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The Committee for Treatment Guidelines of Mood Disorders, Japanese Society of Mood Disorders, published a Japanese guideline for the treatment of late-life depression in 2020. Based on that guideline, the present guideline was developed and revised to incorporate the suggestions of global experts and the latest published evidence. In the diagnosis of late-life depression, it is important to carefully differentiate it from bipolar disorders, depressive states caused by physical and organic brain disease, drug effects, and dementia, and to determine the comorbidity between late-life depression and dementia. It is necessary to fully understand the clinical characteristics and psychosocial background of late-life depression, evaluate the patient's condition, and provide basic interventions based on these factors. Problem-solving therapy, reminiscence therapy/life review therapy, and behavioral activation therapy, and other forms of psychotherapy can reduce depressive symptoms. In terms of pharmacotherapy, newer antidepressants or non-tricyclic antidepressants are recommended for late-life depression, and it is recommended that the efficacy of least the minimal effective dosage should first be determined. Switching antidepressants and aripiprazole augmentation can be used to treatment-resistant therapy. Electroconvulsive therapy and repetitive transcranial magnetic stimulation have demonstrated usefulness for late-life depression. Exercise therapy, high-intensity light therapy, and diet therapy also show some effectiveness and are useful for late-life depression. Continuation therapy should be maintained for at least 1 year after remission.

Objective Mirtazapine and SSRIs are widely prescribed as first-line agents for late-life depression. However, evidence for these drugs is mostly based on non-elderly patients. Therefore, we reanalyzed a randomized controlled trial of mirtazapine versus SSRIs for depression in a sub-population of late-life patients. Methods A randomized controlled trial was conducted with 141 patients, of whom 41 were elderly, and 100 were non-elderly. This study compared SSRIs and mirtazapine in late-life depression, examined late-onset and early adult-onset separately, and compared elderly and non-elderly patients for each drug. Treatment effects and adverse events were assessed using the Hamilton Depression Rating Scale and the Udvalg for Kliniske Undersøgelserside effect rating scale, respectively. Results In late-life depression, mirtazapine showed faster HAM-D total score improvement (3.3 points difference, p=0.021) and higher improvement in insomnia (1.7 points difference, p=0.001) and appetite (1.2 points difference, p=0.020). Similar findings were observed for late-onset depression with the HAM-D total score (4.3 points difference, p=0.007) and appetite (0.9 points difference, p=0.004), favoring mirtazapine. Depressive symptoms were generally less improved in late-life depression than in non-late-life depression. Regarding the effect of mirtazapine on appetite, late-life depression showed greater improvement (0.7 points difference, p=0.008). Nausea and micturition disturbances were more common with SSRIs in late-life depression than in non-late-lifedepression. In contrast, somnolence was less common in late-life depression with mirtazapine. Conclusion The potential usefulness of mirtazapine in elderly patients was demonstrated. The results also showed differences in the treatment response to SSRIs and mirtazapine between elderly and non-elderly patients.

Objectives The aim of this study was to develop a consensus guideline by certified experts of the Japanese Society of Clinical Neuropsychopharmacology on the psychopharmacological treatment for bipolar disorders I and II (BP‐I and BP‐II), in order to fill the gap in the literature and provide more concrete guidance for challenging and controversial real‐world situations. Methods Experts were asked to assess treatment options regarding 19 clinical situations of bipolar disorder with a nine‐point Likert scale (one = “disagree” and nine = “agree”). According to the responses from 119 experts, the options were categorized into the first‐, second‐, and third‐line treatments. Results For the treatment of BP‐I, lithium monotherapy was categorized as a first‐line treatment for manic episodes (mean ± standard deviation score, 7.0 ± 2.2), depressive episodes (7.1 ± 2.0), and the maintenance phase (7.8 ± 1.8). Combination therapy of lithium and an atypical antipsychotic was endorsed for manic episodes (7.7 ± 1.7), depressive episodes with (7.1 ± 2.0) and without mixed features (6.9 ± 2.2), and the maintenance phase (6.9 ± 2.1). Similarly, in BP‐II, lithium monotherapy was categorized as a first‐line treatment for hypomanic episodes (7.3 ± 2.2), depressive episodes (7.0 ± 2.2), and the maintenance phase (7.3 ± 2.3), while combination therapy of lithium and an atypical antipsychotic was recommended for hypomanic episodes (6.9 ± 2.4).No antipsychotic monotherapy or antidepressant treatment was categorized as a first‐line treatment for any type of episode. Conclusions These recommendations reflect the current evidence and represent the experts' consensus on using lithium for the treatment of bipolar disorder. Clinicians should consider the effectiveness and adverse effects of antipsychotic and antidepressant medications for the treatment of bipolar disorder.

Depression is known to be a risk factor for Alzheimer's disease (AD). Changes in amyloid β protein (Aβ) metabolism have been speculated as a factor contributing to the transition from depression to AD. The aim of this study is to reveal the time course and state-dependency of Aβ metabolism.Serum Aβ levels in 277 elderly (≥60 years) patients with depression (both early- and late-onset) were measured at admission, immediately after remission, and 1 year after remission, and compared them with 178 healthy subjects.The analysis revealed decreased Aβ42 levels and increased Aβ42/40 ratios in elderly patients with depression at admission compared with healthy subjects. These changes in the acute phase of depression were not normalized immediately after remission; however, they recovered to healthy levels 1 year after remission.There is a possibility that the results may be influenced by antidepressants.These results suggest that altered Aβ metabolism caused by depression may ameliorate, although after a lengthy period of time after remission. Our findings also suggest that the AD-related pathological changes caused or increased by depression can be reduced by maintaining remission for an extended period of time.

