Young Joon Kwon

Increased levels of plasma brain-derived neurotrophic factor (BDNF) in children with attention deficit-hyperactivity disorder (ADHD)

BACKGROUND Recent reports have suggested a pathophysiological role of brain-derived neurotrophic factor (BDNF) in attention deficit-hyperactivity disorder (ADHD). We evaluated the plasma levels of BDNF in patients with ADHD. METHODS Plasma BDNF levels were measured in 41 drug naive ADHD patients and 107 normal controls. The severity of ADHD symptoms was determined by patient scores on the ADHD rating scale (ARS) and the computerized ADHD diagnostic system (ADS). RESULTS ANCOVA with age and gender as covariates showed that the mean plasma BDNF levels were significantly higher in ADHD patients than in normal controls (F=16.968, p<0.001). There were also significant differences in plasma BDNF levels of ADHD patients and those of normal controls for males and females (Mann-Whitney U-test, p=0.001 and 0.041, respectively). We also found a significant correlation between plasma BDNF levels and omission errors in ADS outcome-variable T-scores (p<0.001). CONCLUSIONS Our study suggests that there is an increase of plasma BDNF levels in untreated ADHD patients, and that plasma BDNF levels had a significant positive correlation with the severity of inattention symptoms. Further studies are required to elucidate the source and role of circulating BDNF in ADHD.

Association between Intracellular Infectious Agents and Schizophrenia.

Objective A number of studies have reported association between Toxoplasma gondii (T. gondii) and Chlamydia infection and the risk of schizophrenia. The aim of the present study was to compare the prevalence of T. gondii and Chlamydia infection between the schizophrenia and normal control subjects and to compare the clinical features between seropositive and seronegative schizophrenia patients. Methods The rate of serum reactivity to T. gondii, Chlamydia trachomatis (C. trachomatis), Chlamydia pneumonia in 96 schizophrenia and 50 control subjects was investigated using enzyme-linked immunosorbent assay and indirect fluorescent antibody technique. The clinical symptoms of the schizophrenia patients were scored with Positive and Negative Syndrome Scale and a comparative analysis was carried out. Results A significant positive association between immunoglobulin G (IgG) antibodies to T. gondii and C. trachomatis in schizophrenia was found, and the odds ratio of schizophrenia associated with IgG antibody was found to be 3.22 and 2.86, respectively. The Toxoplasma-seropositive schizophrenia patient had higher score on the negative subscale N1 and N7 and general psychopathology subscale G13, while C. trachomatis-seropositive schizophrenia patient had higher score on the general psychopathology subscale G10. Conclusion The results from the present study suggest significant association between T. gondii, C. trachomatis infection and schizophrenia. In future, further studies are needed to elucidate the correlation between the two types of infection and schizophrenia.

No Association between Serotonin Receptor 2C-759C/T Polymorphism and Weight Change or Treatment Response to Mirtazapine in Korean Depressive Patients

Objective Activation of one or more serotonin (5-HT) receptors may play a role in mediating the antidepressant effects of serotonergic antidepressants. The serotonin 2C (5HT 2C) receptor is known to be associated with antidepressant action and weight gain. We sought to determine whether the 5-HTR 2C receptor -759C/T polymorphism was associated with weight gain and treatment response to mirtazapine in major depressive disorder (MDD) patients. Methods The 5-HT 2C receptor -759C/T polymorphism was analyzed in 323 MDD patients. All patients were evaluated using the 21-item Hamilton Depression Rating Scale at the beginning of the study and at 1, 2, 4, and 8 weeks of mirtazapine treatment. Results There was no significant difference in the 5-HT 2C receptor -759C/T genotype distribution between responder and non-responder groups. The 5-HT 2C receptor -759C/T polymorphism was not associated with weight change over time after mirtazapine administration. Conclusion The 5-HT 2C receptor -759C/T polymorphism does not appear to be a predictor of treatment response to mirtazapine. This polymorphism was not associated with weight change after 8 weeks of mirtazapine treatment. Further investigation on other polymorphisms of the 5-HT 2C gene is required to determine whether the 5-HT 2C gene influences treatment response and weight change after mirtazapine administration in patients with major depressive disorder.

Efficacy and Tolerability of Generic Mirtazapine (Mirtax) for Major Depressive Disorder: Multicenter, Open-label, Uncontrolled, Prospective Study.

