Hideto Shinno

Decreased levels of whole blood glial cell line-derived neurotrophic factor (GDNF) in remitted patients with mood disorders

Recent post-mortem and imaging studies provide evidence for a glial reduction in different brain areas in mood disorders. This study was aimed to test whether glial cell line-derived neurotrophic factor (GDNF), a member of transforming growth factor (TGF)-beta superfamily, in blood levels was associated with mood disorders. We measured GDNF and TGF-beta levels in whole blood in remitted patients with mood disorders [n=56; major depressive disorders (MDD) 39, bipolar disorders (BD) 17] and control subjects (n=56). GDNF and TGF-beta were assayed with the sandwich ELISA method. Total GDNF levels were significantly lower in MDD and in BD than in control subjects (MDD, p=0.0003; BD, p=0.018), while no significant difference in total TGF-beta1 or total TGF-beta2 levels was found in these groups. Our study suggests that lower GDNF levels might be involved in the pathophysiology of mood disorders, although this preliminary study has several limitations.

Effect of Yi-Gan San on psychiatric symptoms and sleep structure at patients with behavioral and psychological symptoms of dementia.

OBJECTIVE Recently, traditional herbal medicines have been reported to be effective for behavioral and psychological symptoms of dementia (BPSD). This study aims to examine the efficacy of Yi-Gan San (YGS) in the improvement of BPSD and sleep disorders in patients with dementia. METHODS Five patients (1 male and 4 female) with dementia in accordance with DSM-IV criteria were investigated. Participants were treated with YGS for 4 weeks. The Nursing Home version of Neuropsychiatric Inventory (NPI-NH) for the assessment of BPSD, the Mini-Mental State Examination (MMSE) for cognitive function, polysomnography for evaluation of sleep structure, and the Pittsburgh Sleep Quality Index for subjective sleep quality were carried out at baseline and at the end of treatment. RESULTS All patients completed the trial. Significant improvements in the total NPI-NH score (34.0+/-6.5 to 12.8+/-6.6) as well as delusions, hallucinations, agitation/aggression, anxiety, and irritability/lability, whereas MMSE scores were unchanged. PSG revealed increases in total sleep time, sleep efficiency, stage 2 sleep, and decreases in the number of arousals and periodic limb movements. Subjective sleep quality was also improved. No adverse effects were observed. CONCLUSION YGS was effective for BPSD and sleep disturbances, and well tolerated in patients with dementia. Further examinations using a double-blind placebo-controlled design are necessary.

A decrease in N-acetylaspartate and an increase in myoinositol in the anterior cingulate gyrus are associated with behavioral and psychological symptoms in Alzheimer's disease.

BACKGROUND AND PURPOSE The cognitive decline in Alzheimers disease (AD) patients has been reported to involve alterations in the medial temporal lobe and the posterior cingulate gyrus. On the other hand, the neurochemical pathologies of the behavioral and psychological symptoms of dementia (BPSD) have not been sufficiently discussed. The aim of this study was to clarify the pathologies of BPSD in AD patients. METHODS Thirty patients with probable AD were included and underwent the following assessments: Mini Mental State Examination (MMSE), Clock Drawing Test (CDT), Story Recall Test (SRT), Behavioral pathology in Alzheimers disease (BEHAVE-AD) and proton MRS ((1)H-MRS). None of them had been medicated for BPSD. RESULTS The MRS study revealed that MMSE, CDT, and SRT scores were positively related to N-acetyl-aspartate (NAA)/creatine(Cr) and negatively related to myoinositol (mI)/Cr in the posterior cingulate gyrus, but not in the anterior cingulate gyrus. On the other hand, the scores obtained in two categories of BEHAVE-AD (delusional thought/ activity disturbances) were negatively related with NAA/Cr and positively related with mI/Cr in the anterior cingulate gyrus, but not in the posterior cingulate gyrus. CONCLUSION We conclude that BPSD and the decline in cognitive function in AD might have separate pathologies.

Successful treatment with Yi-Gan San for rapid eye movement sleep behavior disorder.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia observed among the elderly, and is characterized by the absence of REM atonia and the appearance of dream-enacting behaviors. These oneiric behaviors are usually violent or injurious (Mahowald and Schenck, 2005). Clonazepam is an effective first-line agent for RBD treatment (Mahowald and Schenck, 2005). It has been reported that clonazepam is effective in nearly 90% of RBD cases (Schenck et al., 1993). A proportion of RBD patients are refractory to clonazepam because of adverse effects characteristic of benzodiazepines. Yi-Gan San (YGS) contains seven different herbal ingredients Atractylodes lanceae rhizoma, Hoelen, Cnidii rhizoma, Angelicae radix, Bupleuri radix and Glycyrrhizae radix. YGS was developed as a remedy for restlessness and agitation. In Japan, YGS prescription has been approved for patients with insomnia, although the mechanism whereby YGS alleviates sleep disturbances remains to be elucidated. We previously reported that YGS improved sleep quality in patients with dementia (Shinno et al., 2008). We encountered three patients with idiopathic RBD that were successfully treatedwithYGS.Here,wepresent the clinical course of RBD (Fig. 1), and discuss the possible mechanisms of YGS treatment for RBD.