Background Possession of the e4 allele of apolipoprotein E (APOE4) is related to the incidence of depression in old age. We investigated whether the presence of APOE4 is also associated with subsequent depression recurrence in a wide range of age groups. Methods Altogether, 163 patients with major depressive disorder (MDD) after remission were recruited between August 2004 and March 2016 and followed up prospectively. The patients were divided into two groups: APOE4 carriers and non-carriers. We compared the time to recurrence of depression between the two groups. Kaplan–Meier survival curves, log-rank test for trend for survivor functions, and Cox proportional hazard ratio estimates for a multivariate model were conducted to examine the effect of the APOE4 allele on risk of a depression recurrence. Results Cumulative probability of developing a depression recurrence was higher in APOE4 carriers than non-carriers. Presence of an APOE4 allele remained significantly associated with the incidence of depression recurrence. Limitations All patients were treated with one or two different antidepressants, which may have had different effects on patients with MDD. Second, participants in the present study comprised patients with both first and multiple episodes of MDD. Third, we did not have the statistical power to perform a stratified analysis in consideration of heterozygous or homozygous genotypes of APOE4. Conclusion Possession of an APOE4 allele may increase the risk of depression recurrence.

Introduction Conventional treatment guidelines of schizophrenia do not necessarily provide solutions on clinically important issues. Methods A total of 141 certified psychiatrists of the Japanese Society of Clinical Neuropsychopharmacology evaluated treatment options regarding 19 clinically relevant situations in the treatment of schizophrenia with a 9-point scale (1=“disagree” and 9=“agree”). Results First-line antipsychotics varied depending on predominant symptoms: risperidone (mean±standard deviation score, 7.9±1.4), olanzapine (7.5±1.6), and aripiprazole (6.9±1.9) were more likely selected for positive symptoms; aripiprazole (7.6±1.6) for negative symptoms; aripiprazole (7.3±1.9), olanzapine (7.2±1.9), and quetiapine (6.9±1.9) for depression and anxiety; and olanzapine (7.9±1.5) and risperidone (7.5±1.5) for excitement and aggression. While only aripiprazole was categorized as a first-line treatment for relapse prevention (7.6±1.0) in patients without noticeable symptoms, aripiprazole (8.0±1.6) and brexpiprazole (6.9±2.3) were categorized as such for social integration. First-line treatments in patients who are vulnerable to extrapyramidal symptoms include quetiapine (7.5±2.0) and aripiprazole (6.9±2.1). Discussion These clinical recommendations represent the expert consensus on the use of a particular antipsychotic medication for a particular situation, filling a current gap in the literature.

Epidemiological studies have demonstrated that depression may be a risk factor for Alzheimer's disease (AD); however, the biological mechanisms of the transition from depression to AD are still not clear. Changes of amyloid β protein (Aβ) metabolism and increased glucocorticoid (GC) levels have been found in both depression and AD. Moreover, several studies in animal models have demonstrated that GC administration changes Aβ metabolism. To reveal whether GC affects amyloid metabolism in patients with depression, we evaluated serum levels of Aβ40, Aβ42 and cortisol at admission in 187 inpatients with major depressive disorder (MDD) and 224 healthy comparisons. Additionally, we re-evaluated the serum levels of Aβs in 27 patients with MDD 1 year later. The results of multiple regression analyses revealed that serum cortisol and Aβ levels are not correlated at the time of admission. However, serum cortisol levels at admission correlated with serum Aβ42 levels and Aβ40/Aβ42 ratio 1 year later. These findings suggest that increased cortisol in patients with MDD may influence the metabolism of Aβ over prolonged periods of time.

Background : Clinically relevant issues in the real-world treatment of depression have not always been captured by conventional treatment guidelines. Methods : Certified psychiatrists of the Japanese Society of Clinical Neuropsychopharmacology were asked to evaluate treatment options regarding 23 clinical situations in the treatment of depression using a 9-point Likert scale (1=“disagree” and 9=“agree”). According to the responses of 114 experts, the options were categorized into first-, second-, and third-line treatments. Results : First-line antidepressants varied depending on predominant symptoms: escitalopram (mean ± standard deviation score, 7.8±1.7) and sertraline (7.3±1.7) were likely selected for anxiety; duloxetine (7.6±1.9) and venlafaxine (7.2±2.1) for loss of interest; mirtazapine for insomnia (8.2±1.6), loss of appetite (7.9±1.9), agitation and severe irritation (7.4±2.0), and suicidal ideation (7.5±1.9). While first-line treatment was switched to either an SNRI (7.7±1.9) or mirtazapine (7.4±2.0) in the case of non-response to an SSRI, switching to mirtazapine (7.1±2.2) was recommended in the case of non-response to an SNRI, and vice versa (switching to an SNRI (7.0±2.0) in the case of non-response to mirtazapine). Augmentation with aripiprazole was considered the first-line treatment for partial response to an SSRI (7.1±2.3) or SNRI (7.0±2.5). Limitations : The evidence level of expert consensus is considered low. All included experts were Japanese. Conclusions : Recommendations made by experts in the field are useful and can supplement guidelines and informed decision making in real-world clinical practice. We suggest that pharmacological strategies for depression be flexible and that each patient's situational needs as well as the pharmacotherapeutic profile of medications be considered.

