 60 % had improved SI scores while 38 % did not change, and among those with no SI, 80 % did not change. After adjusting for covariates, the hazard ratios (HR) of response were significantly lower among those with baseline SI (HR = 0.36, 95 % CI, 0.14–0.92, p = 0.03). The number of treatments to achieve a 50 % reduction in SI score did not depend on group (IN esketamine vs. IV ketamine HR = 0.74 [95 % CI, 0.27–2.05]; p = 0.57). Small sample size and lack of a placebo group. This study suggests that patients with baseline suicidal ideation require more treatments to achieve a response with ketamine or esketamine. The antisuicidal response seemed similar between IV ketamine and IN esketamine. • Rising suicide rates and depression highlight need for urgent interventions to reduce suicidality. • We investigate the antisuicidal properties of ketamine and esketamine among patients with treatment-resistant depression. • The patients with baseline suicidal ideation required more treatments to achieve a response with ketamine/esketamine. • The anti-suicidal response seemed similar between IV ketamine and IN esketamine. [ABSTRACT FROM AUTHOR]

We conducted an open-label clinical trial ("Bio-K") using IV ketamine for treatment-resistant depression to identify biomarkers linked to remission. Here, we report the clinical efficacy and side effect outcomes of Bio-K. Across 4 US sites, 75 patients ages 18–65 with treatment-refractory unipolar or bipolar depression received 3 IV ketamine infusions over an 11-day period. Key exclusion criteria were psychotic symptoms, significant substance abuse, unstable medical conditions, and any use of cannabis. Pre-existing antidepressant medication was maintained. Primary outcome was remission as measured by Montgomery-Asberg Depression Rating Scale (MADRS), with secondary outcome of 50 % reduction in Beck Suicide Scale score. Safety monitoring and varying durations of infusions were also key parameters. Using remission as MADRS score <10, after 3 infusions 52 % achieved remission, with 67 % achieving response. Of those achieving response after a single infusion, 66 % (22 of 33) reached remission after 3 infusions, while 40 % (16 of 40) non-responders after the first infusion went on to achieve remission after 3 infusions. Only 20 % of non-responders after 2 infusions achieved remission. Most (81 %) participants had significant suicidal ideation at baseline; of these, two-thirds (67 %) experienced at least a 50 % reduction in suicidality. Side effects were minimal. Uniquely, we had three different types of infusion categories, with individuals receiving: (1) slow (100-min) infusions only or (2) regular (40-min) infusions only or (3) a mix of infusion durations. These three infusion groups showed comparable safety and efficacy. Exploration of clinical factors revealed no link between BMI, age, or gender to remission. The consistency of outcomes across 4 clinical sites and across multiple instruments, suggests high acute efficacy and safety of IV ketamine for serious depressive episodes. Duration of infusion did not alter outcomes. Meaningfully, 40 % of non-responders after a single infusion did reach remission subsequently, while only 20 % of non-responders after 2 infusions achieved remission, suggesting early response is suggestive for eventual remission. Our data on varying ketamine infusion duration adds novel insights into the clinical administration of this new treatment for refractory and severe patients. Our limitations included a lack of a control group, necessitating caution about conclusions of efficacy, balanced by the utility of reporting "real-world" outcomes across multiple clinical sites. We could also not separately analyze results for bipolar disorder due to small numbers. Together, the Bio-K clinical results are promising and provide significant sample sizes for forthcoming biological markers analyses. • People from 4 sites received standard IV ketamine dosing for TRD in addition to pre-existing medications. • Over half remitted after 3 infusions, with initial response predicting remission;non-response after 2 infusions predicted non-remission. • Both 100-min and 40-min infusions were administered, with similar efficacy and safety outcomes. • Using remission and non-remission categories helps identify clinical and blood biomarker predictors of remission. [ABSTRACT FROM AUTHOR]