Objective Mirtax is a generic mirtazapine widely used since 2003. We conducted an open-label, uncontrolled 6-week study to evaluate the efficacy and safety of Mirtax for major depressive disorder (MDD). Methods Ninety three MDD patients with the diagnosis of MDD and 17-item Hamilton Depression Rating Scale (HDRS) score ≥14 were recruited. The HDRS, Montgomery-Åsberg Depression Rating Scale (MADRS), and the Clinical Global Impressions-Severity Scale (CGI-S) were administered at baseline, 1, 2, 4 and 6 weeks. Response (≥50% decrease in the HDRS or MADRS score), remission (absolute HDRS score ≤7 or MADRS score ≤10) and CGI-I score ≤2 were also calculated. Adverse event (AE) frequency and severity, weight, blood pressure, and pulse rate were checked to assess safety. Results The starting dosage was 11.5±6.4 mg/day, and the maintenance dosage was 23.1±9.4 mg/day. During 6 weeks, HDRS, MADRS and CGI-S scores decreased from 25.1±5.6 to 11.9±8.6 (mean change −13.1±8.3, p<0.001), from 30.2±6.3 to 13.73±10.40 (mean change −16.5±9.8, p<0.001), and from 5.0±0.8 to 2.5±1.3 (mean change −2.5±1.3, p<0.001), respectively. The percentages of responders, remitters by HDRS and patients with a CGI-I score ≤2 were 64.6%, 35.4% and 52.7%, respectively. Significant decreases in HDRS, MADRS and CGI-S scores were confirmed at week 1. The total rate of AEs was 32.3%; the most frequently reported AEs were sedation (4.3%) and constipation (4.3%). Weight was increased from 58.8±10.6 to 60.3±9.3 kg (mean change 0.7±1.7 kg, p=0.004). Conclusion This study, as the first clinical trial of generic mirtazapine, demonstrated the efficacy and tolerability of Mirtax for MDD using a single treatment design.

F45. THE EFFICACY AND SAFETY OF BLONASERIN AFTER SWITCHING FROM OTHER ATYPICAL ANTIPSYCHOTICS IN SCHIZOPHRENIC INPATIENTS: AN OPEN-LABEL, MULTI-CENTER TRIAL

Abstract Background The aim of this study was to investigate the efficacy and safety of blonanserin treatment after switching from other atypical antipsychotics in schizophrenic inpatients who showed inadequate efficacy and poor tolerability. Methods A total of 63 schizophrenic inpatients (inadequate response group=45 and poor tolerability group=18) were included in this study. They were already treated with atypical antipsychotics except blonanserin and not favored due to inadequate responses or intolerable adverse effects. Blonanserin was administered during 12 weeks after switching from their previous antispsychotics. Treatment response was evaluated with Brief Psychiatric Rating Scale (BPRS) and CGI-S, and safety profile were measured with Abnormal Involuntary Movement Scale (AIMS), Simpson-Angus Extrapyramidal Side effects Scale (SAR)S and Barnes Akathisia Rating Scale (BARS). Drug Attitude Inventory (DAI-10) and Subjective Well-being Under Neuroleptic Treatment (SWN) were used for subjective estimates. Assessments were done at baseline, 1, 2, 4, 8 and 12 weeks after blonanserin treatment. Repeated measures of ANOVA were done to analyze the group (inadequate vs. intolerable group) and time effects. Results CGI and BPRS were showed significant treatment responses after switching to Blonaserin. Time effects were significant at 2, 4, 8, 12 weeks after switching and group by time effect were also significant at that time. Mean changes of AIMS, SARS and BARS scores were not significant throughout test trial. Although SWN was significantly improved after switching to Blonaserin, it was not found significant group by time effect. Discussion The results suggest that blonanserin may be effective and well tolerable in schizophrenic patients who showed inadequate treatment response or poor tolerability.

T219. THE ROLE OF MELATONIN AND MELATONIN AGONISTS IN COUNTERACTING ANTIPSYCHOTIC-INDUCED METABOLIC SIDE EFFECTS: A SYSTEMATIC REVIEW

Abstract Background Melatonin administration to high cholesterol-treated and high fat-treated rats has been shown to suppress body weight and visceral adiposity. In addition, in various animal models related to obesity, metabolic syndrome, and diabetes, melatonin has beneficial efficacy in ameliorating various metabolic symptoms, including attenuating weight gain, lowering blood pressure (BP), and improving insulin resistance. This systematic review aims to investigate whether melatonin or melatonin agonists significantly attenuate metabolic side effects among psychiatric populations treated with atypical antipsychotics. Methods Four randomized controlled trials were identified through a comprehensive literature search using MEDLINE, EMBASE, and the Cochrane Library on 22 October 2015. These four trials (including three melatonin studies and one ramelteon study) included 138 patients, of whom 71 were treated with melatonin or ramelteon and 67 were treated with a placebo. Because of high heterogeneity, we did not carry out a meta analysis. Results Melatonin was beneficial in lowering blood pressure among bipolar disorder patients; this blood pressure-lowering effect was not prominent among schizophrenic patients. Melatonin appeared to improve lipid profiles and body composition and attenuated weight gain among both schizophrenic and bipolar disorder patients. Ramelteon showed a significant efficacy in lowering total cholesterol level. Discussion Despite the few studies included, this systematic review provided promising evidence of the potential benefits of melatonin and its agonists in attenuating one or more components of metabolic syndrome among psychiatric patients using atypical antipsychotics.