Aim Epidemiological studies have shown that depression is a risk factor for Alzheimer's disease (AD). Although the biological mechanism underlying the link between depression and AD is unclear, altered amyloid β (Aβ) metabolism in patients with depression has been suggested as a potential mechanism. Results from previous studies of Aβ metabolism in patients with depression have been inconsistent, and Aβ polymerization, which is a crucial process in AD pathology, has not previously been assessed. Methods Serum levels of Aβ40, Aβ42 and Aβ oligomers were evaluated in 104 inpatients with major depressive disorder (MDD) and 132 healthy control individuals. Results Lower serum Aβ42 levels were observed in patients with MDD, but there was no difference in serum Aβ oligomer levels between the MDD group and the healthy control group, even in older adults. Interestingly, serum Aβ oligomer levels in patients with MDD were dependent on serum Aβ42 levels, regardless of age, and this relationship was not observed in the control group. Conclusions These results suggest that Aβ42 is more prone to aggregation and polymerization in patients with depression than in healthy individuals, suggesting a possible mechanism underlying the transition from depression to AD. Geriatr Gerontol Int 2020; 20: 125-129.

Background Recent reports have suggested a relationship between affective disorder including depression and bipolar disorder (BP) and frontotemporal dementia (FTD). TAR DNA binding protein (TDP) -43 is a protein found in the brain and peripheral fluid of patients with FTD. To examine a possible association between affective disorders and FTD, serum levels of TDP-43 were evaluated in late-life patients with major depressive episode (MDE). Methods The subjects were 74 late-life (≥50 years old) inpatients with DSM-IV or -5 MDE (58 had major depressive disorders and 16 had BP) and 58 healthy subjects. Patients were recruited from Juntendo Koshigaya Hospital, Saitama, Japan, between January 2005 and May 2017. Serum TDP-43 levels were measured using an ELISA kit. Results Serum levels of TDP-43 were significantly higher in the MDE group than the control group independent of age and sex. Limitations All patients were on antidepressant medication. Conclusions Our finding suggests that some depressive patients may be in a prodromal stage of FTD or very-early stage of FTD comorbid with depression.

Apathy and depression are frequently observed in neurological disorders including dementia. Because the symptoms of both these states overlap and apathy is commonly comorbid with depression, the discrimination of these states can be challenging. A method to clinically distinguish between these states may be to focus on the primary motivation underlying mood, emotion, motivation, activity and interests, rather than focusing on the patients' complaints about the 'lack of motivation'.

Aim To evaluate the safety, tolerability and pharmacokinetic profile of bapineuzumab after a single intravenous injection in Japanese patients with mild to moderate Alzheimer's disease. Methods Participants received either a placebo (n = 8), or bapineuzumab 0.15 (n = 6), 0.5 (n = 6), 1.0 (n = 6) or 2.0 (n = 6) mg/kg. Serum concentrations of bapineuzumab, antibapineuzumab antibody and total plasma β-amyloidx-40 were assayed. Results Adverse events for bapineuzumab and placebo groups were 71% and 88%, respectively. Treatment-emergent adverse events (cataract, injection site hemorrhage, nasopharyngitis, pneumonia and muscle twitching) reported for ≥2 participants were mild or moderate in severity and unrelated to bapineuzumab dose. No deaths, serious adverse events or withdrawals were reported. Mean peak concentration for bapineuzumab increased with dose, from 3.3 ± 0.9 μg/mL with the 0.15 mg/kg dose to 61.0 ± 32.8 μg/mL with 2.0 mg/kg. Mean bapineuzumab exposure (area under the curve from time 0 to last measurable concentration; μg·h/mL) increased in a linear manner with increasing dose (mean 1260 for 0.15 mg/kg, 4264 for 0.5 mg/kg, 7818 for 1.0 mg/kg, 15 313 for 2.0 mg/kg). Mean half-life ranged from 15 to 28 days, and clearance was similar across dose groups (range 0.12–0.17 mL/h/kg). Conclusions Plasma β-amyloidx-40 levels increased with increasing doses of bapineuzumab. Bapineuzumab was safe and well tolerated at all doses in Japanese patients with mild to moderate Alzheimer's disease. Geriatr Gerontol Int 2016; 16: 644–650.

The aim of the present study was to examine whether the specific personality traits, Harm-Avoidance (HA) and Self-Directedness (SD) as measured by the Temperament and Character Inventory (TCI), were predictive for subsequent depressive episodes in remitted patients with major depressive disorders (MDDs) over a 4-year follow-up. A total of 109 inpatients with MDD participated in this study. The subjects completed the TCI when they were assessed to be in remission. They were divided into high or low HA groups and high or low SD groups, as discriminated by the quartile value. A total of 69 patients were followed-up over a 4-year period or until recurrence. Both Kaplan-Meier analysis and Cox׳s proportional hazards regression analysis indicated that patients with a low SD score had a significantly shorter time to recurrence from remission than patients with a high SD score even when some prognostic predictors were controlled for. In contrast, HA was not found to be a predictor of recurrence for future depressive episodes. A part of MDD patients with low scores in Self-Directedness are likely to develop depression over a subsequent period of time. Interventions that improve SD may help to delay recurrence of depression in MDD patients.