Intravenous (IV) ketamine and FDA-approved intranasal (IN) esketamine are increasingly used for treatment-resistant depression (TRD). Preliminary studies have suggested a synergistic effect of ketamine and lamotrigine, although the data are inconclusive. Herein, we report the response to serial ketamine/esketamine treatment among patients with TRD with or without lamotrigine therapy. In this historical cohort study, we included adult patients with TRD who received serial IV racemic ketamine (0.5 mg/kg over 40−100 min) or IN esketamine (56/84 mg) treatments. A change in depressive symptoms was assessed using the 16-item Quick Inventory of Depressive Symptomatology self-report (QIDS-SR) scale. There were no significant differences in response or remission rates among the patients on or not on lamotrigine during the ketamine/esketamine treatments. For a percent change in the QIDS-SR from baseline, no interaction was found between the lamotrigine groups and treatment number (p = 0.70), nor the overall effect of the group (p = 0.38). There was a trend towards lower dissociation (based on the CADSS score) among current lamotrigine users, especially in patients who received IV ketamine. A major limitation is the limited number of patients taking lamotrigine (n = 13). This preliminary study provides insufficient evidence that continuing lamotrigine therapy attenuates the antidepressant effect of repeated ketamine/esketamine; however, there seems to be a signal toward attenuating dissociation with lamotrigine in patients receiving serial ketamine treatments. Further observational studies or randomized controlled trials are needed to replicate these findings. [ABSTRACT FROM AUTHOR]

Background: Suicide is a leading cause of death in adolescents worldwide. Previous research findings suggest that suicidal adolescents with depression have pathophysiological dorsolateral prefrontal cortex (DLPFC) deficits in γ-aminobutyric acid neurotransmission. Interventions with transcranial magnetic stimulation (TMS) directly address these underlying pathophysiological deficits in the prefrontal cortex. Theta burst stimulation (TBS) is newer dosing approach for TMS. Accelerated TBS (aTBS) involves administering multiple sessions of TMS daily as this dosing may be more efficient, tolerable, and rapid acting than standard TMS. Materials and methods: This is a randomized, double-blind, sham-controlled trial of sequential bilateral aTBS in adolescents with major depressive disorder (MDD) and suicidal ideation. Three sessions are administered daily for 10 days. During each session, continuous TBS is administered first to the right DPFC, in which 1,800 pulses are delivered continuously over 120 seconds. Then intermittent TBS is applied to the left DPFC, in which 1,800 pulses are delivered in 2-second bursts and repeated every 10 seconds for 570 seconds. The TBS parameters were adopted from prior research, with 3-pulse, 50-Hz bursts given every 200 ms (at 5 Hz) with an intensity of 80% active motor threshold. The comparison group will receive 3 daily sessions of bilateral sham TBS treatment for 10 days. All participants will receive the standard of care for patients with depression and suicidal ideation including daily psychotherapeutic skill sessions. Long-interval intracortical inhibition (LICI) biomarkers will be measured before and after treatment. Exploratory measures will be collected with TMS and electroencephalography for biomarker development. Discussion: This is the first known randomized controlled trial to examine the efficacy of sequential bilateral aTBS for treating suicidal ideation in adolescents with MDD. Results from this study will also provide opportunities to further understand the neurophysiological and molecular mechanisms of suicidal ideation in adolescents. Trial registration: Investigational device exemption (IDE) Number: G200220, ClinicalTrials.gov (ID: NCT04701840). Registered August 6, 2020. https://clinicaltrials.gov/ct2/show/NCT04502758?term=NCT04701840&draw=2&rank=1. [ABSTRACT FROM AUTHOR]

Aim: To appraise the current evidence on the efficacy and safety of lamotrigine (LAM) in the treatment of pediatric mood disorders (PMD) (i.e., Major Depressive disorder [MDD], bipolar disorder [BD]). Methods: Major databases were searched for randomized controlled trials (RCTs), open‐label trials, and observational studies reporting on pediatric (age < 18 years) patients treated with LAM for mood disorders. Results: A total of 3061 abstracts were screened and seven articles were selected for inclusion. Seven studies (319 BD and 43 MDD patients), including one RCT (n = 173), three prospective (n = 105), and three retrospective (n = 84) studies, met the study criteria with a study duration range from 8 to 60.9 weeks. The mean age of this pooled data is 14.6 ± 2.0 years. LAM daily dosage varied from 12.5 to 391.3 mg/day among the studies. In an important finding, the RCT reported favorable outcomes with LAM (HR = 0.46; p = 0.02) in 13‐ to 17‐year‐old age group as compared with 10‐ to 12‐year‐old age group (HR = 0.93; p = 0.88). In addition, time to occurrence of a bipolar event trended toward favoring LAM over placebo. All the studies identified LAM as an effective and safe drug in PMDs especially, BDs. Overall, LAM was well tolerated with no major significant side effects and no cases of Stevens–Johnson syndrome. Conclusions: Most studies suggested that LAM was safe and effective in pediatric patients with mood disorders. However, the data regarding the therapeutic range for LAM are lacking. Based on the data, there is inconsistent evidence to make conclusive recommendations on therapeutic LAM dosage for mood improvement in the pediatric population. Further studies including larger sample sizes are required to address this relevant clinical question. [ABSTRACT FROM AUTHOR]

