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Objectives: The aim of this study was to investigate the association between lithium levels in drinking water and prevalence of Alzheimer's dementia (AD)., Methods: Lithium levels in the drinking water of 808 cities and wards (i.e., 785 Japanese cities of 46 prefectures and 23 wards of Tokyo) in Japan were examined in relation to the prevalence of AD during the 5 years from 2010 to 2014, which was calculated on the basis of the national data base of Ministry of Health, Labor, and Welfare of Japan. Multiple regression analyses were used to investigate the association of lithium levels with the prevalence of AD with adjustment for relevant factors (proportions of one-person households as a family factor and people in primary industry employment as a job factor, annual total sunshine hours as a meteorological factor, and total number of beds of psychiatric hospitals as a medical factor) in total, male, and female elderly populations., Results: The adjusted model showed a significant inverse association of lithium levels with female, but not with male, or total prevalence of AD., Conclusions: These findings suggest that higher lithium levels in drinking water may be associated with lower prevalence of AD in female, but not male, populations., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Abstract: In the working population, bipolar disorder can have a significant negative effect on professional relationships, attendance, functioning, and loss of productivity. In Japan, workers who take a leave due to depressive episodes receive a work-focused intervention program called the "return to work program" during their leave. A 39-year-old Japanese woman with bipolar II disorder took a third sick leave of absence. We recommended her the return to work program of our university hospital. At the beginning of the program, she had a rigid thought process toward her perceptions of her duties in the workplace and at home. Through the program, mindfulness might identify rigidity, group cognitive-behavioral therapy might correct rigidity, and self-analysis might have regained flexibility. In conclusion, a variety of effects of our return to work program might have enabled her thought process to evolve from rigid to flexible, and she showed successful reinstatement., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Although many antidepressants are available, they are not always used appropriately. For appropriate use of antidepressants, the old concept of a linear dose-response relationship, in which the dose is linearly increased to achieve a sufficient antidepressant effect, should be reconsidered. Furthermore, there is ongoing debate on the safe and appropriate use of antidepressants in patients with bipolar depression. Antidepressants may be used under certain conditions in patients with bipolar depression. These neglected-but not negligible-aspects of antidepressants have been discussed herein., Methods: A narrative qualitative review RESULTS: Dose-response relationships of antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are not linear. They may be bell-shaped, with efficacy initially increasing with an increase in dose but decreasing when the dose is increased beyond a certain point. Despite using international diagnostic criteria, uncertainty remains on whether operationally diagnosed depression is latent bipolar I depression, latent bipolar II depression, or true depression. Furthermore, operationally diagnosed bipolar II depression may be latent bipolar I depression, true bipolar II depression, or depression with false hypomanic episodes. Manic/hypomanic switches are most likely to occur in patients receiving tricyclic antidepressants, followed by those receiving serotonin and noradrenaline reuptake inhibitors and SSRIs, in that order. Also, these switches are most likely to occur in patients with bipolar I depression, followed by those with bipolar II depression and true depression, in that order., Conclusions: Considering the diagnostic subtype of bipolar depression and antidepressant properties may help to determine the optimal treatment strategy., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Despite the unavailability of essential anti-dementia drugs, lithium may inhibit glycogen synthase kinase-3 (GSK-3) and decrease beta-amyloid and hyper-phosphorylated tau. In this review, we hypothesized that trace to standard levels of lithium (i.e., corresponding to the therapeutic levels for bipolar disorder) may be effective for dementia prevention. Excluding three insufficient level studies, we obtained two and one excellent clinical studies on standard and trace lithium levels, respectively, all of which supported the effects of lithium for dementia prevention. In addition, we identified good clinical and epidemiological studies (four each) on standard lithium levels, of which six studies supported the effects of lithium. Moreover, of three good epidemiological studies on trace lithium levels, two supported the aforementioned effects of lithium. The number of studies were substantially small, particularly those on trace lithium levels. Moreover, studies on standard lithium levels were insufficient to establish the efficacy of lithium for dementia prevention. This necessitates accumulating good or excellent clinical evidence for the effects of trace to standard lithium levels on dementia prevention.