Background: Previously, we compared the hyperthymic scores of residents in Sapporo, Koshigaya, and Oita (which are located at latitudes of 43 degrees N, 36 degrees N, and 33 degrees N in Japan, respectively) using the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-auto questionnaire version (TEMPS-A). We found that residents who lived at lower latitudes had higher hyperthymic temperament scores; however, the mechanism of the effect of latitude on hyperthymic temperament remained unclear. The current study examined the mediators of the latitude effect in additional regions with different annual temperatures and amounts of ambient sunshine. Methods: The Japanese archipelago stretches over 4000 km from north to south and has four large islands: Hokkaido, Honshu, Shikoku, and Kyushu. In addition to the TEMPS-A previously reported data collected at Sapporo (latitude 43 degrees N), Koshigaya (36 degrees N), and Oita (33 degrees N), we collected the TEMPS-A data of 189 and 106 residents from Takaoka (36 degrees N) and Obihiro (42 degrees N), respectively. Taken together, these five regions have different patterns (i.e., highs and lows) of annual ambient total sunshine (hours) and mean temperature (degrees C). The effect of latitude, sunshine, and temperature on affective temperaments was analyzed for five Japanese regions. Results: Multiple regression analyses revealed that latitude predicted significant variance in hyperthymic temperament. Ambient temperature, but not sunshine, significantly affected hyperthymic temperament. Limitations: The light exposure that residents actually received was not measured. The number of regions studied was limited. The findings might not generalize to residents across Japan or other countries. Conclusions: The present findings suggest that latitude affects hyperthymic temperament, and ambient temperature might mediate this effect. (C) 2014 Elsevier B.V. All rights reserved

Background The relationship between psychomotor agitation in unipolar depression and mood-switching from depression to manic, hypomanic and mixed states has been controversial. We investigated the future risk of initial mood-switching as a function of psychomotor agitation in unipolar depression. Methods We identified 189 participants diagnosed with major depressive disorder (MDD). We divided all patients with MDD into two categories (1) agitated patients ( n =74), and (2) non-agitated patients ( n =115). These groups were prospectively followed and compared by time to mood-switching. Kaplan–Meier survival curves, log-rank test for trend for survivor functions, and Cox proportional hazard ratio estimates for a multivariate model were conducted to examine the risk of mood-switching by psychomotor agitation. Results During follow-up, mood-switching occurred in 20.3% of the agitated patients and 7.0% of the non-agitated patients. In the Kaplan–Meier survival estimates for time to incidence of mood-switching with agitated or non-agitated patients, the cumulative probability of developing mood-switching for agitated patients was higher than those for non-agitated patients (log-rank test: χ 2 =7.148, df=1, p =0.008). Survival analysis was also performed using Cox proportional hazards regression within a multivariate model. The agitation remained significantly associated with incidence of mood-switching (HR=2.98, 95% CI: 1.18–7.51). Limitations We did not make a clear distinction between antidepressant-induced mood-switching and spontaneous switching. Conclusions The main finding demonstrated that MDD patients with agitation were nearly threefold as likely to experience mood-switching, suggesting that psychomotor agitation in MDD may be related to an indicator of bipolarity.

The service presented in this paper searches two digital archives of handwritten character pattern images on Japanese historical documents. Any binary character pattern image consisting of black character shapes and white background becomes a search key. The system owns a web-based user-interface, dictionaries of character shape feature vectors extracted from the archives, and character shape similarity evaluation modules, and runs independently from metadata formats of the archives. The service displays a list of similar character pattern image for each of the archives. The images in the lists link to the archives that provide more information of the character patterns. We present the technical details and improvements of the service. Since character shapes on historical documents contain noises, we have employed a noise absorber process for the shape evaluation. The service has received more than 30,000 search requests for a month since it was introduced to the public. For each key, processing time of the shape evaluation is less than one second, and other processes including security checking need another several seconds. As an improvement, we have updated the user-interface for better usability of smartphones. Also, we have created and distributed an application for smartphones to support creating the binary image keys. Users of about 2,900 Apple IDs had downloaded the application. We introduce the latest version of the application that we will soon distribute at the Apple App Store. Evaluating the service and analyzing the search requests are our future tasks.

Background The Japanese archipelago stretches over 4000 km from north to south and has four large islands: Hokkaido, Honshu, Shikoku, and Kyushu. Previously, using the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-auto questionnaire version (TEMPS-A), we compared the hyperthymic scores of residents in Sapporo, Obihiro, Takaoka, Koshigaya, and Oita cities (which are located at latitudes of 43°N, 42°N, 36°N, 36°N and 33°N with various combinations of ambient temperament and sunshine in Japan, respectively). We found that latitude predicted significant variance in hyperthymic temperament, and that ambient temperature, but not sunshine, significantly affected hyperthymic temperament scores. However, the analysis failed to consider the effects of naturally occurring low-dose lithium on temperament. Methods In addition to the TEMPS-A data previously collected, we measured lithium levels of the five cities. The effect of temperature, sunshine, and lithium levels on hyperthymic temperament was analyzed for the five cities. Results A stepwise multiple regression analysis revealed that lithium levels as well as latitude, but not temperature or sunshine, predicted significant variance in hyperthymic temperament scores. Hyperthymic temperament scores were significantly and positively associated with lithium levels whereas they were significantly and negatively associated with latitude. Limitations The light, temperature, lithium exposure that residents actually received was not measured. The number of regions studied was limited. The findings might not be generalized to residents across Japan or other countries. Conclusions The present findings suggest that lithium in drinking water may positively maintain hyperthymic temperament, and that latitude may negatively maintain it.

Patients with major depressive disorder (MDD) are known to present with cognitive deficits; however, the presence of these deficits in the remitted state have been inconsistent. One of the most important factors potentially contributing to inconsistencies between studies may be the influence of medications. To explore the influence of antidepressants on cognitive performance in remitted MDD, we evaluated memory and executive functions using Wechsler Memory Scale-Revised and Stroop Color and Word Test, and compared performance among 50 medicated (29 treated with tricyclic antidepressants [TCA], 21 treated with selective serotonin reuptake inhibitors or serotonin noradrenalin reuptake inhibitors) and 19 medication-free MDD patients and 31 controls. The results showed that all 3 MDD groups had significantly lower performance for verbal memory compared with controls. Both medicated groups showed significantly lower performance for visual memory compared with controls; however, the medication-free group did not differ from controls. For the executive function, only the TCA group showed a significantly lower performance compared with controls. These results suggest that cognitive impairment remained even in remitted patients with MDD, however, part of this impairment may be influenced by class-specific antidepressant side effects.

