The Potential Role of Aripiprazole Augmentation for Major Depressive Disorder with Anxious Distress in Naturalistic Treatment Setting.

Objective: : This study tried to observe clinical benefit of aripiprazole augmentation (ARPA) treatment for major depressive disorder with anxious distress (MDDA) in routine practice. Methods: : Retrospective chart review (n = 41) was conducted for clinical benefit of ARPA in patients with MDDA in routine practice. The primary endpoint was the mean change of Hamilton Anxiety Rating scale (HAMA) total scores from baseline to the endpoint. Additional secondary endpoints were also retrieved. Results: : The changes of primary endpoint HAMA (t = 5.731, -4.6, p = 0.001), and secondary endpoints including Hamilton Depression Rating scale (HAMD, t = 4.284, -3.4, p ＜ 0.001), Clinical Global Impression-Clinical Benefit (CGI-CB, -0.9, t = 1.821, p = 0.026), and Clinical Global Impression Score-Severity (CGI-S, t = 3.556, -0.4, p ＜ 0.001) scores were also significantly improved during the study. No significant adverse events were observed. Conclusion: : This study has shown additional benefit of ARPA treatment for MDDA patients in routine practice. However, adequately-powered and well-controlled studies are necessary for generalization of the present findings.

Estimating Changes in Weight and Metabolic Parameters Before and After Treatment With Cariprazine: A Retrospective Study of Electronic Health Records.

PURPOSE: 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. METHODS: 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. FINDINGS: 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. IMPLICATIONS: 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.

Additional Clinical Benefit of Agomelatine Treatment for Major Depressive Disorder in Naturalistic Treatment Setting.

Objective: This study tried to observe additional benefit of agomelatine (AGO) treatment for major depressive disorder (MDD) in routine practice. Methods: Retrospective chart review (n = 63) was conducted for additional benefit of combination with or switching to AGO in MDD patients without full remission. The primary endpoint was the mean change of Clinical Global Impression-Clinical Benefit (CGI-CB) total scores from baseline to the endpoint. Additional secondary endpoints were also collected. Results: The changes of CGI-CB (Z = -3.073, p = 0.002) and Montgomery-Åsberg Depression Rating Scale (Z = -3.483, p < 0.001) total scores were significantly decreased from baseline to the endpoint, respectively. At the endpoint, the remission rate was 22.6% (n = 18) and 28.6% of patient had improvement in CGI-CB total scores at the endpoint. No significant adverse events were observed. Conclusion: This study has shown additional benefit of AGO treatment as combination or switching agent for MDD patients without full remission in routine practice. However, adequately-powered and well-controlled studies are necessary for generalization of the present findings.

Efficacy and Safety of Escitalopram, Desvenlafaxine, and Vortioxetine in the Acute Treatment of Anxious Depression: A Randomized Rater-blinded 6-week Clinical Trial.

Objective: Anxious depression is associated with greater chronicity, higher severity of symptoms, more severe functional impairment, and poor response to drug treatment. However, evidence for first-choice antidepressants in patients with anxious depression is limited. This study aimed to compare the efficacy and safety of escitalopram, desvenlafaxine, and vortioxetine in the acute treatment of anxious depression. Methods: Patients (n = 124) with major depressive disorder and high levels of anxiety were randomly assigned to an escitalopram treatment group (n = 42), desvenlafaxine treatment group (n = 40), or vortioxetine treatment group (n = 42) in a 6-week randomized rater-blinded head-to-head comparative trial. Changes in overall depressive and anxiety symptoms were assessed using the 17-item Hamilton Depression Rating Scale (HAMD) and Hamilton Anxiety Rating Scale (HAMA), respectively. Results: Patients demonstrated similar baseline-to-endpoint improvement in scores and similar response and remission rates for HAMD and HAMA. Analysis of the individual HAMD items revealed that desvenlafaxine significantly reduced anxiety somatic scores (p = 0.013) and hypochondriasis scores (p = 0.014) compared to escitalopram. With respect to the individual HAMA items, desvenlafaxine treatment showed significantly lower scores for respiratory symptoms (p = 0.013) than escitalopram treatment and cardiovascular symptoms (p = 0.005) than vortioxetine treatment. The treatments were well tolerated, with no significant differences. Conclusion: Our results indicated no significant differences in the efficacy and tolerability of escitalopram, desvenlafaxine, and vortioxetine in this subtype of patients with anxious depression during the acute phase of treatment.

