Showing papers in "Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology in 2021"

Cariprazine Add-on in Inadequate Clozapine Response: A Report on Two Cases.

Abstract: Cariprazine is a novel antipsychotic drug that exerts partial agonism of dopamine D2/D3 receptors with preferential binding to the D3 receptor, antagonism of 5HT2B receptors, and partial agonism of 5HT1A Currently, cariprazine has shown clinical efficacy in patients with schizophrenia and with bipolar disorder, as well as adjunctive treatment in patients with Major Depressive Disorder (MDD) and drug-resistant MDD In the present case series, we report on two patients with treatment-resistant schizophrenia and partial response to clozapine who benefit from combination with cariprazine The effects of cariprazine combination were remarkable also concerning the adverse metabolic effects of clozapine

Biomarkers of Major Depressive Disorder: Knowing is Half the Battle.

Abstract: Major depressive disorder (MDD) is a heterogeneous disease which is why there are currently no specific methods to accurately test the severity, endophenotype or therapy response. This lack of progress is partly attributed to the com-plexity and variability of depression, in association with analytical variability of clinical literature and the wide number of theoretically complex biomarkers. The literature accessible, indicates that markers involved in inflammatory, neuro-trophic and metabolic processes and components of neurotransmitters and neuroendocrine systems are rather strong indicators to be considered clinically and can be measured through genetic and epigenetic, transcriptomic and proteomic, metabolomics and neuroimaging assessments. Promising biologic systems/markers found were i.e., growth biomarkers, endocrine markers, oxidant stress markers, proteomic and chronic inflammatory markers, are discussed in this review. Several lines of evidence suggest that a portion of MDD is a dopamine agonist-responsive subtype. This review analyzes concise reports on the pathophysiological biomarkers of MDD and therapeutic reactions via peripheral developmental factors, inflammative cytokines, endocrine factors and metabolic markers. Various literatures also support that endocrine and metabolism changes are associated with MDD. Accumulating evidence suggests that at least a portion of MDD patients show characteristics pathological changes regarding different clinical pathological biomarkers. By this review we sum up all the different biomarkers playing an important role in the detection or treatment of the different patients suffering from MDD. The review also gives an overview of different biomarker's playing a potential role in modulating effect of MDD.

Personalization of Repetitive Transcranial Magnetic Stimulation for the Treatment of Major Depressive Disorder According to the Existing Psychiatric Comorbidity

Abstract: Repetitive transcranial magnetic stimulation (rTMS) and intermittent theta-burst stimulation (iTBS) are evidenced-based treatments for patients with major depressive disorder (MDD) who fail to respond to standard first-line therapies. However, although various TMS protocols have been proven to be clinically effective, the response rate varies across clinical applications due to the heterogeneity of real-world psychiatric comorbidities, such as generalized anxiety disorder, posttraumatic stress disorder, panic disorder, or substance use disorder, which are often observed in patients with MDD. Therefore, individualized treatment approaches are important to increase treatment response by assigning a given patient to the most optimal TMS treatment protocol based on his or her individual profile. This literature review summarizes different rTMS or TBS protocols that have been applied in researches investigating MDD patients with certain psychiatric comorbidities and discusses biomarkers that may be used to predict rTMS treatment response. Furthermore, we highlight the need for the validation of neuroimaging and electrophysiological biomarkers associated with rTMS treatment responses. Finally, we discuss on which directions future efforts should focus for developing the personalization of the treatment of depression with rTMS or iTBS.

Role of Transcranial Direct Current Stimulation in the Management of Alzheimer's Disease: A Meta-analysis of Effects, Adherence and Adverse Effects.

Abstract: Transcranial direct current stimulation (tDCS) is a form of novel brain stimulating method that has attracted interest owing to its relative inexpensiveness and ease of administration. It has been evaluated in many studies for its effectiveness in improving cognitive symptoms in Alzheimer's disease (AD). However, our understanding regarding its efficacy and the most effective way of administering tDCS (in terms of lead placement to achieve response and prevent harmful consequences) is still evolving. The current meta-analysis was conducted to resolve the above issues. A search using appropriate keywords and medical subject headings was conducted on PubMed, Scopus and DOAJ database. Studies were analysed on pre-defined inclusion and exclusion criteria. Finally 11 studies were included for quantitative analysis from 1,021 obtained from initial search. All the studies included were methodologically of high quality, though an asymmetrical funnel plot raised the possibility of publication bias. tDCS was found to significantly improve the scores on cognition as compared to sham. Anodal tDCS was found to be significantly beneficial in this regards, whereas cathodal and dual stimulation were not. There were no significant difference in the number of drop-outs and adverse reaction in tDCS and sham group. The quality of evidence that we have reviewed in this study is robust. tDCS, particularly anodal tDCS is an effective treatment modality in AD. It is well tolerated in patients with AD. However, further studies are warranted to probe the role of tDCS in other domains of AD.