Previous studies have demonstrated that patients with depression also have memory dysfunctions during depressive episodes. These dysfunctions partially remain immediately after remission from a depressive state; however, it is unclear whether these residual memory dysfunctions may disappear through long-term remission from depression. The present study compared patients during early-life (age60) and late-life (age ≥ 60) depression while in their remitted stage with healthy controls to elucidate the impact of a long-term course on memory.Logical memory from the Wechsler Memory Scale-Revised was administered to 67 patients with major depressive disorder (MDD) (47 patients with early-life depression and residual 20 patients with late-life depression) and 50 healthy controls. MDD patients received memory assessments at the time of their initial remission and at a follow-up three years after remission.At the time of initial remission, scores for logical memory were significantly lower in both patient groups compared to matched controls. At follow-up, memory dysfunction for early-life MDD patients disappeared, whereas scores in the late-life MDD group remained significantly lower than those of matched controls.All patients in the present study were on antidepressant medications.Our findings suggested that the progress of memory performance in late-life MDD patients may be different from early-life MDD patients.

Objective: Testosterone may have a role distinct from cortisol in the pathophysiology of depression. The hypothalamus-pituitary-adrenal (HPA) axis affects the functions of sex steroid hormones through interaction with corticotropin-releasing hormone (CRH) and gonadotropin-releasing hormone (GnRH). The objective of this study was to investigate differences in serum levels of testosterone and cortisol in male and female patients with major depressive disorder (MDD). Methods: Participants included 87 inpatients with MDD at Juntendo University Koshigaya Hospital. Serum levels of testosterone and cortisol were assessed at admission. Matched controls included 128 healthy individuals. Data from MDD patients and controls were compared separately for men and women. Correlations between serum hormone levels and scores on the Hamilton Rating Scale for Depression (HAM-D) of patients were assessed by sex. Effects of various factors on testosterone and cortisol were analyzed using multiple regression analysis. Results: In male patients with MDD, a significant negative correlation was seen between testosterone levels and the “retardation” score of HAM-D. However, serum testosterone levels were not significantly different in either male or female MDD patients compared with controls. Serum testosterone was negatively associated with the number of depressive episodes in male patients with MDD. Serum cortisol levels in female patients were significantly increased compared with female controls with no significant correlations between cortisol levels and HAM-D scores. Conclusions: The negative correlation between the sub-score of the HAM-D and testosterone may be associated with the biological pathophysiology of male depression. Findings of serum cortisol levels in women may suggest distinct characteristics of these hormones in men and women with MDD.

Background There is accumulating evidence regarding gender differences in clinical symptoms or response to antidepressants in patients with depression. However, less attention has been given to sex differences in the underlying biological mechanisms of depression. The adrenal androgens, dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEA-S), play a critical role in controlling affect, mood, and anxiety. Changes in serum adrenal androgen levels have been reported in conditions pertaining to stress as well as in psychiatric disorders. The objective of the present study was to investigate differences in serum levels of adrenal androgens in male and female patients with major depressive disorder (MDD). Methods Participants included 90 inpatients with MDD at the psychiatric ward of Juntendo University Koshigaya Hospital who were receiving antidepressants. Serum levels of DHEA and DHEA-S were assessed at the time of admission. Matched controls (based on sex and age) included 128 healthy individuals. First, data from male and female MDD patients and controls were compared. Second, correlations between serum hormone levels and scores on the Hamilton Rating Scale for Depression (HAM-D) of patients with MDD were assessed by gender. In addition, effects of various factors on adrenal androgens were analyzed using multiple regression analysis. Results Serum DHEA levels were significantly increased in both male and female MDD patients compared with controls. Serum levels of DHEA-S in male patients were significantly decreased compared with male controls, whereas no significant differences were seen in female patients and controls. No significant correlations among adrenal androgens were observed in male patients with MDD, whereas significant positive correlations were found in both male and female controls. No significant correlations were seen between adrenal androgens and HAM-D scores in male or female patients. Multiple regression analysis showed that both hormones were affected by the age at onset of depression. Limitations All subjects in the present study were on antidepressant medications. Conclusions Elevated levels of serum DHEA may be associated with the biological pathophysiology of depression, as DHEA administration has been found to be effective for the treatment of depression. Findings of differential changes in DHEA-S levels in men compared with women may suggest distinct characteristics of these hormones between men and women with depression. However, DHEA/DHEA-S may be a poor indicator for evaluating severity of depression.

Epidemiological studies have demonstrated that suffering from depression and bipolar disorder may be risk factors for developing dementia. A mechanism of interactions of several factors, such as vascular disease and glucocorticoid, has been speculated to play a role in the development of dementia. It is suggested that the onset of dementia can be prevented or delayed by preventing the onset and recurrence of depression and bipolar disorder. In the prevent of depression, the management of daily life, such as diet and exercise, is important. Recently, the possibility of preventive effects of antidepressants and lithium on developing dementia has been suggested, and a future intervention study is expected.