Factors disturbing treatment for cancer in patients with schizophrenia

Abstract  Patients with schizophrenia who develop cancer often have a variety of complicated medical and psychiatric problems. Problems associated with receiving a diagnosis of cancer and with understanding or cooperating with medical treatment may develop. Research in managing and treating schizophrenia patients with cancer is scarce. Presented herein is the experience of the authors’ consultation–liaison psychiatry service in treating patients with schizophrenia who have cancer, and discussion of the medical management of such cases. Fourteen patients were treated between April 1999 and March 2003 and included patients receiving consultation psychiatric services at Shimane University Hospital as well as patients referred from other psychiatric hospitals. These patients were divided into two groups based on whether they were amenable to cancer treatment or not. The treated group consisted of patients who accepted cancer treatment, and the untreated group consisted of patients who refused or interrupted the cancer treatment. The clinical course, clinical psychiatric symptoms, problems in understanding cancer, cancer treatment course and convalescence were retrospectively assessed. Psychiatric symptoms and state were measured using the Brief Psychiatric Rating Scale (BPRS) and the Positive and Negative Syndrome Scale (PANSS). The mean of the duration of schizophrenia in these two groups was not significantly different. The mean scores on measures of psychiatric symptoms in each group (treated and untreated) were as follows: BPRS, 45.3 ± 15.4 and 64.9 ± 9.2 (P < 0.05); positive symptoms scores on PANSS, 14.4 ± 8.8 and 20.6 ± 6.0 (NS); negative symptoms scores on PANSS, 20.6 ± 4.7 and 33.6 ± 4.4 (P < 0.01); and total scores on PANSS, 31.7 ± 7.0 and 48.6 ± 7.4 (P < 0.01). Patients with severe negative symptoms had greater difficulty understanding and cooperating with the cancer treatment. Regarding cancer stage, when cancer was discovered, the disease had already advanced and was no longer amenable to first‐line treatment. Regarding notification of the diagnosis, it was rarely possible to give sufficiently early notice to patients in the untreated group. The important role of consultation–liaison psychiatrist in treating cancer patients is suggested. Some steps are proposed for managing schizophrenia patients with cancer who are not able to give informed consent.

Successful treatment with levothyroxine for idiopathic hypersomnia patients with subclinical hypothyroidism

OBJECTIVE Our objective was to discuss the effect of levothyroxine on excessive daytime sleepiness (EDS) and a prolonged nocturnal sleep at patients with idiopathic hypersomnia who presented with subclinical hypothyroidism. METHODS We present two patients with hypersomnia who complained of EDS and a prolonged nocturnal sleep time. Sleep architecture and subjective daytime sleepiness were estimated by polysomnography (PSG) and Epworth Sleepiness Scale (ESS), respectively. Diagnoses were made using the International Classification of Sleep Disorders, 2nd Edition criteria for idiopathic hypersomnia with long sleep time. RESULTS PSG demonstrated a short sleep latency, a prolonged total sleep time and normal proportions of all non-rapid eye movement (REM) and REM sleep stages. Nocturnal PSG excluded other causes of EDS. No medical, neurological and mental disorders were present. Their laboratory data indicated mildly elevated thyrotropin, despite free thyroxine (T4) and triiodothyronine (T3) estimates within their reference ranges, which is a characteristic of latent hypothyroidism. Levothyroxine (25 microg/day) was administrated orally. After treatment with levothyroxine for 8 weeks, the mean daily sleep times decreased. EDS was also improved, and a significant decrease in the ESS score was observed. Levothyroxine was effective for their hypersomnia and well tolerated. CONCLUSIONS It should be noted that hypersomnia may be associated with subclinical hypothyroidism, although few abnormalities in physical and neurological examinations are present.

Successful treatment with quetiapine for delirium in terminally ill cancer patients

We describe six patients with terminal cancer whose delirium improved after they started quetiapine (QTP). Haloperidol (HPD) had failed to improve their delirium, and they had suffered adverse effects, including over‐sedation, extrapyramidal signs and dysphagia. We prescribed QTP to improve their delirium. We evaluated the severity of the delirium using the Japanese version of the Memorial Delirium Assessment Scale (jMDAS) before QTP treatment and 3, 7 and 14 days after QTP administration. The basal the Japanese version of the Memorial Delirium Assessment Scale score ranged from 18 to 24. Effective doses of QTP in the present cases were 12.5–50 mg/day. Delirium improved in all patients, and no significant adverse effects were observed. Several factors appear to contribute to symptoms of delirium in patients with terminal cancer. These causative factors are usually complicated and delirium often is refractory to usual pharmacotherapy, involving typical neuroleptics like HPD. QTP, however, appeared to be useful for delirium treatment in patients with advanced cancer.