Acute Efficacy and Safety of Escitalopram Versus Desvenlafaxine and Vortioxetine in the Treatment of Depression With Cognitive Complaint: A Rater-Blinded Randomized Comparative Study.

OBJECTIVE: This study aimed to compare the efficacy and safety of escitalopram, vortioxetine, and desvenlafaxine for acute treatment of major depressive disorder (MDD) with cognitive complaint (CC). METHODS: A total of 129 patients with MDD who also complained of CC were randomized evenly to either escitalopram, vortioxetine, or desvenlafaxine group and underwent a multi-center, six-week, rater-blinded, and head-to-head comparative trial. Differences in depressive symptoms following treatment were measured using the Hamilton Depression Rating Scale (HAMD) and the Montgomery-Åsberg Depression Rating Scale (MADRS). Subjective cognitive function and the presence of adverse events were assessed. RESULTS: The three antidepressant treatment groups did not show significant differences in the improvement of depressive symptoms as measured by HAMD and MADRS. Desvenlafaxine treatment was associated with a superior treatment response rate in depressive symptoms compared to vortioxetine or escitalopram treatment. However, no significant differences were found in the remission rate of depressive symptoms. The three antidepressant treatment groups did not show significant differences in the improvement of CC. Adverse profiles of each treatment group were tolerable, with no significant differences. CONCLUSION: In acute antidepressant treatment for MDD with CC, escitalopram, vortioxetine, and desvenlafaxine presented similar efficacy in relief of depressive symptoms; however, desvenlafaxine was associated with a superior treatment. Further studies are needed to confirm these results by investigating the therapeutic efficacy and safety profile of long-term antidepressant treatment of MDD with CC (Clinical Trial Registry, http://cris.nih.go.kr/cris/en/: KCT0002173).

Key considerations for the use of ketamine and esketamine for the treatment of depression: focusing on administration, safety, and tolerability.

INTRODUCTION: Racemic ketamine, a derivative of phencyclidine, has been used as a dissociative anesthetic since 1970. In 2000, the first randomized controlled trial showed a rapid relief of depressive symptoms. Since then, intravenous ketamine and intranasal S-ketamine have been validated for the treatment of depression and suicidal ideation following dose-response and double-blind placebo-controlled clinical trials. In clinical practice, after dose titration and with repeated treatments, patients may experience approximately 2-3 weeks of symptomatic relief from depression. AREAS COVERED: Areas covered in this narrative review include mechanism of action, dosing, safety, and tolerability. Some attention is paid to the possibility of R-ketamine as a future antidepressant. EXPERT OPINION: We recommend further investigation into treatment dosing and frequency strategies as well as approaches that prolong the therapeutic effects. The current fixed dosing of esketamine for obese individuals may be insufficient. Additional investigation into co-administration with somatic and neuromodulation treatments needs investigation. Finally, continuing to monitor research subjects and patients long-term for the emergence of adverse effects on cognition or other organ systems is critical.

Ketamine for treatment of mood disorders and suicidality: A narrative review of recent progress.