Objectives: The aims of the present study thus were (a) to further investigate the association between lithium levels in drinking water and suicide rates by adjusting relevant factors using the so far largest available dataset in Japan, (b) to confirm sex differences, (c) to estimate the effects of long-term exposure to trace lithium, (d) to investigate the effects of drinking bottled instead of tap water, and (e) to exploratorily investigate which lithium levels may be associated with lower suicide rates., Methods: Mean lithium levels in drinking water of all 808 cities and wards (ie, 785 cities of 46 prefectures and 23 wards of Tokyo) in Japan were examined in relation to mean suicide standardized mortality ratios (SMRs) during the 7 years from 2010 to 2016. Multiple regression analyses adjusted for the size of each population were used to investigate the association of lithium levels with suicide SMRs with adjustments for relevant factors., Results: The adjusted model showed significant inverse associations of lithium levels with total and male SMRs, but not with female SMRs. Neither the proportion of residents who continued to live in the same city nor the consumption of bottled water changed the association between lithium levels and suicide SMRs. Finally, it was 30 μg/L or more that was associated with lower suicide SMRs., Conclusions: The present findings reconfirm the inverse association between lithium levels in drinking water and suicide rates particularly in the male population., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: Bright light therapy (BLT) was reported as an effective adjunctive treatment option for bipolar disorder. Previous meta-analytic study showed that augmentation treatment with light therapy significantly decreased the severity of bipolar depression. However, most of included studies were case-control studies and several of them focused on BLT that was provided in combination with sleep deprivation therapy., Methods: In this meta-analysis, we used several electronic databases to search the studies and included only randomized controlled trial (RCT) studies to compare BLT with control experimental groups for treating bipolar depression with pharmacological treatment to clarify the adjunctive efficacy of BLT. We searched the databases of EMBASE, MEDLINE, Scopus, The Cochrane Central Register of Controlled Trials, the Cumulative Index to Nursing and Allied Health Literature, and Clinicaltrials.gov for studies published in English until September 19, 2019. Two researchers conducted the literature screening, data extraction, and methodological quality assessment independently. The main outcome was the response rate and remission rate. We used the Review Manager 5.3 Software for the meta-analysis., Results: Four trials with a total of 190 participants (intervention: 94, control: 96) with bipolar depression were evaluated to gauge the effects of light therapy. The meta-analysis showed risk ratios of 1.78 (95% CI 1.24-2.56, p = .002; I 2  = 17%) demonstrating a significant effect of light therapy in the response rate of bipolar disorder. The meta-analysis shows risk ratios of 2.03 (95% CI 0.48-8.59, p = .34; I 2  = 67%) demonstrating no significant effect of light therapy in the remission rate of patients with bipolar disorder. None of the articles reported any serious adverse effects. Manic switch rate was 1.1% in the light therapy group and 1.2% in the control group., Conclusions: Bright light therapy is an effective treatment for reducing depression symptoms among patients with bipolar depression., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Objectives: To focus on a specific group of patients whose diagnoses were changed from unipolar depression to bipolar disorder, and finally to dementia., Methods: Qualitative review of the relevant articles., Results: A substantial portion of patients with unipolar depression manifest manic and/or hypomanic episodes, resulting in a change of diagnoses to bipolar disorder. Further, a substantial portion of bipolar patients develop dementia. Previous research suggests that genetic variants in the glycogen synthase kinase 3β (GSK-3β) gene are associated with early onset of unipolar depression, a subset of which may be bipolar depression, with three SNPs (rs334555, rs119258668, and rs11927974) identified. Notably, another promotor SNP (rs334558) of the GSK-3β gene is reportedly associated with unipolar depression, bipolar disorders, and dementia. Additionally, lithium, which is reported to inhibit GSK-3, is generally accepted to be effective for bipolar disorder and recently reported to be effective for dementia., Conclusions: There is a specific group of patients whose diagnoses longitudinally change from depression to bipolar disorder and finally to dementia, and GSK-3 may be a common etiological factor in these diseases and in diagnostic conversions., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Lithium therapy is generally accepted as a first-line treatment for bipolar disorder, and it is also identified as one of the best augmenting options for treatment-resistant depression. Furthermore, lithium has been investigated in association with suicide, dementia and aggressiveness. In this review, we examined articles about the effects of very small amounts of lithium in treating suicide, dementia, bipolar disorder and temperament, to assess the present state of trace lithium's effect on mental state. The results indicate that trace lithium may be effective for suicide prevention but randomized, placebo-controlled trials are required to draw a definite conclusion. Indications for using trace lithium in treating such conditions as dementia, bipolar disorder and temperament are supported by very limited evidence and such effects are yet to be determined.