Rapid Onset of Intranasal Esketamine in Patients with Treatment Resistant Depression and Major Depression with Suicide Ideation: A Meta-Analysis

Abstract: Objective We performed a meta-analysis of randomized double-blinded placebo controlled trials (DB-RCTs) to investigate efficacy and safety of intranasal esketamine in treating major depressive disorder (MDD) including treatment resistant depression (TRD) and major depression with suicide ideation (MDSI). Methods Mean change in total scores on Montgomery-Asberg Depression Rating Scale (MADRS) from baseline to different time-points were our primary outcome measure. Secondary efficacy measures included rate of remission of depression and resolution of suicidality. Results Eight DB-RCTs (seven published and one un-published) covering 1,488 patients with MDD were included. Esketamine more significantly improved MADRS total scores than placebo starting from 2-4 hours after the first administration (standardized mean difference, -0.41 [95% CI, -0.58 to -0.25], p < 0.00001), and this superiority maintained until end of double-blinded period (28 days). Sub-group analysis showed that superior antidepressant effects of esketamine over placebo in TRD and MDSI was observed from 2-4 hours, which was maintained until 28 days. Resolution of suicide in MDSI was also greater for esketamine than for placebo at 2-4 hours (OR of 2.04, 95% CIs, 1.37 to 3.05, p = 0.0005), but two groups did not statistically differ at 24 hours and day 28. Total adverse events (AEs), and other common AEs including dissociation, blood pressure increment, nausea, vertigo, dysgeusia, dizziness, and somnolence were more frequent in esketamine than in placebo group. Conclusion Esketamine showed rapid antidepressant effects in patients with MDD, including TRD and MDSI. The study also suggested that esketamine might be associated with rapid anti-suicidal effects for patients with MDSI.

White Matter Alterations Associated with Pro-inflammatory Cytokines in Patients with Major Depressive Disorder.

Abstract: Objective Regarding the neuroinflammatory theory of major depressive disorder (MDD), little is known about the effect of pro-inflammatory cytokines on white matter (WM) changes in MDD. We aimed to investigate the relationship between pro-inflammatory cytokines and WM alterations in patients with MDD. Methods Twenty-two patients with MDD and 22 healthy controls (HC) were evaluated for brain imaging and pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, IL-8, interferon-γ and tumor necrosis factor (TNF)-α. Tract-based spatial statistics and FreeSurfer were used for brain image analysis. Results The levels of TNF-α and IL-8 were significantly higher in the MDD group than in HC. Compared to HC, lower fractional anisotropy (FA), and higher median diffusivity (MD) and radial diffusivity (RD) values were found in the MDD group for several WM regions. Voxel-wise correlation analysis showed that the level of TNF-α was negatively correlated with FA, and positively correlated with MD and RD in the left body and genu of the corpus callosum, left anterior corona radiata, and left superior corona radiata. Conclusion Our findings suggest that TNF-α may play an important role in the WM alterations in depression, possibly through demyelination.

Second-to-Fourth Digit Ratio (2D:4D) in Psychiatric Disorders: A Systematic Review of Case-control Studies.

Abstract: The second-to-fourth digit ratio (2D:4D) is an indirect, retrospective, non-invasive measure that correlates negatively with intrauterine exposure to testosterone. The present meta-analysis aimed to evaluate if 2D:4D differs between patients with psychiatric disorders and controls. In September 2019, we searched in Web of Knowledge, PsycINFO, Embase, and CINHAL, and retrieved 619 papers. We finally included 43 case-control studies which compared the 2D:4D ratio of patients with autism spectrum disorder (ASD) (n = 16), schizophrenia (n = 8), gender non-conformity (n = 7), addictions (n = 5), attention deficit-hyperactivity disorder (ADHD) (n = 4), mood disorders (n = 2), and intellectual disability (n = 1) to non-clinical controls. Meta-analyses showed that, overall, psychiatric patients had lower 2D:4D than healthy controls (n = 43, overall sample = 9,484, mean difference = -0.0056, 95% confidence interval from -0.0093 to -0.002, I2 = 74%), with more pronounced differences in the right hand, males, and children. Considering psychiatric disorders individually, significant differences were found in the ASD, ADHD, and addictions groups, in which 2D:4D was significantly lower than healthy controls. Conversely, the right hand of males with schizophrenia showed higher 2D:4D than healthy controls. No other significant differences were detected. Although our results need to be cautiously interpreted and find limited applications in clinical practice, they may suggest that 2D:4D is altered in some psychopathological conditions, underlining the role of prenatal exposure to sex steroids in the etiology of psychiatric disorders.

Standardization of the Korean Version of the Patient Health Questionnaire-4 (PHQ-4).