BACKGROUND: Mood disorders are a leading cause of morbidity. Many patients experience treatment-resistant depression (TRD), and suicide rates are rising. Faster-acting and more effective antidepressant medications are needed. Four decades of research has transformed the use of ketamine from an anesthetic to an outpatient treatment for major depressive disorder (MDD). Ketamine is a N-methyl-d-aspartate (NMDA) receptor antagonist and has been shown to rapidly improve mood symptoms and suicidal ideation by targeting the glutamate system directly. METHODS: We used the PubMed database to identify relevant articles published until September 1, 2020. We focused on meta-analyses, randomized controlled trials, and original observational studies. We included relevant studies for depression, MDD, TRD, bipolar disorder, anxiety, posttraumatic stress disorder (PTSD), suicide, ketamine, and esketamine. RESULTS: Both racemic ketamine and esketamine have been shown to rapidly treat depression and suicidality. There is evidence that ketamine can be helpful for anxiety and PTSD; however, more research is needed. Intranasal esketamine has been FDA approved to treat depression. CONCLUSIONS: This narrative review describes the evolution of ketamine to treat mood disorders and suicidality. We provide the evidence supporting recent developments using esketamine as well as unresolved issues in the field, such as dosing and safety.

Exploring Hidden Issues in the Use of Antipsychotic Polypharmacy in the Treatment of Schizophrenia.

The mainstay of schizophrenia treatment is pharmacological therapy using various antipsychotics including first- and second-generation antipsychotics which have different pharmacokinetic and pharmacodynamic property leading to differential presentation of adverse events (AEs) and treatment effects such as negative symptoms, cognitive symptoms and cormorbid symptoms. Major treatment guidelines suggest the use of antipsychotic monotherapy (APM) as a gold standard in the treatment of schizophrenia. However, the effects of APM is inadequate and less potent to achieve symptom remission as well as functional recovery in real practice which has been consistently reported in numerous controlled clinical trials, large practical trials, independent small studies and systematic reviews till today. Therefore anti-psychotic polypharmacy (APP) regardless of the class of antipsychotics has been also commonly utilized for many reasons in real world practice. However, APP has also crucial pitfalls including increase of total psychotics including antipsychotics, high-doses of antipsychotics used, poor compliance, drug-drug interaction and risks for developing AEs, all of which are paradoxically related to poor clinical outcomes, whereas APP has also substantial advantages in reduction of re-hospitalization, severe psychopathology and targeted control of concurrent symptoms. Given currently limited therapeutic options, it is also important to properly utilize APP in order to maximize its clinical utility and minimize its risk for better treatment outcomes for patients with schizophrenia, based on risk/benefit with full understanding of pharmacological and clinical issues on APP. The present paper intends to address intriguing and important issues in the use of APP in real world practice.

Consideration of Long-Acting Injectable Antipsychotics for Polypharmacy Regimen in the Treatment of Schizophrenia: Put It on the Table or Not?

Antipsychotic monotherapy (APM) is considered best-acceptable treatment option regardless of antipsychotic class and formulation types for treating schizophrenia. However, antipsychotic polypharmacy (APP) has been also widely utilized in routine clinical practice. Despite APP has some clinical benefits it has also numerous pitfalls in relation with increased total number and doses of APs leading to adverse events as well as decrease of treatment adherence and persistence resulting in poor clinical outcomes. Recent introduction of long-acting injectable antipsychotics (LAIs) to the market has offered a chance for better medication adherence/persistence and also provided a simplification of treatment regime leading to more stabilized treatment for schizophrenia patients. When we cannot stay away from APP in the treatment of schizophrenia, clinicians need to find more proper APP regimens and thereby utilization of APP in efficient way should be a practical strategy to benefit schizophrenia patient in a real world treatment setting. With this regard, LAIs can be one of available APP regimen for treatment of schizophrenia in routine practice since their clinical utility and pharmacokinetic stability over oral APs have been well-elaborated today. However, when we have to commence LAIs as a part of APP with oral APs or other LAIs, every effort should be made before doing so whether or not validated and available treatment options or other clinical factors were not done or evaluated yet. Any treatment guidelines do not support APP regardless of the formulation of APP regimen or address two or more LAIs for treatment of schizophrenia till today.