Background Brain-derived neurotrophic factor (BDNF) may have an important role in the pathophysiology of depression. Previous studies indicate that serum BDNF levels were lower in patients with depression and increased after treatment with antidepressants. However, results of studies on serum BDNF levels in remitted patients with depression have been inconsistent. The purpose of the present study was to determine which factors influence the alteration of serum BDNF levels in depression in the remitted state. Methods Serum BDNF levels were evaluated in 75 remitted inpatients with major depressive disorder (MDD) and 108 controls. Multiple regression analyses were conducted using serum BDNF levels as the dependent variable; and the number of episodes, Hamilton Rating Scale for Depression score at admission, or duration of last depressive episode as independent variables. Results Serum BDNF levels were lower in remitted patients with MDD than in controls (P < .001). Multiple regression analysis showed a significant effect between the duration of the last depressive episode and serum BDNF levels (P < .022). Conclusions Serum BDNF levels in remitted patients with MDD did not recover to the level of healthy controls, and lower serum BDNF levels were influenced by a longer duration of last depressive episode. It is possible that persistent hippocampal reduction in remitted depression may be caused by lower BDNF levels associated with a longer duration of the last depressive episode.

Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family and plays a critical role in growth, differentiation, maintenance and synaptic plasticity of neuronal systems. Previous studies have demonstrated lower serum BDNF concentrations in major depressive disorder (MDD), with concentrations negatively correlating with the severity of the disease. However, few investigations have examined the relationship between serum BDNF and detailed clinical symptoms. The aim of present study was to clarify the magnitudes of the relationships between various depressive symptom and serum BDNF.Serum BDNF concentrations were evaluated from 109 inpatients with MDD and 163 healthy controls. Depressive symptoms were assessed using the Hamilton rating scale for depression (HAM-D), and symptoms were categorized into four groups: "anxiety somatization"; "cognitive disturbance"; "retardation"; and "sleep disturbance".Serum BDNF concentration was significantly lower in patients with MDD compared to controls (p0.001). We identified significant negative correlations between serum BDNF concentration and both total score (R=-0.19, p=0.044) and "anxiety somatization" sub-score (R=-0.32, p=0.001) from the HAM-D in patients with MDD.All patients in the present study were on antidepressant medications.These results suggest that serum BDNF level may offer a biological marker for anxiety symptoms in medicated patients with MDD.

Disrupted glutamatergic neurotransmission may be a pathophysiological feature in the brains from patients with schizophrenia, and glutamatergic amino acids including D-serine have been found to be involved in pathophysiology. Endogenous and exogenous D-serine have shown potential as biological markers for the pathophysiology of schizophrenia and especially as a therapeutic strategy in treatment-resistant schizophrenia (TRS). This is the first study investigating whether SLC7A10, a d-serine transporter gene, is associated with schizophrenia in Japanese patients. We investigated the association between schizophrenia in Japanese patients with SLC7A10 using six tag single nucleotide polymorphisms (SNPs). Results failed to show any association between Japanese schizophrenia and each individual SNP or with two-, three-, or four-window haplotype analyses. We also investigated whether SLC7A10 contributes to TRS in Japanese participants. Results showed no association. In conclusion, SLC7A10 had no apparent degree of association with schizophrenia as a candidate susceptibility gene in the disease per se.

OBJECTIVE Epidemiologic studies have demonstrated that a history of depression increases the risk of developing Alzheimer's disease, particularly among individuals with early-onset depression. On the other hand, recent studies have suggested that a higher amyloid-β protein (Aβ)40 to Aβ42 ratio may be associated with the future onset of Alzheimer's disease. Our objective was to assess whether the pathophysiology of early-onset depression may involve or affect Aβ metabolism. METHOD In this extension of a case-control pilot study, 193 inpatients with DSM-IV major depressive disorder (MDD) (mean age = 55.9 years) from the Juntendo Koshigaya Hospital, Saitama, Japan, and 413 healthy controls from the community (mean age = 56.6 years) were recruited between May 2004 and April 2009. Serum Aβ40 and Aβ42 levels, Aβ40/Aβ42 ratio, and other clinical and biological factors were compared between controls and patients in 3 age groups: young (< 40 years), middle-aged (≥ 40 to < 65 years), and elderly (≥ 65 years). Depressive symptoms were assessed with the Hamilton Depression Rating Scale. All patients were receiving antidepressant medication at the time of the study, and doses of current antidepressants were converted to an equivalent imipramine dose. RESULTS The serum Aβ40/Aβ42 ratio was significantly higher in MDD patients than controls in all age groups (young: P = .003; middle-aged: P < .001; elderly: P = .006). These differences were also observed in noncarriers of the apolipoprotein E e4 allele. CONCLUSIONS Our findings suggest that Aβ metabolism may be affected in depression; these findings also possibly answer the question of why even early-onset depression is a risk factor for developing Alzheimer's disease.

Background: Previous papers have reported that clusterin (CLU, also called apolipoprotein J) maintains amyloid β-peptide (Aβ) solubility and protects against Aβ neurotoxicity. Recently, two large genome-wide association studies (GWAS) identified that a specific single nucleotide polymorphism (SNP) on the gene has been reported to modify the risk for Alzheimer's disease (AD). The present study aimed to investigate whether common single nucleotide polymorphisms (SNP) of the CLU gene are associated with AD. Methods: Six SNP, genotyped using TaqMan technology, were analyzed using a case–control study design. Furthermore, an analysis of the cases divided according to apolipoprotein E (APO E) status was also carried out. Our case–control dataset consisted of 180 AD patients and 130 age-matched controls. Results: The present study failed to detect any association between the SNP of the CLU gene and AD. Although rs7982 and rs1532277 showed marginal association in the APO E4 negative group, the linkage disequilibrium analysis results suggest this to be a false positive. Conclusion: The negative associations were mainly the result of our small sample size. Larger genetic studies in different ethnics and future meta-analysis are needed to clarify the relationship between the CLU gene and AD.