Abstract: Objective The Patient Health Questionnaire-4 (PHQ-4) has been used for screening owing to ease of use and brevity. In this study, we developed the Korean version of the PHQ-4 and tested its validity. Methods One hundred sixteen new adult outpatients at the Department of Psychiatry of the Korea University Ansan Hospital participated in the study. We simultaneously administered other depression/anxiety scales: the Hamilton Rating Scale for Depression, the Hamilton Anxiety Scale, the Beck Depression Inventory, and the Beck Anxiety Inventory. Results The mean PHQ-4 score was 6.52 (standard deviation = 3.45). Cronbach's α was 0.792, and the intraclass correlation coefficient of test and 2-week interval retest was 0.827 (p < 0.01). The Pearson correlation coefficients between the PHQ-4 total score and other depression/anxiety scales were all over 0.6. Confirmatory factorial analysis showed acceptable convergent validity and reliability but questionable discriminant validity for some model fit values. Conclusion The Korean version of the PHQ-4 has sufficient internal consistency, test-retest reliability, and construct validity, but its two-factor structure showed incompleteness. However, we suggest that it should be used as a brief screening measure for common psychiatric distress that warrants further detailed assessment, but not to separately assess the severity of depression and anxiety symptoms.

Autism-like Behaviors in Male Juvenile Offspring after Maternal Glyphosate Exposure.

Abstract: Objective Exposure to the herbicide glyphosate during pregnancy and lactation may increase the risk for autism spectrum disorder (ASD) in offspring. Recently, we reported that maternal exposure of formulated glyphosate caused ASD-like behaviors in juvenile offspring. Here, we investigated whether maternal exposure of pure glyphosate could cause ASD-like behaviors in juvenile offspring. Methods Water or 0.098% glyphosate was administered as drinking water from E5 to P21 (weaning). Behavioral tests such as grooming test and three-chamber social interaction test in male offspring were performed from P28 to P35. Results Male offspring showed ASD-like behavioral abnormalities (i.e., increasing grooming behavior and social interaction deficit) after maternal exposure of glyphosate. Conclusion The findings suggest that the exposure of glyphosate during pregnancy and lactation may cause ASD-like behavioral abnormalities in male juvenile offspring. It is likely that glyphosate itself, but not the other ingredients, may contribute to ASD-like behavioral abnormalities in juvenile offspring.

Machine Learning and Deep Learning for the Pharmacogenomics of Antidepressant Treatments.

Abstract: A growing body of evidence now proposes that machine learning and deep learning techniques can serve as a vital foundation for the pharmacogenomics of antidepressant treatments in patients with major depressive disorder (MDD). In this review, we focus on the latest developments for pharmacogenomics research using machine learning and deep learning approaches together with neuroimaging and multi-omics data. First, we review relevant pharmacogenomics studies that leverage numerous machine learning and deep learning techniques to determine treatment prediction and potential biomarkers for antidepressant treatments in MDD. In addition, we depict some neuroimaging pharmacogenomics studies that utilize various machine learning approaches to predict antidepressant treatment outcomes in MDD based on the integration of research on pharmacogenomics and neuroimaging. Moreover, we summarize the limitations in regard to the past pharmacogenomics studies of antidepressant treatments in MDD. Finally, we outline a discussion of challenges and directions for future research. In light of latest advancements in neuroimaging and multi-omics, various genomic variants and biomarkers associated with antidepressant treatments in MDD are being identified in pharmacogenomics research by employing machine learning and deep learning algorithms.

Apathy: Neurobiology, Assessment and Treatment.

Abstract: Apathy is a highly prevalent, disabling and treatment resistant syndrome. It is defined as a quantitative reduction of goal-directed activity in comparison to the patient's previous level of in multiple dimensions including behavior/cognition, emotion and social interaction. It has been described in major depressive disorder, Alzheimer's disease, frontotemporal dementia, Parkinson's Disease, cerebrovascular disease, and vascular dementia, among others. This review will address the neuropsychology and associated neurobiological underpinnings of apathy in the above conditions, identify specific methods to assess apathy clinically, and review the literature on managing apathy across these various disorders.

Novel Biomarkers of Alzheimer's Disease: Based Upon N-methyl-D-aspartate Receptor Hypoactivation and Oxidative Stress

Abstract: Early detection and prevention of Alzheimer's disease (AD) is important. The current treatment for early AD is acetylcholine esterase inhibitors (AChEIs); however, the efficacy is poor. Besides, AChEI did not show efficacy in mild cognitive impairment (MCI). Beta-amyloid (A) deposits have been regarded to be highly related to the pathogenesis of AD. However, many clinical trials aiming at the clearance of A deposits failed to improve the cognitive decline of AD, even at its early phase. There should be other important mechanisms unproven in the course of AD and MCI. Feasible biomarkers for the diagnosis and treatment response of AD are lacking to date. The N-methyl-D-aspartate receptor (NMDAR) activation plays an important role in learning and memory. On the other hand, oxidative stress has been regarded to contribute to aging with the assumption that free radicals damage cell constituents and connective tissues. Our recent study found that an NMDAR enhancer, sodium benzoate (the pivotal inhibitor of D-amino acid oxidase [DAAO]), improved the cognitive and global function of patients with early-phase AD. Further, we found that peripheral DAAO levels were higher in patients with MCI and AD than healthy controls. We also found that sodium benzoate was able to change the activity of antioxidant. These pieces of evidence suggest that the NMDAR function is associated with anti-oxidation, and have potential to be biomarkers for the diagnosis and treatment response of AD.

