A Predictive Model of Plasma Lamotrigine Levels.

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.

Postcomparison of [(18) F]-fluorodeoxyglucose uptake in the brain after short-term bright light exposure and no intervention.

OBJECTIVE: Bright light therapy is widely used as the treatment of choice for seasonal affective disorder. Nonetheless, our understanding of the mechanisms of bright light is limited and it is important to investigate the mechanisms. The purpose of this study is to examine the hypothesis that bright light exposure may increase [(18) F]-fluorodeoxyglucose (FDG) uptake in olfactory bulb and/or hippocampus which may be associated neurogenesis in the human brain. METHOD: A randomized controlled trial comparing 5-day bright light exposure + environmental light (bright light exposure group) with environmental light alone (no intervention group) was performed for 55 participants in a university hospital. The uptake of [(18) F]FDG in olfactory bulb and hippocampus using FDG positron emission tomography was compared between two groups. RESULTS: There was a significant increase of uptake in both right and left olfactory bulb for bright light exposure group vs. no intervention group. After adjustment of log-transformed illuminance, there remained a significant increase of uptake in the right olfactory bulb. CONCLUSION: The present findings suggest a possibility that 5-day bright light exposure may increase [(18) F]FDG in the right olfactory bulb of the human brain, suggesting a possibility of neurogenesis. Further studies are warranted to directly confirm this possibility.

Reply to the letter from Grunze and Walden.

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

Therapeutic window of lamotrigine for mood disorders: a naturalistic retrospective study.

INTRODUCTION: Lamotrigine is widely used for mood disorders including bipolar disorder and major depression, but its therapeutic levels have yet to be determined. This study was conducted to investigate the hypothesis that lamotrigine may have a therapeutic window for mood disorders. METHODS: 25 patients with mood disorders received lamotrigine for more than one year during which time plasma lamotrigine levels were measured at least once. Their mental state was retrospectively and regularly but blindly assessed using the Clinical Global Impression-Severity (CGI-S) scale. In order to investigate our hypothesis, we depicted the relationship between the last lamotrigine levels and the last CGI scores in 25 patients. If any, the potential therapeutic window was further investigated. RESULTS: The relationship between the last lamotrigine levels and the last CGI scores in the 25 patients indicated the presence of a therapeutic window of lamotrigine from 5 to 11 µg/mL. The repeated measures of ANOVA reached a significant tendency of the effects of lamotrigine levels within 5-11 µg/mL on better CGI-S scores, and the CGI-S scores at the last observation of the 15 patients whose lamotrigine levels were within 5-11 µg/mL were significantly better than those of 10 patients whose lamotrigine levels were not within 5-11 µg/mL. CONCLUSION: These findings suggest that lamotrigine may have a therapeutic window for patients with mood disorder from 5 to 11 µg/mL.

Life-threatening hemorrhage and prolonged wound healing are remarkable phenotypes manifested by complete plasminogen activator inhibitor-1 deficiency in humans.

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological regulator of urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA) activity. A number of studies have shown that elevated levels of PAI-1 are related to pathological states such as an increased risk of arterial thrombotic events and a poor prognosis for cancer patients; however, there are few reports about PAI-1 deficiency in humans because the disorder is very rare. OBJECTIVE: To understand the in vivo impact of a complete PAI-1 deficiency, Serpine1(-/-) mice were generated; a number of in vivo studies have been conducted to elucidate the function of PAI-1 using Serpine1(-/-) mice. The phenotypes demonstrated in Serpine1(-/-) mice, however, were quite different from those in humans. Therefore, it is necessary to find out and analyze SERPINE1 deficiency in humans. PATIENT AND METHODS: The patient is a 47-year-old woman who has had multiple episodes of major bleeding. Although most of the patient's blood coagulation factors were functionally normal, her PAI-1 antigen levels were undetectable. Therefore, DNA sequencing of the SERPINE1 gene were analyzed. RESULTS: The proband had a homozygous 1-bp duplication (C) at exon 3 (c.356dupC; p.Ile120AspfsX42). Both wild-type PAI-1 (42.7 kDa) and mutated (Mut) PAI-1 (14.7kDa) were expressed in COS-1 cells, although the level of Mut PAI-1 expressed in the cell lysates was much lower. Wild-type PAI-1 was observed in the culture supernatant, whereas no Mut PAI-1 was detected in the supernatant. CONCLUSIONS: Considering the results of the present study, the translation of mouse studies to humans must be performed with great care.