Background: The treatment of depression in children and adolescents is a substantial public health challenge. This study examined artificial intelligence tools for the prediction of early outcomes in depressed children and adolescents treated with fluoxetine, duloxetine, or placebo. Methods: The study samples included training datasets (N = 271) from patients with major depressive disorder (MDD) treated with fluoxetine and testing datasets from patients with MDD treated with duloxetine (N = 255) or placebo (N = 265). Treatment trajectories were generated using probabilistic graphical models (PGMs). Unsupervised machine learning identified specific depressive symptom profiles and related thresholds of improvement during acute treatment. Results: Variation in six depressive symptoms (difficulty having fun, social withdrawal, excessive fatigue, irritability, low self‐esteem, and depressed feelings) assessed with the Children's Depression Rating Scale‐Revised at 4–6 weeks predicted treatment outcomes with fluoxetine at 10–12 weeks with an average accuracy of 73% in the training dataset. The same six symptoms predicted 10–12 week outcomes at 4–6 weeks in (a) duloxetine testing datasets with an average accuracy of 76% and (b) placebo‐treated patients with accuracies of 67%. In placebo‐treated patients, the accuracies of predicting response and remission were similar to antidepressants. Accuracies for predicting nonresponse to placebo treatment were significantly lower than antidepressants. Conclusions: PGMs provided clinically meaningful predictions in samples of depressed children and adolescents treated with fluoxetine or duloxetine. Future work should augment PGMs with biological data for refined predictions to guide the selection of pharmacological and psychotherapeutic treatment in children and adolescents with depression. [ABSTRACT FROM AUTHOR]

Objective: Numerous commercial pharmacogenetics panels are now widely available for clinical use in psychiatric practice. However, there is a paucity of literature evaluating the use of combinatorial pharmacogenetics panels to enhance outcomes in the treatment of adolescents with depression. This study sought to prospectively evaluate the clinical impact of combinatorial pharmacogenetics testing in a double-blind, randomized, controlled effectiveness study for the pharmacologic treatment of adolescents with depression.Method: Adolescents aged 13 to 18 years (N = 176) with moderate to severe major depressive disorder (MDD) were randomized to treatment arm guided by testing in which pharmacogenetic testing results were available at the baseline visit (GENE arm, n = 84) or a treatment-as-usual arm (TAU arm, n = 92) in which testing results were not available until an 8-week visit. Raters, participants, and families were blinded to group allocation. Symptom improvement, side effects, and satisfaction were assessed throughout the study at 4 weeks, 8 weeks, and 6 months.Results: There were no differences between the GENE and TAU arms at 8 weeks or 6 months for symptom improvement, side effect burden, or satisfaction. Selective serotonin reuptake inhibitors were prescribed at higher rates in the TAU arm compared to the GENE arm (p = .024).Conclusion: Combinatorial pharmacogenetics-guided treatment did not demonstrate improved outcomes compared to TAU in adolescents with MDD. Future research should examine how specific medication-gene pairs may affect clinical outcomes in the treatment of adolescents with depression and how best to integrate pharmacogenetics into clinical practice.Clinical Trial Registration Information: A PK/PD Genetic Variation Treatment Algorithm Versus Treatment As Usual for Adolescent Management Of Depression; https://www.clinicaltrials.gov; NCT02286440. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Efficacy of Ketamine with and without Lamotrigine in Treatment-Resistant Depression: A Preliminary Report." The correction states that there were errors in Figure 2B of the original publication, but the scientific conclusions remain unaffected. The correct figure has been provided in the correction notice. The article was authored by Boney Joseph, Nicolas A. Nunez, Simon Kung, Jennifer L. Vande Voort, Vanessa K. Pazdernik, Kathryn M. Schak, Stacey M. Boehm, Brooke Carpenter, Emily K. Johnson, Grigoriy Malyshev, Nathan Smits, Daniel O. Adewunmi, Sarah K. Brown, and Balwinder Singh. [Extracted from the article]