Drug-induced Hyperthermic Syndromes in Psychiatry

Abstract: Hyperthermia, or extreme elevations in body temperature, can be life-threatening and may be caused by prescription drugs or illegal substances acting at a number of different levels of the neuraxis. Several psychotropic drug classes and combinations have been associated with a classic clinical syndrome of hyperthermia, skeletal muscle hyper-metabolism, rigidity or rhabdomyolysis, autonomic dysfunction and altered mental status ranging from catatonic stupor to coma. It is critical for clinicians to have a high index of suspicion for these relatively uncommon drug-induced adverse effects and to become familiar with their management to prevent serious morbidity and mortality. Although these syndromes look alike, they are triggered by quite different mechanisms, and apart from the need to withdraw or restore potential triggering drugs and provide intensive medical care, specific treatments may vary. Clinical similarities have led to theoretical speculations about common mechanisms and shared genetic predispositions underlying these syndromes, suggesting that there may be a common "thermic stress syndrome" triggered in humans and animal models by a variety of pharmacological or environmental challenges.

Elevated Monocyte to High-density Lipoprotein Ratios as an Inflammation Markers for Schizophrenia Patients.

Abstract: Objective Monocyte to high density lipoprotein ratio (MHR) is a new instrument for giving notice inflammation, which plays a main role in schizophrenia. Thus, in this study, our goal was to investigate the possible association between MHR and schizophrenia. Methods The participants of this study consisted of 75 schizophrenia patients and 74 healthy individuals (control group). The Positive and Negative Syndrome Scale was used to collect data from the patient group. Complete blood count parameters and lipid profile were analyzed in all study participants. Results The patients with schizophrenia had higher MHR values (15.04 ± 3.31 in schizophrenia patients and 12.62 ± 2.99 in controls; p = 0.001). Monocyte counts and MHR of the schizophrenia patients were significantly higher than the control group. There was a significant and positive correlation between age, body mass index, severity of disease and MHR. Conclusion To our knowledge, this study was the first to demonstrate inflammatory markers such as MHR levels in schizophrenia patients. Both monocyte counts and MHR values in schizophrenia patients were higher than the control group. MHR might be an available and useful inflammatory marker to evaluate inflammation in schizophrenia patients.

Improved Executive Functions and Reduced Craving in Youths with Methamphetamine Addiction: Evidence from Combined Transcranial Direct Current Stimulation with Mindfulness Treatment.

Abstract: Objective: Transcranial direct current stimulation (tDCS) and mindfulness practices have been proposed as a potential approach to improve executive functions (EFs) and reduce craving in persons with substance use disorders. Based on the neural mechanisms of action of each of these interventions, the combination of both non-pharmacological interventions might have additive effects. In the current study, the effects of tDCS combined with mindfulness-based substance abuse treatment (MBSAT) to improve EFs and reduce craving were investigated in early abstinent methamphetamine abuse. Methods: Eighty (youths aged between 18 and 21) early-abstinent methamphetamine users were randomly assigned to the research groups (tDCS group [n = 20], mindfulness group [n = 20], combined mindfulness-tDCS group [n = 20], and sham group [n = 20]). Active tDCS (1.5 mA,20 min, 12 sessions) or sham tDCS was appliedover the left dorsolateral prefrontal cortex and the MBSAT protocol was used over twelve 50-min sessions. Results: Both in the post-test phase (immediately after the intervention) and follow-up phase (one month after the intervention), performance in most EFs tasks significantly improved in the combination group which received real tDCS ＋ MBSAT, as compared to baseline values and sham stimulation group. Similarly, a significant reduction in craving was observed after intervention inall treatment groups, but not the sham stimulation group. Interestingly, the increase in EFs and the reduction in craving post versus pre tDCS ＋ MBSAT intervention were correlated. Conclusion: Findings from the current study provide initial support for the clinical effectiveness of combination tDCS ＋ MBSAT, possibly influencing cognitive/affective processes.

Clinical Usefulness of Amisulpride Add-on Therapy in Schizophrenia Patients without Treatment Response to Second-generation Antipsychotics.

