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•Observed weight gain with cariprazine was less than 1.5 kg up to a year of follow-up.•Changes in other metabolic parameters (HbA1c, HDL, LDL) were small with cariprazine.•Most patients with high baseline cholesterol/triglycerides shifted to normal range.•Most patients with normal baseline cholesterol/triglycerides remained normal. Weight gain and associated negative cardiometabolic effects can occur as a result of mental illness or treatment with second-generation antipsychotics (SGAs), leading to increased rates of morbidity and mortality. In this analysis, we evaluated the effect of the SGA cariprazine on weight and metabolic parameters in a real-world, retrospective, observational dataset. Electronic health records from the Optum Humedica database (October 1, 2014–December 31, 2020) were analyzed during the 12-month period before starting cariprazine (baseline) and for up to 12 months following cariprazine initiation; approved and off-label indications were included. Body weight trajectories were estimated in the overall patient cohort and at 3-, 6-, and 12-month timepoints (primary objective). Changes in hemoglobin A1c (HbA1c), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides were also evaluated (secondary objectives). Percentages of patients with clinically relevant shifts in body weight, total cholesterol, and fasting triglycerides were also determined. Discontinuation rates for metabolic regulating medications were calculated. Average predicted values were estimated by linear mixed-effects regression models. A total of 2,301 patients were included; average duration of follow-up was 133.7 days. Average predicted weight change for patients during the cariprazine overall follow-up period was +2.4 kg, with predicted weight changes of +0.8 kg (n = 811), +1.1 kg (n = 350), and +1.4 kg (n = 107) at months 3, 6, and 12, respectively. Overall, the majority of patients did not experience clinically significant (≥7%) weight gain (82.8%) or loss (90.5%) after starting cariprazine. Average predicted HbA1c levels (n = 189) increased during baseline (0.15%/year) and decreased during cariprazine treatment (−0.2%/year). Average predicted triglyceride levels (n = 257) increased during baseline (15.0 mg/dL/year) and decreased during cariprazine treatment (−0.7 mg/dL/year). Predicted LDL (n = 247) and HDL (n = 255) values decreased during baseline (−7.3 and −1.1 mg/dL/year, respectively); during cariprazine treatment, LDL increased by 5.6 mg/dL/year and HDL decreased by −0.6 mg/dL/year. During follow-up, most patients did not shift from normal/borderline to high total cholesterol (<240 to ≥240 mg/dL; 522 [90.2%]) or fasting triglyceride (<200 to ≥200 mg/dL; 143 [88.8%] patients) levels; shifts from high to normal/borderline levels occurred in 44 (61.1%) patients for total cholesterol and 38 (57.6%) patients for fasting triglycerides. After starting cariprazine, the discontinuation rate per 100 patient-years was 60.4 for antihyperglycemic medication and 87.4 for hyperlipidemia medication. These real-world results support short-term clinical trial findings describing a neutral weight and metabolic profile associated with cariprazine treatment and they expand the dataset to include long-term follow-up.

Depression affects 7% of the elderly population, and it often remains misdiagnosed or untreated. Peripheral biomarkers might aid clinicians by allowing more accurate and well-timed recognition of the disease. We sought to determine if plasma protein levels predict the severity of depressive symptomatology or distinguish patients from healthy individuals. The severity of depressive symptoms and global cognitive functioning were assessed by the Geriatric Depression Scale (GDS) and Mini-Mental State Examination (MMSE) in 152 elderly subjects, 76 of which with major depressive disorder (MDD). Plasma levels of 24 proteins were measured by multiplexing and analyzed as continuous predictors or dichotomized using the median value. The association between individual plasma proteins and MDD risk or depressive symptoms severity was investigated using multiple logistic and linear regressions including relevant covariates. Sensitivity analyses were performed excluding cognitively impaired individuals or non-acute patients with MDD. After adjusting for possible confounders and false discovery rate (FDR) correction, we found lower Fetuin-A levels in MDD patients vs. controls (pFDR = 1.95 × 10–6). This result was confirmed by the sensitivity and dichotomized analyses. Lower prolactin (PRL) levels predicted more severe depressive symptoms in acute MDD patients (pFDR = 0.024). Fetuin-A is a promising biomarker of MDD in the elderly as this protein was negatively associated with the disorder in our sample, regardless of the global cognitive functioning. Lower PRL levels may be a peripheral signature of impaired neuroprotective processes and serotoninergic neurotransmission in more severely depressed patients.