Objective: The preventive effects of mood stabilizers on recurrence/relapse in bipolar disorders have been investigated mostly in bipolar I disorder (BPI) patients, with limited reports on bipolar II disorder (BPII) patients. Here, we conducted an explorative data analysis to investigate whether the preventive effect of lamotrigine on recurrence /relapse in BPII is better than in BPI., Methods: Data from Japanese patients with a diagnosis of BPI or BPII according to DSM-IV-TR were analyzed in an open-label, noninterventional, naturalistic, prospective postmarketing surveillance study of lamotrigine. This study was carried out from October 2011 to November 2014, and each patient was observed for 1 year. The time to recurrence/relapse of mood episodes after commencement of lamotrigine treatment was evaluated as a primary endpoint. Kaplan-Meier curves were generated to compare the time to recurrence/relapse of mood episodes in BPI with in BPII using a log-rank test., Results: Lamotrigine was associated with a significantly longer time to recurrence/relapse of mood episodes in BPII than in BPI (log-rank test, P = .0103). Lamotrigine also prolonged time to recurrence/relapse of mania-related episodes, including hypomanic episodes, more in BPII than in BPI (P = .0110)., Conclusions: Although the preventive effect of lamotrigine on recurrence/relapse of mood episodes in BPI has been established in a variety of clinical studies, the present study suggests that lamotrigine may be more suitable for maintenance treatment in BPII than in BPI., (© Copyright 2017 Physicians Postgraduate Press, Inc.)