Abstract: Objective The response to antipsychotics in patients with schizophrenia is still unsatisfactory. Therefore, augmentation with other antipsychotics is common in clinical situations. The purpose of this study was to evaluate the improvement of psychiatric symptoms and side effects after amisulpride add-on therapy. Methods Forty patients with schizophrenia or schizoaffective disorder without treatment response to second-generation antipsychotics were included in this study. Psychotic symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS) and the Korean version of Calgary Depression Scale for Schizophrenia (CDSS) at baseline, 4 weeks, and 8 weeks after the addition of amisulpride. Results Among the 29 subjects who completed the 8-week study, 34.5% were responders according to PANSS total score. At week 8, the mean positive (p < 0.001), negative (p < 0.001), general (p < 0.001), and total (p < 0.001) PANSS scores and CDSS scores (p = 0.002) showed significant improvement compared to baseline. There was no increase in extrapyramidal side effects according to Simpson Angus Scale (p = 0.379) and Barnes Akathisia Rating Scale (p = 0.070) and no weight gain (p = 0.308) after the add-on treatment. Conclusion The addition of amisulpride for schizophrenia patients without therapeutic response to second-generation antipsychotics is considered an effective and safe treatment. This study's results suggested that augmentation of second-generation antipsychotics with amisulpride could be a useful option for patients with schizophrenia unresponsive to second-generation antipsychotics. Further studies investigating the efficacy of amisulpride add-on therapy using placebo control are necessary to confirm these results.

Trazodone Add-on in COVID-19-related Selective Serotonin Reuptake Inhibitor-resistant Post-traumatic Stress Disorder in Healthcare Workers: Two Case Reports.

Abstract: COVID-19 represents a significant stress factor for all people worldwide due to several factors, including quarantine, lockdowns, fear of contagion, deaths, and other traumatic events. However, the healthcare workers (HCWs) have paid the higher price of this pandemic in terms of fatalities, contagions, and psychological well-being. Studies suggest that this particular population is at increased risk of developing a severe post-traumatic stress disorder (PTSD). The early diagnosis and timely treatment of PTSD in HCWs may restore well-being and significantly impact health services functioning, reducing burnout, days spent far from work, disrupted personal and team empowerment, and worse job performances. In the present article, we reported on two cases of HCWs directly involved in the treatment of COVID-19 patients who showed selective serotonin reuptake inhibitor-resistant PTSD, which was successfully treated with extended-release trazodone TRZ ContramidⓇ add-on.

miR-132 and miR-942 Expression Levels in Children with Attention Deficit and Hyperactivity Disorder: A Controlled Study.

Abstract: Objective Although attention deficit hyperactivity disorder (ADHD) is a disease with high genetic transition, our knowledge about the mechanism of the disease is limited. In this study, it was aimed to evaluate the levels of miR-132-3p and miR-942-5p that are associated with the dopamine carrier protein gene (DAT1) and dopamine receptor 5 (DRD5) genes, which have been shown to play a role in the development of ADHD. Methods According to the Diagnostic and Statistical Manual of Mental Disorders 5th edition, 50 children diagnosed with ADHD and 48 healthy controls were included in the study. Affective Disorders and Schizophrenia Interview Schedule-Now and Lifetime Version-Turkish Adaptation was used to evaluate ADHD and the diagnoses accompanying ADHD. Quantitative Real-Time Polymerase Chain Reaction was used to evaluate miR-132-3p and miR-942-5p expression levels. Results It was observed that miR-132-3p level (p = 0.001) was significantly higher with children with ADHD compared to the control group, and the level of miR-942-5p (p = 0.181) was higher in ADHD but did not reach statistically significant level. Conclusion In our study, we found that the increase in the miR-132-3p levels of children with ADHD may be a therapeutic target of the disease.

‘Z-trip’? A Comprehensive Overview and a Case-series of Zolpidem Misuse

Abstract: Although believed safer compared to short-acting benzodiazepines (BZD), in the past few years a growing concern has developed relating to the abuse of Z-drugs, and specifically of zolpidem. Here we aim to review the evidence for the misuse of zolpidem and describe several related cases collected in Italy. A comprehensive overview is here carried by using several databases, and by combining the search strategy of free text terms and exploding a range of MESH headings relating to the topics of Zolpidem and Abuse and/or Misuse as follows: ((Zolpidem[Title/Abstract]) AND (Abuse[Title/Abstract]) OR (Misuse[Title/Abstract])), without time and/or language restrictions. Furthermore, a case series of 8 cases of zolpidem misuse and/or abuse, collected in different Italian psychiatric settings (psychiatric public hospital, psychiatric private rehabilitation clinic, and private practice), have been here described. According to our findings, zolpidem should be prescribed with the same caution as BZDs, especially in patients with a history of drug abuse or in the elderly. Behavioural modifications, including bizarre behaviours, psychomotor agitation, sleep-related complex behaviours have been reported. Monitoring of zolpidem use in selected populations is warranted. Psychiatrists and physicians should be aware of the misuse potential of zolpidem and adopt measures restricting its use.

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

Abstract: 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.

Korean Medication Algorithm for Depressive Disorder 2021, Fourth Revision: An Executive Summary.