Major depressive disorder (MDD) is a chronic and recurrent mental condition leading to huge impacts on direct and indirect personal and public medical costs. To overcome such a serious mental disorder, we currently have a number of different classes of antidepressants, such as selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, noradrenergic and specific serotonin receptor antagonists, dopamine and norepinephrine reuptake inhibitors, along with newly introduced antidepressants (e.g., vilazodone and agomelatine). However, a number of well-controlled clinical trials, meta-analyses and practical clinical studies have found that only a third of such MDD patients remit following adequate antidepressant treatment, while most MDD patients suffer from significant core depressive or residual symptoms during their clinical course. There have been some treatment approaches to overcome such a shortage of antidepressant efficacy, such as augmentation of psychotropics other than antidepressants, switching to a different antidepressant and combinations of different antidepressants. Among these different second treatment options, augmentation treatment has some favorable points compared with the combination and switching option (e.g., maintaining previous antidepressant partial response, synergistic effect between different pharmacological profile and no need to wash out previous antidepressants). Recently, second-generation antipsychotics (SGAs), olanzapine plus fluoxetine, quetiapine extended release and aripiprazole have clearly demonstrated efficacy in the treatment of MDD patients through a number of small-scale, open-label studies or randomized, placebo-controlled clinical trials. Eventually, in November 2007, aripiprazole was the first approved by the US FDA as an adjunctive treatment to antidepressants for treating MDD, followed by the approval of quetiapine and olanzapine plus fluoxetine at 2009. This comprehensive review provides an overview of the clinical trial data of SGAs for treating MDD and clinical issues raised in the use of SGA therapy in patients with MDD in clinical practice.

Background Genome-wide association studies (GWAS) represent the current frontier in pharmacogenomics. Thousands of subjects of Caucasian ancestry have been included in previous GWAS investigating antidepressant response. GWAS focused on this phenotype are lacking in Asian populations. Methods A sample of 109 major depressive disorder (MDD) patients of Korean origin in antidepressant treatment was collected. Phenotypes were response and remission according to the Hamilton Rating Scale for Depression (HRSD). Genome-wide genotyping was performed using the Illumina Human Omni2.5-8 platform. The same phenotypes were used in the STAR*D level 1 ( n  = 1677) for independent replication. In order to corroborate findings and increase the comparability between the two datasets, three levels of analysis (SNPs, genes and pathways) were carried out. Bonferroni correction, permutations, and replication across samples were used to reduce the risk of false positives. Results Among the genes replicated across the two samples (permutated p  < 0.05 in both of them), CTNNA3 appeared promising. The inorganic cation transmembrane transporter activity pathway (GO:0022890) was associated with antidepressant response in both samples ( p  = 2.9e-5 and p  = 0.001 in the Korean and STAR*D samples, respectively) and this pathway included CACNA1A , CACNA1C , and CACNB2 genes. Conclusions The present study supported the involvement of genes coding for subunits of L-type voltage-gated calcium channel in antidepressant efficacy across different ethnicities but replication of findings is required before any definitive statement.

Fatigue is one of the most common symptoms found in both community and medical care settings. Fatigue may imply a prodromal or residual symptom of major depressive disorder or an adverse reaction to antidepressant treatment. Fatigue may also compromise antidepressant treatment by delaying response to antidepressants. Despite the importance of fatigue as a core depressive symptom, data specific to the effects of fatigue on pharmacological treatment are still lacking. Bupropion is an atypical antidepressant, chemically unrelated to classical agents such as tricyclic antidepressants, selective serotonin reuptake inhibitors and other contemporary antidepressants. With a pharmacological profile that involves neurotransmitter reuptake inhibition, bupropion shares a broad range of biological properties with psychostimulants. The primary action mode of bupropion involves dopaminergic and noradrenergic neurotransmissions rather than serotonergic mechanisms, although its exact pharmacodynamic properties remain uncertain. Hence, it is possible that bupropion may play a role in the treatment of fatigue-related symptoms of major depressive disorder. This paper presents a brief overview of the clinical implications and neurobiology of major depressive disorder-related fatigue, as well as the pharmacological profile of bupropion and currently available clinical data related to its treatment of fatigue-related symptoms of major depressive disorder.