Pathogenesis and symptomatology of hallucinations (delusions) of organic brain disorder and schizophrenia.

In this review article, in order to explore the mechanisms underlying the hallucinations/delusions of schizophrenia, we discuss the contribution of the following four questions: (i) can an understanding of dreams contribute to our understanding of the genesis of halluciations and/or delusions; (ii) are the mechanisms underlying psychotropic drug‐induced psychoses the same as those underlying the hallucinations and/or delusions in schizophrenia; (iii) does disturbed consciousness contribute to the manifestation of psychotic features; and (iv) are the psychoses caused by organic brain disorders any different to the hallucinations and/or delusions seen in schizophrenia? We conclude that there is a strong association between drug‐induced hallucinations or hallucinations associated with organic brain disorders and simple hallucinosis or fluctuations in arousal level. Because intermediate configurations and/or cross‐staining phenomena exist for hallucinations and delusions, especially in schizophrenic disorders, it is difficult to isolate the hallucinations and to recognize them as being abnormal experiences.

Effect of levothyroxine on prolonged nocturnal sleep time and excessive daytime somnolence in patients with idiopathic hypersomnia

OBJECTIVE This study aims to examine the effect of levothyroxine, a thyroid hormone, on a prolonged nocturnal sleep and excessive daytime somnolence (EDS) in patients with idiopathic hypersomnia. METHODS In a prospective, open-label study, nine patients were enrolled. All subjects met criteria for idiopathic hypersomnia with long sleep time defined by the International Classification of Sleep Disorders, 2nd edition (ICSD-2). Subjects with sleep apnea syndrome, obesity or hypothyroidism were excluded. Sleep architecture and subjective daytime somnolence were estimated by polysomnography (PSG) and Epworth Sleepiness Scale (ESS), respectively. After baseline examinations, levothyroxine (25μg/day) was orally administered every day. Mean total sleep time, ESS score at baseline were compared with those after treatment (2, 4 and 8 weeks). RESULTS Mean age of participants was 23.8±13.7 years old. At baseline, mean total sleep time (hours) and ESS score were 12.9±0.3 and 17.8±1.4, respectively. Mean total sleep times after treatment were 9.1±0.7 and 8.5±1.0h at 4 and 8 treatment weeks, respectively. Mean ESS scores were 8.8±2.3 and 7.4±2.8 at 4 and 8 treatment weeks, respectively. One patient dropped out at the 2nd week due to poor effect. No adverse effects were noted. CONCLUSIONS After treatment with levothyroxine for over 4 weeks, prolonged sleep time and EDS were improved. Levothyroxine was effective for hypersomnia and well tolerated.

Proposed dose equivalence between clonazepam and pramipexole in patients with restless legs syndrome

BACKGROUND Dopamine agonists are accepted as the first-line medications for restless legs syndrome (RLS). In some Asian countries, clonazepam is one of the prevalent medications for RLS because of its effect on sleep disturbances. To date, there have not been any studies that examined equivalent doses of pramipexole and clonazepam. To evaluate equivalent doses of pramipexole and clonazepam in RLS, we investigated the efficacy and tolerability after conversion from clonazepam to pramipexole, and examined dose equivalence between the two prescriptions. METHODS In a prospective, open-label, multicenter study, 26 RLS patients treated with clonazepam (mean age: 69.2+/-11.0years old) were enrolled and then rapidly switched to pramipexole using a conversion calculation of 4:1 for daily doses. Then the daily dose of pramipexole was up titrated or tapered by 0.125mg/day at each subsequent examination. RLS symptoms and daytime somnolence were evaluated using the International RLS Study Group rating scale (IRLS), Clinical Global Impressions - Severity of illness (CGI-S) and the Epworth Sleepiness Scale (ESS), respectively. RESULTS Conversion from clonazepam to pramipexole resulted in significant reductions of IRLS (16.3+/-8.7 to 9.1+/-6.3) and ESS (6.5+/-4.2 to 4.4+/-3.2). CGI scores demonstrated improvement after conversion. In 4 patients (15%), adverse events such as somnolence, sensation of oppression in the lower limbs, diarrhea, or nausea were present. Correlation analysis demonstrated a significant relationship between these daily doses. Spearmans correlation coefficient was 0.662. Our study, however, has some limitations since it is an open-label trial and includes only 26 patients. Further studies using a double-blind design or a crossover design are recommended. CONCLUSIONS Statistical analysis demonstrated a 4:1 conversion for clonazepam to pramipexole. When switchover from clonazepam to pramipexole is done, this conversion ratio may be helpful to determine the initial dose of pramipexole for treating RLS.