Clinical Benefit and Utility of Switching to Aripiprazole Once Monthly in Patients with Antipsychotic Polypharmacy or Long Acting Injectable Antipsychotics for Patients with Schizophrenia in Routine Practice: A Retrospective, Observation Study.

OBJECTIVE: In a number of controlled clinical trials and naturalistic studies, aripiprazole once monthly (AOM) has been found to be effective and safe as acute and maintenance treatment options for schizophrenia. However, such clinical data have been presented in selected patient population (i.e., antipsychotic monotherapy, etc.), in particular, clinical information on switching to AOM from antipsychotic polypharmacy and/or other long acting injectable antipsychotics (LAIs) has been scarce till today. METHODS: The study period was from the first switching day to AOM up to 12 months in patients with antipsychotic polypharmacy (APpoly)/LAIs (baseline, month 3, month 6, and month 12). Available demographics and clinical information were retrieved from electronic medical records (EMRs). Available scores of Global Assessment of Functioning (GAF), Clinical Global Impression-Clinical Benefit (CGI-CB), CGI-severity, Visual Analog Scale on Satisfaction-Patient/Health Professional (VAS-P/HP), and the Positive and Negative Syndrome Scale-Insigh (PANSS-I) scores were also taken from EMR. Proportional change of functional impairment before and after AOM was also captured. RESULTS: Data of 18 patients were available. Most commonly used combined APs before AOM were aripiprazole, blonanserin, quetiapine, and risperidone. At least 2 APs (n = 2.4) were combined before AOM. Scores of GAF (10.7% increase), CGI-CB (46.2% decrease), VAS-P (47.8% increase), VAS-HP (40.8% increase), and PANSS-I (27.9% increase) (all p = 0.001) were significantly improved from baseline to month 12, respectively. Approximately 59% of patients improved individual functioning with different level (i.e., employment, back to school, etc.) after AOM treatment at month 12. CONCLUSION: The present study have clearly shown the clinical benefit and utility of switching to AOM for treatment of patients with APpoly/LAIs in routine practice. Subsequent, adequately-powered, well-controlled clinical trials may be necessary to confirm our findings in near future.

The Rapid Mood Screener (RMS): a novel and pragmatic screener for bipolar I disorder.

OBJECTIVE: Depressive episodes and symptoms of bipolar I disorder are commonly misdiagnosed as major depressive disorder (MDD) in primary care. The novel and pragmatic Rapid Mood Screener (RMS) was developed to screen for manic symptoms and bipolar I disorder features (e.g. age of depression onset) to address this unmet clinical need. METHODS: A targeted literature search was conducted to select concepts thought to differentiate bipolar I from MDD and screener tool items were drafted. Items were tested and refined in cognitive debriefing interviews with individuals with self-reported bipolar I or MDD (n = 12). An observational study was conducted to evaluate predictive validity. Participants with clinical interview-confirmed bipolar I or MDD diagnoses (n = 139) completed a draft 10-item screening tool and other questionnaires. Data were analyzed to identify the smallest possible subset of items with optimized sensitivity and specificity. RESULTS: Adults with confirmed bipolar I (n = 67) or MDD (n = 72) participated in the observational study. Ten draft screening tool items were reduced to 6 final RMS items based on the item-level analysis. When 4 or more items of the RMS were endorsed ("yes"), sensitivity was 0.88 and specificity was 0.80; positive and negative predictive values were 0.80 and 0.88, respectively. These properties were an improvement over the Mood Disorder Questionnaire in the same analysis sample while using 60% fewer items. CONCLUSION: The pragmatic 6-item RMS differentiates bipolar I disorder from MDD in patients with depressive symptoms, providing real-world guidance to primary care practitioners on whether a more comprehensive assessment for bipolar I disorder is warranted.

The effect of intravenous, intranasal, and oral ketamine in mood disorders: A meta-analysis.