Improving medication adherence is critical to improving outcomes in patients with schizophrenia. A long-acting injectable (depot) antipsychotic is one of the most effective methods for improving treatment adherence and decreasing rehospitalization rates in patients with schizophrenia. Until recently, only three second-generation antipsychotics were available in a long-acting injectable formulation (risperidone, paliperidone, and olanzapine). In this respect, the emergence of long-acting aripiprazole injection (ALAI), approved by the US Food and Drug Administration for the treatment of schizophrenia in 2013, is timely. ALAI is a lyophilized powder of aripiprazole, and the aripiprazole molecule is unmodified. The initial and target dosage of ALAI is 400 mg once monthly, but it could be reduced to 300 mg if adverse reactions occur with 400 mg. When first administering ALAI, it is recommended to continue treatment with oral aripiprazole (10-20 mg/day) or another oral antipsychotic for 2 weeks in order to maintain therapeutic antipsychotic concentrations. The primary clearance route for ALAI is hepatic, ie, cytochrome P450 (CYP)2D6 and CYP3A4, so dose adjustment is required in poor CYP2D6 metabolizers. The efficacy of ALAI was demonstrated in three studies. A randomized controlled trial that formed the basis for approval of ALAI in the treatment of schizophrenia showed that ALAI significantly delayed time to impending relapse when compared with placebo (P<0.0001, log-rank test). An open-label, mirror study demonstrated that total psychiatric hospitalization rates were significantly lower after switching from oral antipsychotics to ALAI. Another randomized controlled trial presented in poster form suggested that ALAI 400 mg was comparable with oral aripiprazole 10-30 mg in preventing relapse. ALAI was generally well tolerated during both short-term and long-term studies. Its tolerability profile, including extrapyramidal symptoms and clinically relevant metabolic parameters, was similar to placebo. However, insomnia, headache, anxiety, akathisia, weight gain, injection site pain, and tremor need clinical attention. These studies suggest that ALAI is a viable treatment option for patients with schizophrenia, but direct head-to-head comparisons between ALAI and other long-acting injectable antipsychotics are needed to elucidate its risk-benefit profile.

Efficacy analyses that go beyond the primary outcome of major depressive disorder (MDD) clinical trials and consider clinical relevance, response range, disease severity, and patient subpopulations may inform clinical decision-making. This post hoc analysis assessed clinically relevant outcomes associated with adjunctive cariprazine for MDD. Data from a randomized controlled trial (NCT03738215) of cariprazine 1.5 or 3 mg/d + antidepressant therapy (ADT) versus placebo + ADT were analyzed. Change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score was assessed and number of patients achieving thresholds of MADRS response (≥5, ≥10, ≥15, ≥20, and ≥25 points) were determined. MADRS severity shifts were reported as the proportion of patients with no change or worsened severity, 1, ≥1, and ≥2 category improvements. Other efficacy characterizations included improvements in each MADRS item score and MADRS total score improvement across demographic-defined (age, sex, race) patient subgroups, baseline ADT response, and number of prior ADTs. More patients treated with adjunctive cariprazine versus placebo had MADRS total score improvements across all response thresholds and achieved ≥1 MADRS severity category improvement. Adjunctive cariprazine was associated with numerically greater improvements versus placebo in all individual MADRS items, with statistically significant improvements in 7/10 items. Adjunctive cariprazine was also associated with MADRS total score reductions, regardless of patient demographics, baseline ADT response, or number of prior ADTs. Results suggest that adjunctive cariprazine provides clinically meaningful improvements in depressive symptoms, with efficacy ranging across individual depressive symptoms and in diverse subpopulations.

Background: Despite the availability of effective antidepressants, recurrence and relapse rates for depression are high (up to 80%), treatment failures are common (40% to 60%), and as many as 20% of patients remain inadequately treated. Depression treatment guidelines are often not followed, and rates of nonadherence to treatment are high, with 28% of patients discontinuing antidepressant treatment within the first month and 44% discontinuing within 3 months of initiating therapy. Objective: The aim of this article was to summarize research on antidepressant therapy nonadherence and examine the limitations of strategies used to minimize adverse events (AEs) and improve treatment duration. Methods: A thorough search of the published literature from 1990 to the present was performed on MEDLINE and other search engines. The following search terms were used: tolerability, antidepressants, patient compliance, adherence, therapy, SSRIs, tricyclics, and other related terms focusing on specific agents. Results: Physician-specific issues represent some of the most important obstacles to adequate antidepressant therapy. Inadequate patient education, prescription of inappropriate medications or inadequate dosages, and lack of follow-up care are all issues the physician can control to improve patient adherence. Patient-specific issues include poor motivation (due to symptoms of depression) to continue therapy, failure to perceive a benefit, and concerns about cost of therapy. Medication-specific issues such as treatment-related AEs, delayed onset of action, complicated dosing or titration schedule, and subtherapeutic dosing also contribute to treatment discontinuation. Therapy with ≥I antidepressant and/or atypical antipsychotic may improve symptom control, but little evidence exists regarding efficacy and safety. Dosage reduction has been attempted to reduce events that may lead to patient discontinuation, but this may increase the risk of recurrent depressive episodes. Conclusions: To maximize patient adherence to antidepressant therapy, it is necessary to combine adequate treatment duration, realistic patient expectations, and the right dose of an agent capable of treating the full range of symptoms while controlling for AEs.