Introduction: Lamotrigine is one of several mood stabilizers and its effects for the treatment and prevention of depressive episodes, particularly in bipolar disorder, are generally accepted. Although the findings about a therapeutic window of lamotrigine are yet to be determined, it seems important to obtain information on individual pharmacokinetic peculiarities. This study was conducted to formulate the predictive model of plasma lamotrigine levels. Methods: Using the data of 47 patients whose lamotrigine levels, liver function, and renal function were measured, predictive models of lamotrigine levels were formulated by stepwise multiple regression analyses. The predictive power of the models was compared using another dataset of 25 patients. Results: Two models were created using stepwise multiple regression. The first model was: plasma lamotrigine level (μg/mL)=2.308+0.019×lamotrigine dose (mg/day). The second model was: plasma lamotrigine level (μg/mL)=0.08+0.024×lamotrigine dose (mg/day)+4.088×valproate combination (no=0, yes=1). The predictive power of the second model was better than that of the first model. Discussion: The present study proposes a prompt and relatively accurate equation to predict lamotrigine levels., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: In a previous study examining the association of hyperthymic temperament and daily light exposure (illuminance), we compared hyperthymic scores of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-auto questionnaire version (TEMPS-A) acquired from residents in Sapporo and Oita in Japan, which are located at 43° and 33° of latitude. We found that residents of Oita had significantly higher hyperthymic scores than residents of Sapporo. Moreover, a comparison of 3 regions rather than 2 regions may show a dose-response relationship in hyperthymic temperament and illuminance., Methods: Japan has 4 large islands-Hokkaido, Honshu, Shikoku, and Kyushu. Sapporo is in Hokkaido and Oita is in Kyushu. As the 3rd location, we recently collected TEMPS-A data from 125 residents in Koshigaya which is located in Honshu at 36°. We combined the data of the Koshigaya residents with the data of 94 residents from Sapporo and 95 from Oita., Results: The mean yearly total sunshine of the past 20 years (1993-2012) was 1684.6h in Sapporo, 1862.9h in Koshigaya, and 2002.9h in Oita. Multiple regression analyses revealed that sunshine predicted significant variance of hyperthymic temperament in a dose-dependent manner., Limitations: The limitation of the present study is the lack of the consideration of the effects of temperature on hyperthymic temperament. Since correlations are fairly small, other factors are also at work for hyperthymic temperament., Conclusions: The present findings suggest that higher illuminance may maintain hyperthymic temperament via light effects in a dose-dependent manner., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Although the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-auto questionnaire (TEMPS-A) was designed to identify temperaments which derive from traits but not states, there is a possibility that TEMPS-A scores might be affected by mental state in non-clinical populations. For the purpose of clarifying the effects of mental state on TEMPS-A scores, it is worthwhile to examine associations of the full version of the TEMPS-A with various depressive scales and, if possible, mania rating scales., Methods: TEMPS-A data acquired from 314 medical students and staff was used to investigate the association of temperament scores with mental assessment scores such as the Beck Depression Inventory (BDI), the Quick Inventory of Depressive Symptomatology Self-Report Japanese version (QIDS-SR-J), the Patient Health Questionnaire-9 (PHQ-9), the Hamilton Depression rating scale (HAM-D) and the Young Mania Rating Scale (YMRS)., Results: Depressive state scores were significantly and positively associated with depressive, anxious, cyclothymic, and irritable temperament scores of TEMPS-A whereas sub-threshold hypomanic state scores were significantly and positively associated with irritable temperament of TEMPS-A. There was no association between depressive state or sub-threshold hypomanic state and hyperthymic temperament scores., Limitations: The nature of the present study is cross-sectional, and it is unknown whether depressive and/or sub-threshold hypomanic states may have affected temperament scores or whether temperament scores might have affected depressive and/or sub-threshold hypomanic scores. Other limitations are that the sample may not represent the entire population and that there is no evidence that Japanese findings can be applicable outside Japan., Conclusions: It is worthwhile to consider the effects of mental state on temperament scores of TEMPS-A even in non-clinical population., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Hyperthymic temperament has been generally accepted as one of premorbid temperament of bipolar disorders. Although several studies indicate that subjects with hyperthymic temperament receive more illuminance, our recent study suggests that the threshold of brightness and darkness judgment is not different between more and less hyperthymic subjects, and that hyperthymic temperament may be associated with left inferior orbitofrontal cortex, which has been reported to be associated with bipolar disorder. Therefore, at the next stage, it can be hypothesized that hyperthymic subjects may prefer brightness (i.e., heliotropism) and thereby seek illuminance, and that percent signal changes of left inferior orbitofrontal cortex during the preference task may be associated with hyperthymic temperament scores., Methods: We compared brightness preference and un-preference between more and less hyperthymic subjects, and investigated percent signal changes of left inferior orbitofrontal cortex during brightness preference judgment, brightness un-preference judgment, and control task by using functional Magnetic Resonance Imaging (fMRI)., Results: There were significant differences in brightness preference judgment and un-preference judgment, showing that more hyperthymic subjects preferred brighter illuminace levels and un-preferred darker illuminance levels than less hyperthymic subjects. Moreover, fMRI signal changes of left inferior orbitofrontal cortex was significantly and negatively associated with hyperthymic temperament scores., Limitations: It is unknown why left but not right inferior orbitofrontal cortex was associated with hyperthymic temperament scores., Conclusions: The present findings suggest that more hyperthymic subjects may prefer brightness and un-prefer darkness than less hyperthymic subjects (i.e., heliotropism), and reconfirm that hyperthymic temperament may be associated with left inferior orbitofrontal cortex, which have been reported to be associated with bipolar disorders., (© 2013 Elsevier B.V. All rights reserved.)

Background: Hyperthymic temperament has been generally accepted as one of premorbid temperament of bipolar disorders. Since recent several studies indicate an association between illuminance and hyperthymic temperament, it can be hypothesized that more hyperthymic temperament subjects have a different threshold of brightness or darkness perception in comparison with less hyperthymic temperament subjects., Methods: We compared the threshold of brightness and darkness judgment between more and less hyperthymic subjects, and by simultaneously using fMRI we compared activations of whole brain between these subjects by two sample t-test. Furthermore, the association between the activations and hyperthymic temperament scores was analyzed., Results: Although there was no significant difference in the threshold of brightness or darkness judgment between more and less hyperthymic subjects, there was a significant difference in activations of the regions including left superior temporal gyrus, left inferior orbitofrontal cortex, left triangular inferior frontal gyrus and left insula between these subjects. Moreover, there was a significantly positive association between a cluster containing left inferior orbitofrontal cortex and hyperthymic temperament scores. The common activated region of these two analyses (categorical and continuous ones) was determined as left inferior orbitofrontal cortex., Limitations: Limitation of the present study is a lack of brightness and darkness preference experiment between more and less hyperthymic subjects., Conclusions: The present findings suggest that the threshold of brightness and darkness judgment is not different between more and less hyperthymic subjects, and that hyperthymic temperament may be associated with left inferior orbitofrontal cortex, which has been reported to be associated with bipolar disorder., (© 2013 Elsevier B.V. All rights reserved.)