S220. BLONANSERIN AUGMENTATION IN PATIENTS WITH SCHIZOPHRENIA – WHO IS BENEFITED FROM BLONANSERIN AUGMENTATION? AN OPEN-LABEL, PROSPECTIVE, MULTI-CENTER STUDY

Abstract Background Evidences for antipsychotic augmentation for schizophrenic patients with sub-optimal efficacy have been lacking although it has been widespread therapeutic strategy in clinical practice. The purpose of this study was to investigate the efficacy and tolerability of blonanserin augmentation with an atypical antipsychotics (AAPs) in schizophrenic patients. Methods A total of 100 patients with schizophrenia partially or completely unresponsive to treatment with an AAP recruited in this 12-week, open-label, non-comparative, multicenter study. Blonanserin was added to existing AAPs which were maintained during the study period. Efficacy was primarily evaluated using Positive and Negative Syndrome Scale (PANSS) at baseline, week 2, 4, 8, and 12. Predictors for PANSS response (≥20% reduction) was investigated. Results The PANSS total score was significantly decreased at 12 weeks after blonanserin augmentation (-21.0 ± 18.1, F=105.849, p<0.001). Response rate on PANSS at week 12 was 51.0%. Premature discontinuation was occurred in 17 patients (17.0%) and 4 patients among them discontinued the study due to adverse events. Nine patients experienced significant weight gain during the study. Response to blonanserin augmentation was associated with severe (PANSS>85) baseline symptom (OR=10.298, p=0.007) and higher dose (>600mg/day of chlorpromazine equivalent dose) of existing AAPs (OR=4.594, p=0.014). Discussion Blonanserin augmentation improved psychiatric symptoms of schizophrenic patients in cases of partial or non-responsive to an AAP treatment with favorable tolerability. Patients with severe symptom despite treatment with higher dose of AAP were benefited from this augmentation. These results suggested that blonanserin augmentation could be an effective strategy for specific patients with schizophrenia.

S7. NEOSENSITIZATION TO MULTIPLE DRUGS FOLLOWING DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS SYNDROME (DRESS)

Abstract Background Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is associated with severe skin eruptions, fever, hematological abnormalities, and multi-organ involvement. Although aromatic anticonvulsant drugs have been frequently associated with the manifestation of DRESS syndrome, its induction following treatment with nonaromatic anticonvulsants, such as valproate, has rarely been reported. Moreover, there are limited data regarding the development of neosensitization related to chemically unrelated drugs following an episode of DRESS syndrome. Methods Here, a case of neosensitization to multiple drugs is described. The present case report describes a female patient who experienced neosensitization to amoxicillin, olanzapine, and quetiapine following the manifestation of DRESS syndrome induced by valproate. Results A 50-year-old woman with a 15-year history of schizophrenia was being treated with lithium (1200 mg) and quetiapine (600 mg) about 1 month, but due to high lithium serum concentrations, the lithium was changed to valproate (600 mg). Seven days later, the patient developed a whole-body skin rash, facial edema, and hyperthermia. Laboratory tests revealed an abnormal white cell count (25.2 × 103 /μL with 6% eosinophils) and aspartate transaminase (AST) and alanine transaminase (ALT) concentrations of 2729 IU/L and 2749IU/L, respectively. At that time, the patient had no any other medical history including drug allergy. A diagnosis of DRESS syndrome due to valproate treatment was established by a consulting dermatologist. As a result, all medicines were discontinued because of severe hepatitis, and intravenous methylprednisolone (60 mg per day) was administered for 1 week. The skin rash, fever, and liver dysfunction progressively disappeared. After discharge, the patient was treated with quetiapine (200 mg). However, she became lost to follow up after 6 months. Approximately 3 years later, the patient was admitted to a local hospital for psychotic symptoms aggravation because she was not taken antipsychotics for 3 years. She treated with lithium (900 mg), sulpiride (600 mg), risperidone (2 mg), and quetiapine (100 mg) for 2 weeks. Additionally, the patient initiated treatment with amoxicillin for acute tonsillitis. On the first day of amoxicillin intake, she developed fever, diffuse erythematous macules on her trunk, and facial edema, and she was transferred to a general hospital via the emergency department. To control her psychotic symptoms she is prescribed olanzapine, haloperidol and quetiapine step by step but all these medications develop fever, skin rash and abnormal AST/ALT. Finally she was given amisulpiride which had not been previously prescribed. Within 2 months, the patient’s psychotic symptoms had gradually decreased and ultimately remitted. Discussion To our knowledge, this is the first case report of neosensitization to multiple drugs after valproate-induced DRESS syndrome. A thorough search of Pubmed was performed to identify similar cases, which confirmed that no cases of hypersensitivity to amoxicillin or neosensitization to multiple drugs after a valproate-related DRESS episode have been reported. Furthermore, only two studies have reported possible neosensitization to amoxicillin following DRESS episodes induced by carbamazepine, and only one case reported neosensitization to amoxicillin following a DRESS episode induced by allopurinol.