Aims: Schizophrenia is a major psychiatric disorder with complex genetic, environmental, and psychological causes, and oxidative stress may be involved in the pathogenesis of the disease. Glutathione (GSH), one of the main cellular non-protein antioxidants and redox regulators, and altered GSH levels have been reported in various regions in patients with schizophrenia. Three enzymes are responsible for GSH synthesis: glutamate cysteine ligase modifier (GCLM), glutamate cysteine ligase catalytic subunit (GCLC), and glutathione synthetase (GSS). Previously, positive associations between GCLM and schizophrenia were reported in Europeans, but not in the Japanese population. Thus, in this study, we investigated the association between the GSH synthesis genes (GCLM, GCLC, and GSS) and schizophrenia in Japanese individuals. Methods: Seventeen single-nucleotide polymorphisms (SNP) in GCLM, GCLC, and GSS were genotyped in 358 patients with schizophrenia and in 359 controls. Results: No SNP showed a significant association between their allelic or genotypic frequencies and schizophrenia. Case–control haplotype association analysis using windows of two or three SNP showed no significant associations with schizophrenia. The case–control haplotype analyses based on the ascertained linkage disequilibrium blocks also showed no significant associations in any genes with schizophrenia. Conclusions: The three primary GSH synthesis genes do not have an apparent degree of association with schizophrenia in the Japanese population.

The authors aimed to investigate whether remitted adult and elderly major depressive disorder patients show different patterns of executive dysfunction. Executive functions of 20 euthymic major depressive disorder patients and 29 healthy comparison subjects were evaluated using the Behavioral Assessment of the Dysexecutive Syndrome. Relative to adult patients and healthy comparison subjects, euthymic elderly patients were more impaired in the subtest of Modified Six Elements. Since the regions most implicated in this subtest are the medial prefrontal, the anterior cingulate, and the dorsolateral prefrontal areas, the authors conclude that dysfunctions of such frontal neural networks remain unresolved even in the remission phase of late-life depression.

We systematically surveyed period variations of superhumps in SU UMa-type dwarf novae based on newly obtained data and past publications. In many systems, the evolution of superhump period are found to be composed of three distinct stages: early evolutionary stage with a longer superhump period, middle stage with systematically varying periods, final stage with a shorter, stable superhump period. During the middle stage, many systems with superhump periods less than 0.08 d show positive period derivatives. Contrary to the earlier claim, we found no clear evidence for variation of period derivatives between superoutburst of the same object. We present an interpretation that the lengthening of the superhump period is a result of outward propagation of the eccentricity wave and is limited by the radius near the tidal truncation. We interpret that late stage superhumps are rejuvenized excitation of 3:1 resonance when the superhumps in the outer disk is effectively quenched. Many of WZ Sge-type dwarf novae showed long-enduring superhumps during the post-superoutburst stage having periods longer than those during the main superoutburst. The period derivatives in WZ Sge-type dwarf novae are found to be strongly correlated with the fractional superhump excess, or consequently, mass ratio. WZ Sge-type dwarf novae with a long-lasting rebrightening or with multiple rebrightenings tend to have smaller period derivatives and are excellent candidate for the systems around or after the period minimum of evolution of cataclysmic variables (abridged)., Comment: 239 pages, 225 figures, PASJ accepted

Glutamatergic dysfunction may be a pathophysiological feature in the brains of schizophrenic patients. In addition to glutamate receptors, excitatory amino acid transporters (EAATs) have received much attention because they directly affect glutamatergic neurotransmission by excluding excessive glutamate from the synaptic cleft. Among these, EAAT2 (also known as solute carrier family 1, member 2; SLC1A2 ) has been widely studied in schizophrenia pathophysiology. During the last decade, we reported significant decreases in EAAT2 mRNA expression in the prefrontal cortex and parahippocampal gyrus in postmortem schizophrenic brains. Previously, a haplotype association between SLC1A2 and Japanese patients with schizophrenia was reported. In this study, we reinvestigated the association between SLC1A2 and schizophrenia by performing a case–control association study with twice as many subjects (401 cases and 407 controls) as compared to a previous study, and especially focused on the region where a previous association with schizophrenia had been shown. Our current results failed to show any significant association with schizophrenia in individual single nucleotide polymorphisms (SNPs), two- and three-SNP-based haplotypes, or with possible pairwise haplotype analysis. SCL1A2 appears not to be a genetic risk factor for schizophrenia.

Differences in the levels of the glutamate-related amino acids glycine and serine in brain/plasma between schizophrenic patients and normal subjects and changes in the plasma concentrations of these amino acids according to the clinical course have been reported. It has been hypothesized that glycine and serine metabolism may be altered in schizophrenia. In fact, some genes related to the metabolism of these amino acids have been suggested to be candidate genes for schizophrenia. Thus, we performed a genomic case–control analysis of amino acid metabolism-related genes in Japanese patients with schizophrenia. Case–control genetic association analysis of PHGDH, SHMT1, SRR, and DAO was performed. In addition, the effect of the various genotypes resulting from these four genes on changes in plasma amino acid levels in schizophrenia was assessed. The genetic case–control analysis showed that no individual single-nucleotide polymorphism (SNP) in any of the four genes was associated with schizophrenia; only the two (rs3918347–rs4964770, P = 0.0009) and three (rs3825251–rs3918347–rs4964770, P = 0.002) SNP-based haplotype analysis of the DAO gene showed an association with schizophrenia even after correction for multiple testing. None of the genotypes studied was associated with changes in the plasma glycine and l - and d -serine levels during the schizophrenic clinical course. The DAO gene may be a susceptibility locus for schizophrenia.