Background: Although lamotrigine may be useful for treating bipolar depressive patients, some lamotrigine-associated adverse effects may prevent the continuation of treatment. The purpose of the present study was to identify risk factors for lamotrigine discontinuation after adjustment for several potential interactive factors., Methods: We examined tolerability in those who discontinued lamotrigine within 2 months of treatment and those who maintained lamotrigine for more than 2 months. Groups were examined separately because 6-8 weeks are necessary to titrate dose and drug eruptions can often occur within 2 months of treatment commencement., Results: Multiple regression analysis revealed that valproate combination was positively and significantly associated with lamotrigine discontinuation after adjustment for other factors., Limitations: The limitations of the present study were retrospective observation and a relatively small number of subjects., Conclusions: The present findings reconfirm that lamotrigine and valproate combination treatment may prevent the continuation of lamotrigine in some patients., (© 2013 Elsevier B.V. All rights reserved.)

The Japanese Society of Mood Disorders established a committee for treatment guidelines of mood disorders, which created the first edition of a treatment guideline for bipolar disorders on 10 March 2011. The committee has now created a second edition, which we report here. In creating this treatment guideline, the first step was to have several bipolar disorder specialists review well-conducted studies and meta-analyses. Based on this evidence, and with a consensus among the specialists, treatment procedures that were considered optimal were compiled and the strength of recommendation for each treatment method was determined. The first draft, prepared in this manner, was further revised through a process of critical investigation by all committee members to produce the final edition., (© 2013 The Authors. Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology.)