F3. A CASE OF LEUKOCYTOSIS ASSOCIATED WITH CLOZAPINE TREATMENT FOR THE MANAGEMENT OF CHRONIC SCHIZOPHRENIA

Abstract Background Clozapine is an atypical antipsychotic drug with therapeutic efficacy through serotonin-dopamine antagonism. It has been used for the management of treatment-resistant schizophrenia and reducing the risk of suicidal behavior. In addition to agranulocytosis and leukopenia, clozapine has also been reported to be associated with other types of blood dyscrasias, including leukocytosis. We wish to report a case of leukocytosis associated with clozapine treatment in a patient of chronic schizophrenia. Methods Our patient is a 48-year-old woman with a diagnosis of schizophrenia since the age of 22. She has a history of numerous hospitalizations and substantial treatment with conservative antipsychotics. We evaluated her medical and psychiatric history as well as mental status. Then We assumed that she might have treatment-resistant schizophrenia and accordingly commenced treatment with clozapine. At the time of admission, her WBC count was 8.01 × 109/L and ANC was 5110. Clozapine was started at 3rd hospital day. We stopped aripiprazole and gradually increased clozapine. Only 2mg of lorazepam was used in combination with clozapine. Remission was achieved with 450 mg/day of clozapine. WBC on the 1st day of treatment was 12.41 × 109/L (ANC; 9481) and clozapine was 300mg/day. WBC on the 18th day of treatment was 15.32 × 109/L (ANC; 12501), and at that time, her clozapine dosage was 450mg/day. At this point, her vital sign was within normal range and physical examination did not showed any infectious signs. On the 25th day of treatment, WBC count was 22.1 × 109/L and ANC was 17680. However, no general medical condition to explain the leukocytosis was found. We concluded that her leukocytosis was linked to clozapine, and decided to taper out clozapine despite there being no medical contraindication. After two weeks from starting blonanserin and olanzapine, WBC count normalized. Fortunately, despite replacing the medication, the remission was maintained. Results In our case, the increase in white blood cell count with increasing dose of clozapine was evident and did not reveal any other medical cause to explain leukocytosis in the patient. In addition, leukocytosis improved significantly after discontinuing clozapine. Also, there have been reports of cases of leukocytosis associated with clozapine treatment, and the mechanism of leukocytosis has been explained to some extent. Considering these temporal associations, mechanisms, and previous cases, it is reasonable to consider leukocytosis associated with clozapine in this case. Discussion This case suggests a temporal relationship between the use of clozapine and leukocytosis. It also shows the rapid resolution of leukocytosis after discontinuation of clozapine. The mechanisms of clozapine-induced leukocytosis may be related to changes in plasmatic concentrations of granulocyte colony-stimulating factor, tumor necrosis factor-α, interleukin (IL)-2 and IL-6 cytokines, which could be stimulated by clozapine. In our case, an increase in WBC count was consistent with an increase in clozapine dose, suggesting a dose-dependent effect. However, the appearance of leukocytosis during clozapine treatment does not mean that clozapine should be discontinued. Nevertheless, the WBC continued to increase steadily, and clinicians inevitably replaced the drugs in consideration of the fact that he was not a general hospital but a psychiatric clinic. In this paper we have reported a patient of chronic schizophrenia who developed leukocytosis during clozapine treatment. It appears that most of clozapine-associated leukocytosis can be benign medical condition. However, clinicians should be aware of the dangers of other blood disorders such as leukocytosis.