Background: Pharmacogenomic testing, specifically for pharmacokinetic (PK) and pharmacodynamic (PD) genetic variation, may contribute to a better understanding of baseline genetic differences in patients seeking treatment for depression, which may further impact clinical antidepressant treatment recommendations. This study evaluated PK and PD genetic variation and the clinical use of such testing in treatment seeking patients with bipolar disorder (BP) and major depressive disorder (MDD) and history of multiple drug failures/treatment resistance. Methods: Consecutive depressed patients evaluated at the Mayo Clinic Depression Center over a 10-year study time frame (2003–2013) were included in this retrospective analysis. Diagnoses of BP or MDD were confirmed using a semi-structured diagnostic interview. Clinical rating scales included the Hamilton Rating Scale for Depression (HRSD24), Generalized Anxiety Disorder 7-item scale (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and Adverse Childhood Experiences (ACE) Questionnaire. Clinically selected patients underwent genotyping of cytochrome P450 CYP2D6 / CYP2C19 and the serotonin transporter SLC6A4. PK and PD differences and whether clinicians incorporated test results in providing recommendations were compared between the two patient groups. Results: Of the 1795 patients, 167/523 (31.9%) with BP and 446/1272 (35.1%) with MDD were genotyped. Genotyped patients had significantly higher self-report measures of depression and anxiety compared to non-genotyped patients. There were significantly more CYP2C19 poor metabolizer (PM) phenotypes in BP (9.3%) vs. MDD patients (1.7%, p = 0.003); among participants with an S-allele, the rate of CYP2C19 PM phenotype was even higher in the BP (9.8%) vs. MDD (0.6%, p = 0.003). There was a significant difference in the distribution of SLC6A4 genotypes between BP (l/l = 28.1%, s/l = 59.3%, s/s = 12.6%) and MDD (l/l = 31.4%, s/l = 46.1%, s/s = 22.7%) patients (p < 0.01). Conclusion: There may be underlying pharmacogenomic differences in treatment seeking depressed patients that potentially have impact on serum levels of CYP2C19 metabolized antidepressants (i.e., citalopram / escitalopram) contributing to rates of efficacy vs. side effect burden with additional potential risk of antidepressant response vs. induced mania. The evidence for utilizing pharmacogenomics-guided therapy in MDD and BP is still developing with a much needed focus on drug safety, side effect burden, and treatment adherence. [ABSTRACT FROM AUTHOR]

Background: Little is known about the antidepressive effects of repeated intravenous ketamine infusions beyond the acute phase of treatment in patients with refractory depression.Methods: Twelve subjects with treatment-resistant non-psychotic unipolar or bipolar major depression and suicidal ideation were given repeated (up to 6) thrice-weekly acute-phase intravenous infusions of ketamine (0.5mg/kg, administered over 100min). Those who remitted during acute-phase treatment received continuation-phase treatment that consisted of 4 weekly ketamine infusions, followed by 4 weeks of post-continuation phase follow-up (during which no further ketamine infusions were administered). Clinical measures were assessed at baseline, at 24h following each infusion, at the last acute-phase observation, and during continuation and post-continuation follow-up (acute phase remitters only).Results: Of the 12 enrollees, 5 (41.7%) remitted and 7 (58.3%) responded to ketamine treatment during the acute-phase. All five subjects who remitted during the acute-phase experienced further depressive symptom improvement during continuation-phase treatment. Four subjects lost remission status during the post-continuation phase, but all were still classified as positive treatment responders at the end of the post-continuation phase. Adverse effects were generally mild and transient during acute- and continuation-phase treatment; however, one subject developed behavioral outbursts and suicide threats during follow-up while hospitalized, and one subject died by suicide several weeks after the end of follow-up.Limitations: This was an uncontrolled feasibility study with a small sample size.Conclusions: The continuation-phase administration of ketamine at weekly intervals to patients with treatment-resistant depression who remitted during acute-phase ketamine treatment can extend the duration of depressive symptom remission. The antidepressive effect of ketamine persisted for several weeks after the end of continuation-phase treatment. Our results highlight the need for close monitoring of subjects who are at high baseline risk for suicide but do not respond clinically to ketamine. CLINICALTRIALS.Gov Identifier: NCT02094898. [ABSTRACT FROM AUTHOR]