Intramedullary spinal cord metastases of malignant melanoma: an autopsy case report and review of the literature.

INTRODUCTION: Compared with brain metastasis of malignant melanoma (MM), spinal metastasis, and in particular intramedullary spinal cord metastasis (ISCM), is extremely rare. CASE: A 78-year-old female patient suffered from disturbance of gait and mild dementia. Radiological investigations revealed multiple hemorrhagic lesions in the brain. She underwent surgical resection of a right parietal lesion, the diagnosis of which was MM. Re-examination of her past history revealed that the patient had undergone surgical resection of a nevus on her left cheek 3 years previously, the diagnosis of which had been MM. After she had died of the tumor 3 months later, complete autopsy was performed. Multiple ISCMs with hemorrhage were detected in the cervical, thoracic, and lumbar cord. DISCUSSION: We found 9 cases of ISCM of MM in the literature, 5 of which were located in the cervical cord, 3 in the thoracic cord, and 1 in the lumbar cord. One difference between the findings noted in the literature and those in the present case involved the cross-sectional location of metastases in the spinal cord. In the present case, it appeared that postoperative management for the left buccal melanoma, which did not include adjuvant therapy, affected the postoperative clinical course. The prognosis was also affected by overlooking of ISCM. The brain metastases in the present case induced deterioration of her neurological symptoms rapid enough that the possibility of ISCM was not considered. On evaluation of tumor spread from MM, it is important to take into account not only intracranial metastases but ISCM as well.

Pindolol augmentation of serotonin reuptake inhibitors for the treatment of depressive disorder: a systematic review.

UNLABELLED: Adding pindolol to serotonergic antidepressant treatment offers a potential strategy for producing a more rapid onset of action and an enhanced antidepressant effect. This review investigated whether pindolol enhances the efficacy of serotonergic antidepressant treatment in adult patients with depressive disorders at sequential time points up to 6 weeks. SEARCH STRATEGY: Cochrane Collaboration Depression, Anxiety and Neurosis-Controlled Trials Register plus unpublished trial data. STUDY SELECTION: Randomised trials including depressed patients, comparing serotonergic antidepressants + pindolol with serotonergic antidepressants + placebo and using depressive symptom clinical outcomes scales. DATA EXTRACTION: Clinical response at time points up to 6 weeks as defined by >50% depression scale score reduction was extracted for each trial as possible. Eleven studies were identified including unpublished data. The pooled odds ratios for dichotomous response to treatment at time points from 1 to 6 weeks were 2.39 (95% CI 1.40-4.06), 2.39 (1.74-3.29), 1.94 (1.46-2.58), 1.59 (1.16-2.18), 1.42 (0.87-2.31) and 1.28 (0.91-1.81). Time-to-event analysis showed a greater response with pindolol augmentation versus placebo (P = 0.04). There was significant heterogeneity between studies at some time points. Dropout rates did not significantly differ between treatment arms. This review suggests an overall beneficial clinical effect of pindolol augmentation, most clearly up to 4 weeks of treatment.

Microelectrode findings and topographic reorganisation of kinaesthetic cells after gamma knife thalamotomy.

A 64-year-old woman with Parkinson is disease had a severe resting tremor that was not completely relieved by right-sided gamma knife thalamotomy (GKT). We performed bilateral staged thalamic deep brain stimulation (DBS) and compared the right and left ventral intermediate nucleus (Vim) of the thalamus including the frequency of single units recorded with microelectrodes, and also the somatotopical distribution of kinaesthetic cells (Ki). The average frequency of units for the presumed left Vim exceeded that of the right (22.6 +/- 19.2 Hz vs. 14.3 +/- 8.8 Hz). Regarding the somatotopic distribution of Ki, the receptive field for the leg, which is usually situated in the dorsolateral Vim, was more widely scattered in the right Vim than the non-lesioned left side. Our findings raise the possibility that the specific properties of the neurons changed due to partial coagulation by GKT within both the coagulated and the surrounding thalamic lesions.

Serum CA125 level before the development of ovarian cancer.