Abstract: Objective In the 19 years since the Korean College of Neuropsychopharmacology and the Korean Society for Affective Disorders developed the Korean Medication Algorithm Project for Depressive Disorder (KMAP-DD) in 2002, four revisions have been conducted. Methods To increase survey efficiency in this revision, to cover the general clinical practice, and to compare the results with previous KMAP-DD series, the overall structure of the questionnaire was maintained. The six sections of the questionnaire were as follows: 1) pharmacological treatment strategies for major depressive disorder (MDD) with/without psychotic features; 2) pharmacological treatment strategies for persistent depressive disorder and other depressive disorder subtypes; 3) consensus for treatment-resistant depression; 4) the choice of an antidepressant in the context of safety, adverse effects, and comorbid physical illnesses; 5) treatment strategies for special populations (children/adolescents, elderly, and women); and 6) non-pharmacological biological therapies. Recommended first-, second-, and third-line strategies were derived statistically. Results There has been little change in the four years since KMAP-DD 2017 due to the lack of newly introduced drug or treatment strategies. However, shortened waiting time between the initial and subsequent treatments, increased preference for atypical antipsychotics (AAPs), especially aripiprazole, and combination strategies with AAPs yield an active and somewhat aggressive treatment trend in Korea. Conclusion We expect KMAP-DD to provide clinicians with useful information about the specific strategies and medications appropriate for treating patients with MDD by bridging the gap between clinical real practice and the evidence-based world.

Rapid Symptom Improvement in Major Depressive Disorder Using Accelerated Repetitive Transcranial Magnetic Stimulation

Abstract: Objective Repetitive transcranial magnetic stimulation (rTMS) has contributed to increase in the remission rate for patients with major depressive disorder (MDD). However, current rTMS treatment is practically inconvenient because it requires daily treatment sessions for several weeks. Accelerated rTMS treatment is as efficient and safe for MDD patients as conventional rTMS. Methods Fifty-one patients with MDD participated in this study; they were randomized into accelerated rTMS (n = 21), conventional rTMS (n = 22), and sham-treatment (n = 8) groups. The accelerated and conventional rTMS groups received 15 sessions for 3 days and 3 weeks, respectively. The sham-treatment group received 15 sham rTMS sessions for 3 days. Primary outcome was assessed using self-report and clinician-rated Korean Quick Inventory of Depressive Symptomatology (KQIDS-SR and KQIDS-C, respectively). Adverse effects were monitored using the Frequency, Intensity, and Burden of Side Effects Rating scale. Changes in depressive symptoms were compared among the three groups using mixed model analyses. Results For the KQIDS-SR score, there was a significant main effect of "time" (F3,47 = 11.05, p < 0.001), but no effect of "group" (F2,47 = 2.04, p = 0.142), and a trend-level interaction effect of "group × time" (F6,47 = 2.26, p = 0.053). Improvement in depressive symptoms, based on the KQIDS-SR score 3 weeks after treatment, was more prominent in the accelerated rTMS group than in the sham-treatment group (p = 0.011). Tolerability was comparable among the three groups. Conclusion The accelerated rTMS treatment group showed rapid improvement of depressive symptoms compared with the sham-treatment and conventional rTMS treatment groups. Therefore, accelerated rTMS treatment could be a viable option for MDD, with improved accessibility.

Decreased Cortical Thickness and Local Gyrification in Individuals with Subjective Cognitive Impairment.

Abstract: Objective Subjective cognitive impairment (SCI) is associated with future cognitive decline. This study aimed to compare cortical thickness and local gyrification index (LGI) between individuals with SCI and normal control (NC) subjects. Methods Forty-seven participants (27 SCI and 20 NC) were recruited. All participants underwent brain magnetic resonance imaging scanning and were clinically assessed using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery of tests. We compared cortical thickness and LGI between the two groups and analyzed correlations between cortical thickness/LGI and scores on CERAD protocol subtests in the SCI group for region of interests with significant between-group differences. Results Cortical thickness reduction in the left entorhinal, superior temporal, insular, rostral middle frontal, precentral, superior frontal, and supramarginal regions, and right supramarginal, precentral, insular, postcentral, and posterior cingulate regions was observed in the SCI compared to the NC group. Cortical thickness in these regions correlated with scores of constructional praxis, word list memory, word list recall, constructional recall, trail making test A, and verbal fluency under the CERAD protocol. Significantly decreased gyrification was observed in the left lingual gyrus of the SCI group. In addition, gyrification of this region was positively associated with scores of constructional praxis. Conclusion Our results may provide an additional reference to the notion that SCI may be associated with future cognitive impairment. This study may help clinicians to assess individuals with SCI who may progress to mild cognitive impairment and Alzheimer's dementia.

A Different View on the Etiopathogenesis of Attention-deficit Hyperactivity Disorder from an Inflammation Perspective.