Introduction: Transcranial magnetic stimulation (TMS) research has suggested dysfunction in cortical glutamatergic systems in adolescent depression, while proton magnetic resonance spectroscopy (¹H-MRS) studies have demonstrated deficits in concentrations of glutamatergic metabolites in depressed individuals in several cortical regions, including the anterior cingulate cortex (ACC). However, few studies have combined TMS and MRS methods to examine relationships between glutamatergic neurochemistry and excitatory and inhibitory neural functions, and none have utilized TMS-MRS methodology in clinical populations or in youth. This exploratory study aimed to examine relationships between TMS measures of cortical excitability and inhibition and concentrations of glutamatergic metabolites as measured by ¹H-MRS in depressed adolescents. Methods: Twenty-four adolescents (aged 11-18 years) with depressive symptoms underwent TMS testing, which included measures of the resting motor threshold (RMT), cortical silent period (CSP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). Fourteen participants from the same sample also completed ¹H-MRS in a 3 T MRI scanner after TMS testing. Glutamate + glutamine (Glx) concentrations were measured in medial ACC and left primary motor cortex voxels with a TE-optimized PRESS sequence. Metabolite concentrations were corrected for cerebrospinal fluid (CSF) after tissue segmentation. Pearson product-moment and Spearman rank-order correlations were calculated to assess relationships between TMS measures and [Glx]. Results: In the left primary motor cortex voxel, [Glx] had a significant positive correlation with the RMT. In the medial ACC voxel, [Glx] had significant positive correlations with ICF at the 10-ms and 20-ms interstimulus intervals (ISIs). Conclusion: These preliminary data implicate glutamate in cortical excitatory processes measured by TMS. Limitations included small sample size, lack of healthy control comparators, possible age- and sex-related effects, and observational nature of the study. Further research aimed at examining the relationship between glutamatergic metabolite concentrations measured through MRS and the excitatory and inhibitory physiology measured through TMS is warranted. Combined TMS-MRS methods show promise for future investigations of the pathophysiology of depression in adults as well as in children and adolescents. [ABSTRACT FROM AUTHOR]

There is an urgent need for more rapidly effective pharmacotherapies for major depressive disorder and bipolar disorder (BP) that are efficacious and tolerable for depressed patients who respond poorly to conventional treatments. Multiple controlled trials have now demonstrated a rapid, nonsustained antidepressive response to a single intravenous infusion of ketamine. Early controlled studies of intranasal or serial infusion therapy appear promising. The effective dose for depression is lower than the typical anesthetic doses, and side-effects are generally mild and transient. The data investigating the adjunctive use of concurrent ketamine in the course of electroconvulsive therapy (ECT) for depression do not suggest efficacy or tolerability. The therapeutic potential of ketamine has stimulated considerable excitement among clinicians, patients, and industry, and has led to the increasing use of ketamine as an off-label substitute for ECT and other antidepressive treatments. This clinical review of ketamine will assess the evidence-based use of ketamine and initial clinical implications of further development of a potentially novel treatment for rapid reduction of symptoms in depressed patients. [ABSTRACT FROM AUTHOR]

Ketamine and lithium both inhibit glycogen synthase kinase 3. In addition, lithium and ketamine have synergistic antidepressant-like effects at individually subeffective doses in rodents. We hypothesized that ketamine’s antidepressant effects would be improved by therapeutic doses of lithium versus valproate and that serum lithium levels would positively correlate with ketamine’s antidepressant efficacy. Thirty-six patients with treatment-resistant bipolar depression maintained on therapeutic-dose lithium (n=23, 0.79 ± 0.15 mEq/L) or valproate (n=13, 79.6 ± 12.4 mg/mL) received 0.5 mg/kg ketamine infusion in a randomized, double-blind, placebo-controlled, crossover trial. The primary depression outcome measure—the Montgomery-Åsberg Depression Rating Scale (MADRS)—was assessed before infusion and at numerous postinfusion time points. Both lithium (F1,118 = 152.08, p<0.001, and d=2.27) and valproate (F1,128 = 20.12, p<0.001, and d=0.79) significantly improved depressive symptoms, but no statistically significant difference was observed between mood stabilizer groups (F1,28 = 2.51, p=0.12, and d=0.60). Serum lithium and valproate levels did not correlate with ketamine’s antidepressant efficacy. Although the study was potentially underpowered, our results suggest that lithium may not potentiate ketamine’s antidepressant efficacy in treatment-resistant bipolar depression. [ABSTRACT FROM AUTHOR]