BACKGROUND: Little is known about the natural history of ovarian cancer with respect to the change of serum CA125 level. METHODS: The Shizuoka Cohort Study on Ovarian Cancer Screening (SCSOCS) Trial contains approximately 100,000 data on serum tumor marker CA125 prospectively obtained from more than 70,000 women. We reviewed the clinical charts and collected serum samples 2 months to 9.4 years prior to the surgery were available. RESULTS: In 396 (95%) of the 419 patients with ovarian cancer, one serum sample was present before the diagnosis (mean, 4.1 years). The change of CA125 level before the diagnosis of ovarian cancer could be clearly separated into two groups according to the length of the following intervals: 47% (107/228) of patients with non-serous-type ovarian cancers develop secondarily from slightly elevated CA125 level (35

Risk of developing ovarian cancer among women with ovarian endometrioma: a cohort study in Shizuoka, Japan.

Although some studies have indicated that endometriosis may increase the risk of developing ovarian cancer, there are no data from epidemiologic studies in Japan. We prospectively analyzed all cases of ovarian endometrioma enrolled in the prefecture-wide Shizuoka Cohort Study on Endometriosis and Ovarian Cancer Programme, which was initiated in 1985. To evaluate the risk of ovarian cancer by time periods subsequent to ovarian endometrioma diagnosis, a cohort of 6,398 women with a clinically documented ovarian endometrioma in Shizuoka between 1985 and 1995 was identified from the Shizuoka Cancer Registry (SCR), with follow-up through 2002. Ovarian cancer incidence among cohort members was ascertained by linkage to the SCR using a unique person-identification number. Standardized incidence ratios (SIR) and their 95% confidence intervals (CI) were computed by a use of prefecture-wide rates of ovarian cancer, adjusted for age and calendar year. During follow-up of up to 17 years of the ovarian endometrioma cohort, 46 incident ovarian cancers were identified, yielding that the ovarian cancer risk was elevated significantly among patients with ovarian endometrioma (SIR = 8.95, 95% CI = 4.12-15.3). The SIR did not increase with increasing follow-up duration. The risk increased with increasing age at ovarian endometrioma diagnosis, with a SIR equal to 13.2 (95% CI = 6.90-20.9) in women above 50 years of age. Our findings for the first time support the hypothesis that ovarian endometrioma increases the subsequent risk of developing ovarian cancer in Shizuoka, Japan.

Fluctuating serotonergic function in premenstrual dysphoric disorder and premenstrual syndrome: findings from neuroendocrine challenge tests.

RATIONALE: Premenstrual dysphoric disorder (PMDD) has been assumed to be a subtype of premenstrual syndrome (PMS) with depressive symptoms, such as depressive mood, tension, anxiety, and mood liability during luteal phase. At present, no conclusion has been established about serotonergic function in PMDD. OBJECTIVE: The purpose of this study was to investigate the serotonergic function of PMDD subjects in comparison to PMS without PMDD subjects and normal controls via neuroendocrine challenge tests. SUBJECTS AND METHODS: Twenty-four women (seven with PMDD, eight with PMS without PMDD, and nine normal controls) were tested on three occasions (follicular phase, early luteal phase, and late luteal phase) receiving paroxetine 20 mg orally as a serotonergic probe at 8:00 A: .M: . Plasma ACTH and cortisol were measured prior to the administration and every hour for 6 h thereafter. RESULTS: As a whole, there were significant differences in serotonergic function measured by ACTH and cortisol responses to paroxetine challenge across these three groups. PMDD subjects showed higher serotonergic function in follicular phase but lower serotonergic function in luteal phase, compared with women with PMS without PMDD and normal controls. CONCLUSION: The present findings suggest that PMDD women have fluctuating serotonergic function across their menstrual cycles and that the pattern may be different from PMS without PMDD.

Role of prostaglandin E2 receptor subtypes in ovarian follicle growth in the rat in vivo. Correlation with interleukin-8 and neutrophils.