Abstract: Objective Attention-deficit hyperactivity disorder (ADHD) has a complex etiology and genetic, environmental and biological factors are considered to play a role in the etiology of ADHD by mutually interacting. Recent studies have emphasized that inflammation may be present in the etiology of ADHD. This study aims to investigate the possible role of visfatin, IL-6, IL-1b and TNF-α molecules in the etiology of ADHD. Methods The study included 60 patients and 20 healthy controls between the ages of 6-18. Serum visfatin, IL-6, IL-1b and TNF-α levels were evaluated with enzyme-linked immunosorbent assay (ELISA) kits at a biochemistry laboratory. Results The study showed no statistically significant difference between children with ADHD and healthy controls in terms of visfatin, IL-6, IL-1b and TNF-α levels. When ADHD subgroups (combined and predominantly inattentive types) and the control group were compared in terms of visfatin, IL-6, IL-1b and TNF-α levels, no statistically significant difference was recorded. Conclusion Data on the relationship between ADHD and IL-6, IL-1b and TNF-α in this study are in compliance with the literature. However, no study was found on visfatin in ADHD. This study is the first one evaluating the ADHD-Visfatin relationship.

Effect of Haloperidol and Risperidone on Serum Melatonin and GAP-43 in Patients with Schizophrenia: A Prospective Cohort Study

Abstract: Objective Serum melatonin, a biomarker of circadian rhythm, can upregulate Growth-associated protein 43 (GAP-43) which is involved in neural regeneration and plasticity. The present study was conducted to investigate the adequacy of the first-line antipsychotic drugs to improve sleep and circadian rhythm disruptions by assessing the effect of haloperidol and risperidone on serum melatonin and GAP-43 in schizophrenia. Methods In this cohort study, 100 schizophrenic patients were recruited, and clinical evaluations were done using the Positive and Negative Syndrome Scale (PANSS) and the Pittsburgh sleep quality index (PSQI). The patients with predominantly positive symptoms taking haloperidol (Group I) and patients with predominantly negative symptoms taking risperidone (Group II) were admitted and serum melatonin, arylalkylamine N-acetyltransferase, GAP-43 and urinary melatonin were estimated. After 8 weeks, all clinical and biochemical parameters were repeated. Results Serum melatonin (2:00 hours) was significantly decreased in both haloperidol (2.42; 95% confidence interval [95% CI]: 0.67-4.17; p = 0.008) and risperidone group (3.40; 95% CI: 0.54-6.25; p = 0.021). Urinary melatonin was significantly decreased in both haloperidol (p = 0.005) and risperidone group (p = 0.014). PSQI score was significantly increased in both haloperidol (p = 0.001) and risperidone group (p = 0.003). Serum GAP-43 was significantly decreased in both haloperidol and risperidone group (p < 0.001). PANSS decreased significantly in both the groups and there was a significant negative correlation between serum melatonin at 2:00 hours and PANSS (r = -0.5) at baseline. Conclusion Monotherapy with haloperidol and risperidone can achieve symptomatic improvement but cannot improve sleep and circadian rhythm disturbances in schizophrenia.

Challenges in Prescribing Clozapine in the Era of COVID-19: A Review Focused on Immunological Implications

Abstract: The global COVID-19 pandemic has disrupted every aspect of the healthcare system. Apart from the issues surrounding COVID-19 itself, care for existing patients has met many challenges. One such challenge is caring for patients who are on clozapine treatment and have been confirmed positive for COVID-19. Schizophrenia has been considered to have a deep connection with the immune system, and clozapine can induce further changes in this system. COVID-19 can ravage the compromised immune system and aggravate tissue damage. The intricate relations between schizophrenia, clozapine, and COVID-19 make it difficult to predict the clinical course of COVID-19 in clozapine-treated patients. However, the rigid prohibition on using clozapine if COVID-19 is confirmed may harm patients. Patients who have to use clozapine are often refractory cases with no alternatives. Therefore, the decision to maintain or stop clozapine must be made after a comprehensive review of the patient's unique situation. To do this, theoretical and practical issues surrounding the use of clozapine in COVID-19 should be reviewed and discussed. In this review, we gather useful information surrounding this issue and present an overview. Focusing on the immune system, various theoretical possibilities that could arise from schizophrenia, clozapine, and COVID-19 were carefully examined, and practical checklists for the care of these patients were explored. It is hoped that this review will convince many clinicians to pay attention to this momentous issue and facilitate more active sharing of clinical experiences.

Does the Loudness Dependence of Auditory Evoked Potential Predict Response to Selective Serotonin Reuptake Inhibitors?: A Meta-analysis.