Background: Growing evidence points to an association of daily light exposure and both mood and mood disorders. In recent studies, we demonstrated that higher illuminance of daytime may be positively associated with hyperthymic temperament while lower illuminance of daytime may be positively associated with cyclothymic temperament. However, it is not possible to determine whether hyperthymic or cyclothymic temperament induces higher or lower illuminance via heliotropism or non-heliotropism or whether higher or lower illuminance induces hyperthymic or cyclothymic temperament via light effects., Methods: In order to elucidate these questions, we sought to compare bipolar temperaments between residents who live in regions with varying levels of sunshine. Japan has 4 large islands -Hokkaido, Honshu, Shikoku, and Kyushu. Sapporo in Hokkaido and Oita in Kyushu located at 43° and 33° of latitude differ significantly in mean yearly sunshine. We investigated the data of 189 subjects (94 from Sapporo and 95 from Oita) including their data of Temperament Evaluation of Memphis, Pisa, Paris and San Diego-auto questionnaire version (TEMPS-A)., Results: Multiple regression analyses revealed that latitude (Sapporo or Oita) effect predicted significant variance of hyperthymic temperament, but not of the other temperaments., Limitations: The limitation of the present study was that there was a small but significant difference in age between the subjects of Sapporo and those of Oita. Therefore, we included age in the multiple regression analysis. Second, there were several climate factors other than sunshine which were significantly different between Sapporo and Oita. We cannot exclude these effects completely. Finally, we did not consider other factors such as psychosocial factors which might have affected bipolar temperaments., Conclusions: The present findings suggest that relatively lower latitude (potentially via more sunshine) may induce hyperthymic temperament., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Converging lines of evidence have established a relationship between exposure to ambient light and both mood state and mood disorders. In view of the association between mood disorder and affective disposition, in this study, the relationship between temperament (depressive, cyclothymic, hyperthymic, irritable and anxious) and daily light exposure was closely examined., Methods: Fifty-six subjects completed the Japanese standardized version of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-auto questionnaire version (TEMPS-A) and illuminance of daytime using actigraphy., Results: Cyclothymic temperament scores were significantly and negatively associated with illuminance of daytime whereas hyperthymic temperament scores were significantly and positively associated with illuminance of daytime., Limitations: Sample size was relatively small and they were only healthy subjects and no patients., Conclusions: The findings suggest that illuminance of daytime may be related to both cyclothymic and hyperthymic temperaments but that the associations lie in opposite directions. If this is the case, it seems important to consider individual patients' temperaments when light therapy is used to treat their depressive episode. Further studies are required to determine why and how these temperaments are associated with illuminance., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Type A behavior pattern (TABP) has traditionally been reported to be associated with coronary heart disease and, more recently, several researchers have examined its association with depression and bipolar disorder. According to Akiskal and Pinto (1999), there are 2 subtypes of bipolar spectrum which are not associated with manic or hypomanic state. These are bipolar II1/2 (depression in those who have cyclothymic temperament) and bipolar IV (depression in those who have hyperthymic temperament). Our hypothesis is that individuals with hyperthymic temperament may have a tendency towards TABP., Objectives: The purposes of the present study are to investigate the association between TABP and hyperthymic temperament and to determine other biological factors associated with TABP., Methods: Fifty healthy subjects were assessed for TABP and hyperthymic temperament by self-rating scales, daily activity, sleep time and illuminance by actigraphy, and central serotonergic function via the neuroendocrine challenge test. Serum brain-derived neurotrophic factor (BDNF) levels were also measured., Results: Stepwise regression analysis indicated that hyperthymic temperament score was positively associated with TABP scores and both sleep time and snooze time were negatively associated with TABP scores. BDNF levels were not associated with TABP scores., Conclusions: These findings suggest that individuals with hyperthymic temperament may have a tendency towards TABP, and TABP persons may have short sleep time and short snooze time. Although further studies are required to investigate the association between TABP and affective disorders, the present findings clearly indicate the association between TABP and hyperthymic temperament, which may be associated with bipolar IV disorder. Taking TABP as a risk factor of cardiovascular events into consideration, this association between TABP and bipolar IV disorder may account for the well-known cardiovascular mortality in bipolar disorder., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: The concept of soft bipolar spectrum has not been fully confirmed. The aim of the present study is to investigate the validity of bipolar II1/2 and IV concept., Methods: The subjects were 46 consecutive outpatients. The individual temperament of each patient was recorded using the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Autoquestionnaire (TEMPS-A). The operational definition of bipolar II1/2 was those who had depression with cyclothymic temperament and that of bipolar IV was those who had depression with hyperthymic temperament. Finally, drug responses were investigated., Results: DSM-IV-TR diagnoses were bipolar I (N=1), bipolar II (N=9), major depressive disorder (N=34) and depressive disorder not otherwise specified (N=2). Excluding one bipolar I patient, who had both cyclothymic and hyperthymic temperaments, patients with bipolar II1/2 (N=32) and IV (N=13) as well as bipolar II (N=9) were classified into the soft bipolar spectrum, although there was considerable overlap. The categorization of soft bipolar spectrum and unipolar depression significantly predicted depressive, cyclothymic, irritable, and anxious temperaments. Moreover, soft bipolar spectrum patients with lithium treatment were significantly more in remission than those without lithium treatment. In addition, more of those with selective serotonin reuptake inhibitors (SSRIs) had a significant tendency to lower remission than those without SSRIs., Limitations: This is a cross-sectional study with a relatively small number of subjects., Conclusions: The present findings suggest that cyclothymic and hyperthymic temperaments may predict bipolarity, and the validity of bipolar II1/2 and IV concept is supported., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The therapeutic guideline for the treatment of a manic episode is as follows: Firstly, lithium is the prime recommendation. In the case of a severe manic episode, the combination of lithium and atypical antipsychotic drug is recommended. Secondly, valproate, atypical antipsychotic drugs, and carbamazepine are recommended. In the case of a severe manic episode, the combination of valproate and an atypical antipsychotic drug is recommended. Finally, the combination of mood stabilizers, or the combination of mood stabilizer and typical antipsychotic drug, and electroconvulsive therapy are recommended in refractory situations.