UNLABELLED: This study was conducted to elucidate the role of three of prostaglandin E2 (PGE2) receptor subtype (EP2, EP3, and EP4) agonists in the process of follicular growth. The influence of these agonists on ovarian expression of intimately related factors to follicle development (neutrophils and interleukin-8 (IL-8)) was also investigated. Immature female Wistar rats were injected once with these agonists and killed 48 hours later. Another group of rats were injected pregnant mare serum gonadotrophin. For evaluation of follicle growth, morphometric assessment of antral and ovulatory follicles was performed in serial ovarian sections. The study demonstrated that, EP2 and EP4 agonists showed the maximum follicle counts and diameters versus the control. EP2 and EP4 agonists mimicked PMSG induced follicle growth. Injection of the three agonists induced neutrophil infiltration into theca layer. EP4 agonist showed the most intense ovarian neutrophil accumulation. In addition, dense ovarian IL-8 expression was observed only after EP4 agonist injection. CONCLUSIONS: Our data suggests that: 1) EP2 and EP4 receptors are the key PGE2 receptors engaged in follicle growth. 2) Ovarian IL-8 expression and neutrophil infiltration are chiefly mediated via the EP4 receptor. EP2 and EP4 receptor agonists may be candidates for promising reagents that induce follicle maturation in clinical or agricultural fields. This knowledge could provide numerous targets for manipulation of fertility.

Dendritic cell differentiation and maturation in embryonic rat liver: immunohistochemistry and electron microscopy with reference to dendritic cell contacts.

This study investigated the dendritic cell (DC) differentiation in embryonic rat liver utilizing in situ ultrastructural characterization and immunohistochemistry. The study revealed the existence of DCs early in hepatic ontogeny with positive immune staining to the OX-62 monoclonal antibody. DCs existed in three differentiating stages: immature, mature and transitional forms in between. At 14 and 16 days of gestation, immature and transitional forms of DCs dominated. Mature cells increased significantly in number through late gestational days (18 days onwards). DCs (particularly mature and moderate mature forms) revealed signs of active phagocytosis manifested by the existence of cytoplasmic phagosomes and heterophagosomes. At 18 days of gestation as well as newborn liver mature DCs displayed two distinct morphological phenotypes according to the degree of development of either the smooth endoplasmic reticulum or the lysosomal compartment. Mature DCs delineated close appositions to other DCs, hepatocytes, and clustering with lymphocytes especially through their cellular processes. The features of phagocytosis and DC-T-cell contacts may signify a role of DCs in immune surveillance in the embryonic liver.

Switching female schizophrenic patients to quetiapine from conventional antipsychotic drugs: effects on hyperprolactinemia.

INTRODUCTION: Conventional antipsychotic medications are associated with elevated prolactin levels, resulting in hyperprolactinemia and a number of unwanted side effects. Several atypical antipsychotics, on the other hand, are less likely to evoke hyperprolactinemia. The aim of this study was to investigate the prevalence of hyperprolactinemia induced by conventional antipsychotic drugs, examine changes in serum prolactin levels and psychiatric symptoms after switching to quetiapine, and identify the relevant characteristics of patients who may be suitable to switch to quetiapine. METHOD: Sixty-nine of 74 consecutive female patients who had received conventional antipsychotic drugs were initially included in the study. Of these, 49 (71 %) patients suffered from hyperprolactinemia, of which a further 25 were subsequently switched to quetiapine. Psychiatric symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS), and serum prolactin levels were measured just before and at 4 and 8 weeks after switching. RESULTS: Eight of the 25 (32 %) "switch" patients dropped out due to psychotic exacerbation during the 8 weeks. In the remaining 17 (68 %) patients, serum prolactin levels were significantly decreased without any significant change in PANSS scores after switching. The 17 patients who completed the switch had previously demonstrated significantly lower positive symptom scores compared to the 8 dropout patients. CONCLUSION: The present findings suggest that 71 % of female patients receiving conventional antipsychotic drugs may suffer from hyperprolactinemia and that approximately two-thirds of patients can be switched to quetiapine, resulting in an improvement in hyperprolactinemia. The main characteristic of the switched patients may be fewer positive symptoms.

A male case of monosymptomatic hypochondriacal psychosis responding to olanzapine: a case report.

We report the case of a 62-year-old man with monosymptomatic hypochondriacal psychosis who failed to respond to paroxetine treatment. Olanzapine addition brought about dramatic improvement in the patient's condition and thereafter paroxetine withdrawal further eliminated his psychosis. These findings suggest that olanzapine itself may be effective for the treatment of monosymptomatic hypochondriacal psychosis. Further controlled studies are required, but this is the first report describing an olanzapine effect in a male patient with monosymptomatic hypochondriacal psychosis.