Disturbed glutamatergic neurotransmission has become recognized as a key component in the pathophysiology of schizophrenia. The change in serum/plasma glutamate with the use of antipsychotic medication has been studied and may be a possible clinical marker. In the present study, we examined plasma glutamate concentration, including a comprehensive investigation of its involvement with clinical course of schizophrenia and a genomic analysis. We performed a case-control genetic association analysis of the glutaminase 1 (GLS) and 2 (GLS2) genes. In addition, the difference in plasma glutamate concentration between the "acute stage" and "remission stage", and the effect of genotypes of SNPs within the two genes were assessed. The genetic association analysis of the GLS and GLS2 genes showed no association with schizophrenia. Plasma glutamate was increased with antipsychotic medication at "remission stage". Although GLS and GLS2 are not likely genetic risk factors for schizophrenia, changes in plasma glutamate concentration might be connected with clinical course of schizophrenia.

Objective Epidemiologic studies have demonstrated that suffering from depression may be a risk for Alzheimer disease (AD). As a possible biologic mechanism underlying the transition from depression to AD, it has been speculated that pathologic changes in β-amyloid (Aβ) metabolism are involved. To further understand the peripheral kinetics of amyloid in patients with depression, we investigated serum levels of free Aβ and albumin-bound Aβ. Methods Seventy inpatients with DSM-IV major depressive disorder (MDD) and 81 healthy individuals (the comparison group) were recruited between June 2012 and February 2014. Serum Aβ40 and Aβ42 levels, Aβ40/Aβ42 ratio, and serum levels of albumin–Aβ complexes (SLAACs) were compared between the comparison group and patients in two age groups comprising younger ( Results SLAAC was decreased in older patients with MDD but not in younger patients. The serum-free Aβ40/Aβ42 ratio was higher in patients with depression, even in younger patients. Conclusion Our findings suggest that free Aβ and the albumin-bound Aβ reflect a different serum amyloid kinetics in depression. We speculate that serum-free Aβ reflects changes in amyloid metabolism in patients suffering from depression and albumin-bound Aβ reflects AD pathology and may be a potential predictor of the prodromal stage of AD.

To evaluate the safety, tolerability and pharmacokinetic profile of bapineuzumab after a single intravenous injection in Japanese patients with mild to moderate Alzheimer's disease.Participants received either a placebo (n = 8), or bapineuzumab 0.15 (n = 6), 0.5 (n = 6), 1.0 (n = 6) or 2.0 (n = 6) mg/kg. Serum concentrations of bapineuzumab, antibapineuzumab antibody and total plasma β-amyloidx-40 were assayed.Adverse events for bapineuzumab and placebo groups were 71% and 88%, respectively. Treatment-emergent adverse events (cataract, injection site hemorrhage, nasopharyngitis, pneumonia and muscle twitching) reported for ≥2 participants were mild or moderate in severity and unrelated to bapineuzumab dose. No deaths, serious adverse events or withdrawals were reported. Mean peak concentration for bapineuzumab increased with dose, from 3.3 ± 0.9 μg/mL with the 0.15 mg/kg dose to 61.0 ± 32.8 μg/mL with 2.0 mg/kg. Mean bapineuzumab exposure (area under the curve from time 0 to last measurable concentration; μg·h/mL) increased in a linear manner with increasing dose (mean 1260 for 0.15 mg/kg, 4264 for 0.5 mg/kg, 7818 for 1.0 mg/kg, 15 313 for 2.0 mg/kg). Mean half-life ranged from 15 to 28 days, and clearance was similar across dose groups (range 0.12-0.17 mL/h/kg).Plasma β-amyloidx-40 levels increased with increasing doses of bapineuzumab. Bapineuzumab was safe and well tolerated at all doses in Japanese patients with mild to moderate Alzheimer's disease. Geriatr Gerontol Int 2016; 16: 644-650.

We report on time-resolved photometric observations of the WZ Sge-type dwarf nova, EG Cnc (Huruhata's variable, see also http://www.kusastro.kyoto-u.ac.jp/vsnet/DNe/egcnc.html), during its superoutburst in 1996-1997. EG Cnc, after the main superoutburst accompanied with development of superhumps typical of a WZ Sge-type dwarf nova, exhibited a series of six major rebrightenings. During these rebrightenings and the following long fading tail, EG Cnc persistently showed superhumps having a period equal to the superhump period observed during the main superoutburst. The persistent superhumps had a constant superhump flux with respect to the rebrightening phase. These findings suggest the superhumps observed during the rebrightening stage and the fading tail are a "remnant" of usual superhumps, and are not newly triggered by rebrightenings. By comparison with the 1977 outburst of this object and outbursts of other WZ Sge-type dwarf novae, we propose an activity sequence of WZ Sge-type superoutbursts, in which the current outburst of EG Cnc is placed between a single-rebrightening event and distinct outbursts separated by a dip. The post-superoutburst behavior of WZ Sge-type dwarf novae can be understood in the presence of considerable amount of remnant matter behind the cooling front in the outer accretion disk, even after the main superoutburst. We consider the premature quenching of the hot state due to the weak tidal effect under the extreme mass ratio of the WZ Sge-type binary is responsible for the origin of the remnant mass., 16 pages, 15 figures, to appear in PASJ (special issue on VSNET), for more information, see http://www.kusastro.kyoto-u.ac.jp/vsnet/