BackgroundPatients with major depressive disorder (MDD) often do not respond to antidepressant (ADT) monotherapy alone and may require adjunctive treatment to provide adequate symptom relief. Cariprazine (CAR) is a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with schizophrenia and manic, mixed, or depressive episodes of bipolar I disorder. Post hoc analysis of data from a randomized controlled trial evaluated clinically relevant improvements in depressive symptom severity with adjunctive cariprazine in patients with MDD and inadequate response to ADT monotherapy.MethodsPost hoc analysis evaluated data from a randomized, double-blind, placebo-controlled MDD trial (NCT03738215) in patients treated with CAR (1.5 mg/d or 3 mg/d) + ADT or placebo + ADT; the primary outcome was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Post hoc analysis evaluated category shifts from baseline to week 6 in MADRS severity (normal <6, mild 7–19, moderate 20–34, severe ≥35). MADRS severity shifts were reported as the percentage of patients with no change or worsened severity, 1 category improvement, ≥1 category improvement, and ≥2 category improvement. Examples of categorical shifts in depressive symptoms at week 6 include change from severe at baseline to moderate (1 category improvement) and change from severe at baseline to mild (2 category improvement).ResultsOf the 751 patients in the intent-to-treat (ITT) population (CAR: 1.5 mg/d=250, 3.0 mg/d=252; placebo=249), baseline MADRS severity was mild in 1.5%, moderate in 64%, and severe in 35%. Fewer CAR + ADT patients compared to placebo + ADT had no change or worsened MADRS severity at week 6 (CAR: 1.5 mg/d=32%, 3.0 mg/d=33%; placebo=42%). Approximately 68% of patients treated with CAR + ADT demonstrated a MADRS severity improvement of 1 category or greater by week 6 (CAR: 1.5 mg/d=68%, 3.0 mg/d=67%; placebo=58%). A greater percentage of patients in the CAR 1.5 mg/d group also had a 2 or greater category improvement versus CAR 3.0 mg/d or placebo 6 (CAR: 1.5 mg/d=28%, 3.0 mg/d=17%; placebo=19%).ConclusionsIn this post hoc analysis, CAR + ADT was associated with a greater proportion of patients with improvements in depressive symptom severity categories compared with placebo + ADT. These results may suggest that CAR + ADT is associated with clinically meaningful depressive symptom improvement in MDD patients.FundingAbbVie

Major depressive disorder (MDD) is a disabling condition that may require adjunctive treatment with atypical antipsychotics (AAs). However, little is known about how different adjunctive AAs impact disability outcomes. This analysis compared disability events, days, and costs among patients with MDD before and after initiating adjunctive treatment with cariprazine, brexpiprazole, or aripiprazole, which all belong to a class of AAs known as dopamine partial agonists. The Merative MarketScan Commercial Database and the Health and Productivity Management Database (1/1/2015-12/31/2022) were used to identify adults with MDD and ≥2 dispensings of cariprazine, brexpiprazole, or aripiprazole (first dispensing=index) adjunctive to antidepressant therapy. Baseline characteristics between cohorts were balanced using inverse probability of treatment weighting. Changes (post-index minus pre-index) in all-cause and mental health (MH)-related disability claim rates, days, and costs were compared for cariprazine vs brexpiprazole and cariprazine vs aripiprazole via a difference-in-difference analysis; 95% CIs were generated using nonparametric bootstrap procedures. -values <0.05 were considered statistically significant. In the cariprazine (n=224) vs brexpiprazole (n=643) analysis, the cariprazine cohort had significantly greater reductions in all-cause disability claims, days, and costs vs the brexpiprazole cohort (between-cohort difference: -0.23 claims [ <0.05], -25.27 days [ <0.001], -$4577.08 [ <0.01], respectively). The cariprazine cohort also had a significantly greater reduction in MH-related disability days (-12.07 [ <0.05]); reductions in MH-related disability claims and mean costs vs brexpiprazole were similar. In the cariprazine (n=174) vs aripiprazole (n=2931) analysis, a significantly greater reduction for cariprazine vs aripiprazole was observed for all-cause and MH-related disability costs (all-cause: -$3275.91 [ <0.01]; MH-related: -$2196.36 [ <0.05]); reductions in all-cause and MH-related disability claims and days were similar. In this real-world analysis of patients with MDD using AAs adjunctively to antidepressants, significantly greater reductions were observed in disability claims and days for cariprazine vs brexpiprazole and in disability costs for cariprazine vs aripiprazole. These results suggest that adjunctive cariprazine may have beneficial effects on disability outcomes for patients with MDD.