Abstract: Objective Loudness of dependence of the auditory evoked potential (LDAEP) is an electroencephalogram-based measure that represents amplitude changes of auditory evoked potentials in primary auditory cortex. Several narrative reviews argued that pre-treatment LDAEP values predict responses to selective serotonin reuptake inhibitors (SSRIs). This study aims to quantify the overall relationship between baseline LDAEP values and treatment response to SSRIs in patients with depression and generalized anxiety disorders, evidenced by clinical symptoms reductions, across multiple studies. Methods In our meta-analysis, seven articles with a total sample of 241 patients were included. Results Our results showed that stronger baseline LDAEP values predicted favorable response to SSRIs for depression and anxiety, with a moderate effect size. Conclusion The current results support the idea that LDAEP is a promising biomarker for SSRIs treatment prediction in patients with depression and generalized anxiety disorder.

Quantitative Resting State Electroencephalography in Patients with Schizophrenia Spectrum Disorders Treated with Strict Monotherapy Using Atypical Antipsychotics.

Abstract: Objective The effect of antipsychotic drugs on quantitative electroencephalography (EEG) has been mainly examined by the administration of a single test dose or among patients using combinations of other psychotropic drugs. We therefore investigated the effects of strict monotherapy with antipsychotic drugs on quantitative EEG among schizophrenia patients. Methods Data from 2,364 medical reports with EEG results from psychiatric patients admitted to the Hokkaido University Hospital were used. We extracted EEG records of patients who were diagnosed with schizophrenia spectrum disorders and who were either undergoing strict antipsychotic monotherapy or were completely free of psychotropic drugs. The spectral power was compared between drug-free patients and patients using antipsychotic drugs. We also performed multiple regression analysis to evaluate the relationship between spectral power and the chlorpromazine equivalent daily dose of antipsychotics in all the patients. Results We included 31 monotherapy and 20 drug-free patients. Compared with drug-free patients, patients receiving antipsychotic drugs demonstrated significant increases in theta, alpha and beta power. When patients taking different types of antipsychotics were compared with drug-free patients, we found no significant change in any spectrum power for the aripiprazole or blonanserin groups. Patients taking risperidone demonstrated significant increases in alpha and beta power. Patients taking clozapine and olanzapine demonstrated significant slow wave increases. Multiple regression analysis revealed that the chlorpromazine equivalent dose was positively associated with theta power. Conclusion Use of any antipsychotic drug by patients was associated with a dose-dependent increase in theta power. However, each type of antipsychotic demonstrated different spectral power changes.

Predictors of Remission in Acute and Continuation Treatment of Depressive Disorders.

Abstract: Objective To identify factors predicting remission of depression during acute (12 weeks) and continuation treatment (12 months) using a 1-year, naturalistic prospective study design. Methods Patients with depressive disorders were recruited from Chonnam National University Hospital in South Korea from March 2012 to April 2017. At baseline, 1,262 patients received outpatient therapy, and sociodemographic and clinical data were obtained. Clinical visits took place every 3 weeks during the acute treatment phase (at 3, 6, 9, and 12 weeks; n = 1,246), and every 3 months during the continuation treatment phase (at 6, 9, and 12 months; n = 1,015). Remission was defined as a Hamilton Depression Rating Scale score ≤ 7. Results The remission rate was 43.3% at 12 weeks and 70.4% at 12 months. In multivariate analyses, remission during the acute treatment phase was more likely in patients with a shorter-duration present episode, higher functioning, and good social support. Remission during the continuation treatment phase was more likely in patients with fewer previous depressive episodes and/or a lower baseline stress score. Conclusion Factors predicting depressive disorder remission may differ between the acute and continuation treatment phases.

Trough Melatonin Levels Differ between Early and Late Phases of Alzheimer Disease.

Abstract: Objective Melatonin has been considered to have an essential role in the pathophysiology of Alzheimer's disease (AD) for its regulatory function on circadian rhythm and interaction with glutamate for the modulation of learning and memory. Previous studies revealed that melatonin levels decreased in patients with AD. However, melatonin supplement didn't show promising efficacy for AD. This study compared trough melatonin levels among elderly people with different severities of cognitive deficits. Methods We enrolled 270 elder individuals (consisting four groups: healthy elderly, amnestic mild cognitive impairment [MCI], mild AD, and moderate-severe AD) in the learning cohort. Trough melatonin levels in plasma were measured using ELISA. Cognitive function was evaluated by Clinical Dementia Rating Scale (CDR) and Mini-Mental State Examination (MMSE). An independent testing cohort, also consisting of four groups, was enrolled for ascertainment. Results In the learning cohort, trough melatonin levels decreased in the MCI group but elevated in the mild and moderate to severe AD groups. Trough melatonin levels were associated with CDR and MMSE in MCI or AD patients significantly. In the testing cohort, the results were similar to those in the learning cohort. Conclusion This study demonstrated that trough melatonin levels in the peripheral blood were decreased in MCI but increased with the severity of AD. The finding supports the trials indicating that melatonin showed efficacy only in MCI but not in AD. Whether trough melatonin level has potential to be a treatment response biomarker for AD, especially its early phase needs further studies.