BACKGROUND: Ketamine is established as a rapid and effective treatment in adults with treatment-resistant depression (TRD). The availability of different formulations and routes of delivery invites the need for evaluating relative effect sizes. METHODS: Effect size with respect to depression symptom reduction for each formulation and route of delivery was compared at discrete time-points (i.e., 24 h, 2-6 days, 7-20 days, 21-28 days) in adults with TRD. A random-effects meta-analysis was conducted to evaluate the effect size across intravenous, intranasal and oral routes of administration. Analysis was also conducted evaluating the effect size of racemic ketamine to esketamine. RESULTS: The pooled effect size for intranasal ketamine/esketamine at 24 h was g = 1.247 (n = 5, 95% CI: 0.591-1.903, p < 0.01). At 2-6 days, the pooled effect size for intravenous ketamine/esketamine was g = 0.949 (n = 14, 95% CI: -0.308-2.206, p = 0.139). At 7-20 days, intranasal ketamine had a pooled effect size of g = 1.018 (n = 4, 95% CI: 0.499-1.538, p < 0.01). At 21-28 days, oral ketamine had a pooled effect size of g = 0.633 (n = 2, 95% CI: 0.368-0.898, p < 0.01). LIMITATIONS: Additional comparative studies are needed with regards to the efficacy of different formulations and routes of delivery. CONCLUSIONS: The short-term efficacy of intravenous and intranasal ketamine/esketamine for adults with TRD was established. Interpreting the efficacy of oral ketamine was limited by the need for studies with larger samples across independent sites. No conclusions regarding comparative efficacy of the disparate formulations and routes of delivery can be derived from this analysis. Direct comparative studies are needed to further inform treatment options for TRD.

ZNF804A Gene Variants Have a Cross-diagnostic Influence on Psychosis and Treatment Improvement in Mood Disorders.

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

Effectiveness and Tolerability of Switching to Aripiprazole Once Monthly from Antipsychotic Polypharmacy and/or Other Long Acting Injectable Antipsychotics for Patients with Schizophrenia in Routine Practice: A Retrospective, Observation Study.

OBJECTIVE: This study was done for collection of real world data of Aripiprazole Once Monthly (AOM) in patients with schizophrenia. METHODS: The observation was up to 12 months from the first use of AOM in patients with antipsychotic polypharmacy (APpoly)/other long acting injectable antipsychotics (LAIs) for treatment of schizophrenia in daily practice. Demographics and available clinical information such as The Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-severity (CGI-S) scores were retrieved from the electronic medical record (EMR). Adverse events were also noted as described in EMR. RESULTS: Eighteen patients were found to be switched from APpoly/LAIs. Mean numbers of previous APs treatment failure and immediate prior APs were 2.2 and 2.4, respectively; most commonly used APs before AOM were aripiprazole, blonanserin, quetiapine, and risperidone. Mean number of combined APs before AOM significantly decreased from 2.4 use to 0.7 at month 12 (p < 0.0001). The PANSS total (71.7 to 62.1, p = 0.000) and CGI-S (3.4 to 3.1, p = 0.008) scores were also significantly decreased from baseline (first use of AOM) to month 12, respectively. Other various psychotropics including anxiolytics were also significantly and substantially decreased at some point from baseline throughout the observation period as well. Mild hand tremor and akathisia were developed in 3 patients. CONCLUSION: The present observation study clearly confirmed the use of AOM should be also effective and tolerable treatment option for patients with APpoly/LAIs in the real world practice. Subsequent, adequately-powered, and well-controlled clinical trials are warranted in near future.

Reduced plasma Fetuin-A is a promising biomarker of depression in the elderly.

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.

Updates on Preclinical and Translational Neuroscience of Mood Disorders: A Brief Historical Focus on Ketamine for the Clinician.