A letter to the editor in response to the article by Olson and colleagues, published in the previous issue, regarding mental health of preadolescent transgender children who are living in with supportive families is presented.

Objective To determine the nature of family distress in families of girls with anorexia nervosa (AN), this study compared aspects of family functioning in adolescent girls with AN to girls with a chronic illness and girls without a condition. Method Participants consisted of 25 adolescent girls with a primary DSM-IV diagnosis of AN, 20 girls with an ICD-10 diagnosis of insulin dependent diabetes mellitus (IDDM), and 20 girls from the community. Mothers and daughters completed questionnaires of family functioning and psychological symptoms. Results When compared with mothers of daughters with IDDM, families of girls with AN experienced greater family conflict, reduced parental alliance, and increased feelings of depression. However, once the emotional impact of the illness on the mothers was statistically controlled, group differences were no longer significant. Discussion Family distress and dysfunction may reflect an accommodation process that occurs in families living with a child with AN. © 2009 by Wiley Periodicals, Inc. Int J Eat Disord 2009 [ABSTRACT FROM AUTHOR]

Introduction: Combinatorial pharmacogenetic testing panels are widely available in clinical practice and often separate medications into columns/bins associated with low, medium, or high probability of gene-drug interactions. The objective of the Adolescent Management of Depression (AMOD) study was to determine the clinical utility of combinatorial pharmacogenetic testing in a double-blind, randomized, controlled effectiveness study by comparing patients who had genetic testing results at time of medication initiation to those that did not have results until week 8. The objective of this post hoc analysis was to assess and report additional outcomes with respect to significant gene-drug interactions (i.e., a medication in the high probability gene-drug interaction bin as defined by a proprietary algorithm) compared with patients taking a medication with minimal to moderate gene-drug interactions (i.e., a medication from the low or medium probability gene-drug interaction bin, respectively). Methods: Adolescents 13–18 years (N = 170) with moderate to severe major depressive disorder received pharmacogenetic testing. Symptom improvement and side effects were assessed at baseline, week 4, week 8, and 6 months. Patients were grouped into three categories based on whether the medication they were prescribed was associated with low, medium, or high risk for gene-drug interactions. Patients taking a medication from the low/medium gene-drug interaction bin were compared with patients taking a medication from the high gene-drug interaction bin. Results: Patients taking a medication from the high gene-drug interaction bin were more likely to endorse side effects compared with patients taking a medication in the low/medium gene-drug interaction bin at week 8 (p = 0.001) and 6 months (p < 0.0001). Depressive symptom severity scores did not differ significantly across the medication bins. Conclusions: This study demonstrates the utility of gene-drug interaction testing to guide medication decisions to minimize side effect burden rather than solely prioritizing the search for the most efficacious medication. (Clinical Trials Registration Identifier: NCT02286440). [ABSTRACT FROM AUTHOR]