It is important to be able to predict a response to lithium before lithium administration because it usually takes 2 or 3 weeks for lithium to manifest its effect sufficiently. We hypothesized that lithium responders have a high post-synaptic serotonergic receptor function, whereas non-responders have low one. This is because it has been suggested that lithium's primary actions on the serotonergic neuron may be presynaptic and several reports have shown that lithium enhances serotonin synthesis and secretion at the presynaptic serotonergic neuron. As a preliminary study, we investigated the relationship between several responses to meta-chlorophenylpiperazine (a serotonergic agonist) reflecting the serotonergic receptor function and the clinical lithium response of 10 patients. No significant relationship between hormone responses and improvement ratios was found. However, there were significant relationships found between 'anger' during the challenge test and the improvement ratio and between 'tension' during the test and the improvement ratio. Thus, it seems that the hormone response to a serotonergic agonist is not useful for predicting lithium response. However, subjective responses such as anger and tension to a serotonergic agonist are possible candidates for predicting lithium response. In any case, further studies with larger numbers of participants are required to investigate whether subjective responses to a serotonergic agonist are useful for predicting lithium response.

Rapid cycling affective disorder (RC) is defined as the presence of at least four affective episodes per year. We report two RC patients whose first manic episodes were considered to be induced by clomipramine. The first case, a 61-year-old female, suffered from RC after a manic episode with respect to oral administration of clomipramine. The second case, a 45-year-old female, showed cycle acceleration after a manic episode regarding intravenous drip infusion treatment with clomipramine. They had no manic or hypomanic episodes before the administration of clomipramine. We discuss the possible induction and worsening of RC through clomipramine-induced mania.

Recently, the authors suggested that the lithium dose prediction equation created by Zetin and associates cannot always accurately predict a required lithium dose and that the inclusion of renal function data may improve the accuracy of the equation. The charts of 70 patients were reviewed to obtain data regarding factors thought to affect serum lithium concentrations, including renal function, and an equation to estimate the dose intended to achieve an expected concentration was derived by stepwise multiple linear regression. The equation was also applied to 30 other patients to evaluate its accuracy. The authors obtained the following equation: daily lithium carbonate dose (in milligrams) = 100.5 + 752.7 x (expected lithium concentration in millimoles per liter) - 3.6 x (age in years) + 7.2 x (weight in kilograms) - 13.7 x (blood urea nitrogen [BUN] in milligrams per deciliter). When the equation was applied to 30 patients, the mean +/- SD of deviations from the expected concentration was 0.15 +/- 0.30 mmol/L, and 19 patients (63%) had deviations of less than 0.20 mmol/L. On the other hand, when the equation set forth by Zetin and associates was applied to the same patients, the mean +/- SD of deviations from the expected concentration was 0.52 +/- 0.42 mmol/L, and only 6 patients (20%) had deviations of less than 0.20 mmol/L. Although it is necessary to measure BUN levels before starting lithium, this equation may be simpler and more accurate than that offered by Zetin and associates.

Although several reports have stated that even therapeutic levels of lithium can induce sinus node dysfunction, the mechanism has not been fully elucidated. We present here two patients with sinus node dysfunction after long-term lithium therapy. Following lithium discontinuation, sinus node function recovered completely. After resuming lithium, however, irreversible sinus node dysfunction recurred and a permanent pacemaker was implanted in one patient. The serum concentration of lithium was within therapeutic levels. Nevertheless, hypothyroidism was associated with the sinus node dysfunction in both patients. Thus, thyroid function may play an important role in sinus node dysfunction induced by lithium.

We present the case of a 56-year-old woman with syncope and sinus node dysfunction after long-term lithium therapy. Following lithium discontinuation, sinus node function recovered completely. After resuming low doses of lithium, however, severe sinus node dysfunction recurred. Thereafter, sinus node function did not recover after lithium was discontinued, and a permanent pacemaker was implanted. These findings suggest that irreversible sinus node dysfunction should be recognized as a potentially fatal, albeit rare, risk of lithium therapy, and that previous recovery from sinus node dysfunction after long-term lithium treatment cannot always guarantee the reversible nature of this abnormality after resumption of lithium therapy.

Professors Grunze and Walden sent a letter associated with our article. In this letter, we reply to their comments. [ABSTRACT FROM AUTHOR]