BACKGROUND: The development of new-generation antidepressants comes at a time of great clinical need when the global burden of depression, suicide, and other psychiatric conditions continues to increase. Our current treatment armamentarium is limited by the time delay needed for antidepressant effects and the significant number of patients who do not show an adequate response to antidepressants. The past 2 decades of psychiatric research has revealed that ketamine, known to be used only as an anesthetic and drug of abuse and to produce experimental models of psychosis, is effective at subanesthetic doses to ameliorate clinical depression. METHODS: We performed a systematic search of PubMed/MEDLINE indexed reports to identify clinical and translational research done with ketamine for purposes of treating depression. RESULTS: We will first present the rationale for investigating ketamine and other N-methyl-D-aspartate receptor antagonists as a novel class of glutamate system targeting antidepressants. We will summarize putative molecular pathways underlying mood disorders and outline a brief history of investigation into ketamine as a treatment for depression. Recent clinical/translational evidence of ketamine's rapid-acting antidepressant mechanism will be critically reviewed in detail. CONCLUSIONS: At the end of this review, we will opine on the role of ketamine and derivatives in clinical practice.

The Potential Utility of Aripiprazole Augmentation for Major Depressive Disorder with Mixed Features Specifier: A Retrospective Study.

OBJECTIVE: The present study aimed to observe potential benefit of aripiprazole augmentation in the treatment of major depressive disorder with mixed specifier (MDDM) in naturalistic treatment setting. METHODS: Data were collected from MDDM patients using a retrospective chart review for 8 weeks (week -8 and week 0) in routine practice. All patients were on current antidepressants upon starting of aripiprazole. Patients were treated without restriction of doses of aripiprazole. The primary endpoint was the mean change of Montgomery-Åsberg Depression Rating Scale (MADRS) total scores along with various secondary endpoint measures. RESULTS: In total 38 patients were analyzed. The changes of MADRS, Clinical Global Impression (CGI)-severity, Young Mania Rating Scale, Sheehan Disability Scale, and CGI-clinical benefit total scores from baseline to the endpoint were -7.1, -0.8, -4.9, -4.1, and -3.6, respectively (all p < 0.0001). At the endpoint, the responder and remitter rates by MADRS score criteria were approximately 32% and 21%, respectively. CONCLUSION: The present findings have clearly shown the effectiveness and tolerability of aripiprazole augmentation for MDDM patients in routine practice. The present study warrants subsequent, adequately-powered, well-controlled studies for generalizability near future.

Genes Involved in Neurodevelopment, Neuroplasticity and Major Depression: No Association for CACNA1C, CHRNA7 and MAPK1.

OBJECTIVE: Genetics factors are likely to play a role in the risk, clinical presentation and treatment outcome in major depressive disorder (MDD). In this study, we investigated the role of three candidate genes for MDD; calcium voltage- gated channel subunit alpha1 C ( CACNA1C ), cholinergic receptor nicotinic alpha 7 subunit ( CHRNA7 ), and mitogen- activated protein kinase 1 ( MAPK1 ). METHODS: Two-hundred forty-two MDD patients and 326 healthy controls of Korean ancestry served as samples for the analyses. Thirty-nine single nucleotide polymorphisms (SNPs) within CACNA1C , CHRNA7 , and MAPK1 genes were genotyped and subsequently tested for association with MDD (primary analysis) and other clinical features (symptoms' severity, age of onset, history of suicide attempt, treatment outcome) (secondary analyses). Single SNPs, haplotypes and epistatic analyses were performed. RESULTS: Single SNPs were not associated with disease risk and clinical features. However, a combination of alleles (haplotype) within MAPK1 was found associated with MDD-status. Secondary analyses detected a possible involvement of CACNA1C haplotype in resistance to antidepressant treatment. CONCLUSION: These data suggest a role for MAPK1 and CACNA1C in MDD risk and treatment resistance, respectively. However, since many limitations characterize the analysis, the results must be considered with great caution and verified.