Evaluate whether early improvement in irritability predicts improvement in depression severity in a naturalistic sample of adolescents undergoing pharmacologic treatment for major depressive disorder. Adolescents (N = 161) aged 13–18 years with a moderate to severe depressive episode were enrolled. Outcome measures included the Children's Depression Rating Scale-Revised (CDRS-R), Quick Inventory of Depressive Symptomatology (QIDS - A 17), and Clinical Global Impression scale (CGI). Paired t -tests were used to estimate the change in irritability items from baseline to week-4, and Cohen's d effect sizes were computed. Separate linear regression analyses with CDRS-R, QIDS-A 17 , and CGI at week-8 as the dependent variables and baseline levels of irritability and baseline-to-week-4 changes in irritability as independent variables of interest were conducted. These analyses were repeated after controlling for overall depression severity (minus the irritability item) at baseline and baseline to week-4 change. Greater baseline to week-4 reduction in irritability was associated with lower levels of CDRS-R, QIDS-A 17 , and CGI at week-8. These findings were significant for QIDS-A 17 and CGI even after controlling for baseline-to-week-4 changes in other depressive symptoms. The single item evaluation of irritability reduced assessment reliability in the absence of validated measures of irritability. Early reduction in irritability is strongly associated with better outcomes in depressed youths, regardless of baseline depression severity. Further research is needed to quantify the burden of irritability, explore it as a tool for measurement-based care, and to develop targeted treatments for irritability. • Irritability decreases in treated youths with MDD regardless of baseline depression. • Early reduction in irritability predicted depression severity after 8 weeks. • Early reduction in irritability was a predictor of overall improvement of disease. [ABSTRACT FROM AUTHOR]

Intravenous (IV) ketamine is an effective therapy for treatment-resistant depression. A large data base is confirmatory and steadily expanding. Qualitative studies can inform best practices and suggest new research directions. As part of a clinical trial designed to identify biomarkers of ketamine response, a qualitative study was conducted to characterize experiences with: receiving infusions; recovering or not recovering from depression; and beliefs about why ketamine worked or did not work. Adults with treatment-resistant depression received three IV ketamine infusions in a two-week period and were characterized as remitters or non-remitters via symptom reduction 24 h after the third infusion. Qualitative interviews of a subset of participants were audio recorded, transcribed verbatim, and coded using deductive and inductive methods. Themes were derived and compared across a broader construct of recovery status. Of the 21 participants, nine (43 %) were characterized as having experienced remission and 12 (57 %) non-remission. Of the 12 non-remitters, five were characterized as having experienced partial recovery based on their subjective experiences, reporting substantial benefit from ketamine infusions despite non-remission status based on scale measurements. Attributions for ketamine's effects included biological and experiential mechanisms. Among non-remitters there was risk of disappointment when adding another failed treatment. A more diverse sample may have yielded different themes. Different patients had different amounts of time elapsed between ketamine infusions and qualitative interview. Qualitative methods may enhance researchers' characterization of IV ketamine's impact on treatment-resistant depression. While requiring confirmation, patients may benefit from a preparatory milieu that prepares them for multiple recovery pathways; decouples the psychedelic experience from clinical outcomes; and addresses potential risks of another failed treatment. • Intravenous ketamine is an effective therapy for treatment-resistant depression. • A qualitative study (N = 21) was conducted to characterize experiences with infusions. • 43 % were remitters and 57 % non-remitters based on scale measurements. • 42 % of non-remitters made significant recovery gains based on qualitative interview. • Among non-remitters there was risk of disappointment when adding another "failed" treatment. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Suicide is a psychiatric emergency. Currently, there are no approved pharmacologic treatments for suicidal ideation. Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that rapidly reduces suicidal ideation as well as depression and anxiety, but the dynamic between these symptoms is not known. The aim of this analysis was to evaluate whether ketamine has an impact on suicidal thoughts, independent of depressive and anxiety symptoms. METHODS: 133 patients with treatment-resistant depression (major depressive disorder or bipolar I/II disorder) received a single subanesthetic infusion of ketamine (0.5 mg/kg over 40 min). Post-hoc correlations and linear mixed models evaluated the relationship between suicidal ideation and depression and anxiety symptoms using the Hamilton Depression Rating Scale (HAMD), Scale for Suicidal Ideation (SSI), Beck Depression Inventory (BDI), and Hamilton Anxiety Rating Scale (HAMA) focusing on 230 min post-infusion. RESULTS: At 230 min post-infusion, correlations between changes in suicidal ideation and depression ranged from 0.23 to 0.44 (p < .05), accounting for up to 19% in the variance of ideation change. Correlations with anxiety ranged from 0.23 to 0.40 (p < .05), accounting for similar levels of variance. Ketamine infusion was associated with significant reductions in suicidal ideation compared to placebo, when controlling for the effects of ketamine on depression (F1,587 = 10.31, p = .001) and anxiety (F1,567 = 8.54, p = .004). CONCLUSIONS: Improvements in suicidal ideation after ketamine infusion are related to, but not completely driven by, improvements in depression and anxiety. Investigation of the specific effects of ketamine on suicidal thoughts is warranted. [ABSTRACT FROM AUTHOR]

Objectives: Neurophysiologic correlates of depression severity potentially have great utility in diagnosis and treatment planning. Transcranial magnetic stimulation (TMS) measures of cortical inhibition and excitability have shown promise as biomarkers in psychiatry, but no prior work has examined correlates of illness severity in pediatric mood disorders. This study sought to examine the relationship between depression severity and TMS measures of cortical inhibition and excitability in children and adolescents.Methods: Twenty-four depressed and 22 healthy control youth underwent TMS testing (cortical silent period [CSP], short-interval intracortical inhibition at 2-ms and 4-ms interstimulus intervals (ISIs) [SICI-2,-4], resting motor threshold [RMT] and intracortical facilitation at 10-, 15-, and 20-ms ISIs [ICF-10,-15,-20]). Symptom severity was assessed with the Quick Inventory of Depressive Symptomatology (QIDS-A17-SR) and the Children's Depression Rating Scale-Revised (CDRS-R).Results: In the overall sample, the following significant negative correlations were observed: CDRS-R and CSP (right hemisphere, ρ=-0.35, p=0.021); QIDS-A17-SR and CSP (left, ρ=-0.33, p=0.031; right, ρ=-0.42, p=0.004); and CDRS-R and SICI-4 (right, ρ=-0.30, p=0.042). Among healthy control participants, additional significant negative correlations were observed between QIDS-A17-SR and right ICF-10; QIDS-A17-SR and right ICF-15; and QIDS-A17-SR and left ICF-20. Among depressed participants, significant negative correlations were observed between QIDS-A17-SR and bilateral CSP; CDRS-R and bilateral ICF-10; CDRS-R and bilateral ICF-15; QIDS-A17-SR and left ICF-10; and QIDS-A17-SR and bilateral ICF-15.Limitations: Small sample, potential developmental/age- and sex-related effects.Conclusions: These preliminary results provide evidence for a relationship between depression severity and dysfunction in GABAergic and glutamatergic cortical processes in a pediatric population. [ABSTRACT FROM AUTHOR]

Sleep disruption is a significant symptom of major depressive disorder (MDD). To our knowledge, no prior work has examined the impact of repetitive transcranial magnetic stimulation (rTMS) on sleep disturbances in adolescents with MDD. Seventeen adolescents with treatment-resistant depression received 30 daily sessions of 10-Hz rTMS applied to the left dorsolateral prefrontal cortex (L-DLPFC). Clinical symptoms were assessed at baseline; after 10, 20, and 30 treatments; and at a 6-month follow-up visit. Insomnia was measured with a 3-item subscale of the Quick Inventory of Depressive Symptomatology – Adolescent (17 Item) – Self Report (QIDS-A 17 -SR). Hypersomnia was measured with a single QIDS-A 17 -SR item. Depression severity was rated with the Children's Depression Rating Scale, Revised (CDRS-R). The effect of rTMS on sleep was examined via linear mixed model analyses, with fixed effects of time (as a proxy of treatment), depression severity, age, and hypnotic medication use. No significant main effect of time was observed on the insomnia subscale (F 4,43.442 = 1.078, p = 0.379). However, there was a significant main effect of time on the QIDS-A 17 -SR hypersomnia score (F 4,46.124 = 2.733, p = 0.040), with significant improvement from baseline to treatment 10 (p adj = 0.019) and from baseline to 6-month follow-up (p adj = 0.044). In exploratory sensitivity analyses, response/nonresponse to rTMS for overall depressive symptoms had no significant effect on sleep outcomes. rTMS may have intrinsic effects on hypersomnia apart from its antidepressant effects in depressed adolescents. Future work should utilize sham controls and objective, quantitative measurements of sleep architecture to assess effects of rTMS in depressed adolescents. Clinicaltrials.gov identifiers are NCT00587639 , NCT01502033 , NCT01804270. • Sleep disturbance is a common symptom in adolescents with depression. This open-label study examined the impact of rTMS on insomnia and hypersomnia. • This pilot study found that rTMS resulted in an improvement in hypersomnia in a sample of adolescents with treatment-resistant depression. [ABSTRACT FROM AUTHOR]