Short- and long-term evaluation of cognitive functions after electroconvulsive therapy in a Japanese population.

AIM: While electroconvulsive therapy (ECT) is a well-established, safe, and effective treatment for mental illnesses, the potential for adverse effects on cognitive functions remains controversial. We aimed to evaluate multiple cognitive functions in different time periods before and after ECT in a Japanese population. METHODS: A battery of five neurocognitive tests was administered to patients who underwent a course of ECT treatment at three time points: before, immediately after, and 4 weeks after ECT. RESULTS: A transient but significant decline in letter fluency function was observed immediately after ECT, but had recovered well by 4 weeks. We also observed a significant improvement in the trail-making task at 4 weeks after ECT. CONCLUSION: In a Japanese population, adverse effects of ECT on verbal fluency function-related and other cognitive impairments were transient. Over the longer term, we detected significant improvements in the performance of tasks that presumably reflected information processing speed and executive functions.

Plasma Amyloid-ß and Alzheimer's Disease-Related Changes in Late-Life Depression.

To elucidate an involvement of amyloid dysmetabolism in the pathophysiology of depression, we investigated associations of plasma amyloid-ß (Aß) levels with Alzheimer's disease-related changes in neuroimaging and cognitive dysfunction in patients with late-life depression. Higher plasma Aß40, but not Aß42 nor Aß40/Aß42 ratio, was associated with higher degree of parahippocampal atrophy and lower verbal fluency performance. Indeed, high plasma Aß40 predicted poor cognitive prognosis of depressed patients with mild cognitive impairment. As an anti-depressive treatment, electroconvulsive therapy (ECT) resulted in a marginally significant reduction of plasma Aß40 compared to pharmacotherapy alone, suggesting protective effects of ECT against amyloid dysmetabolism.

Clinical impact of (11)C-Pittsburgh compound-B positron emission tomography carried out in addition to magnetic resonance imaging and single-photon emission computed tomography on the diagnosis of Alzheimer's disease in patients with dementia and mild cognitive impairment.

AIMS: The purpose of this study was to evaluate the clinical impact of addition of [(11)C]Pittsburgh compound-B positron emission tomography ((11)C-PiB PET) on routine clinical diagnosis of Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI), and to assess diagnostic agreement between clinical criteria and research criteria of the National Institute on Aging-Alzheimer's Association. METHODS: The diagnosis in 85 patients was made according to clinical criteria. Imaging examinations, including both magnetic resonance imaging and single-photon emission computed tomography/computed tomography to identify neuronal injury (NI), and (11)C-PiB PET to identify amyloid were performed, and all subjects were re-categorized according to the research criteria. RESULTS: Among 40 patients with probable AD dementia (ProAD), 37 were NI-positive, 29 were (11)C-PiB-positive, and 27 who were both NI- and (11C-PiB-positive were categorized as having 'ProAD dementia with a high level of evidence of the AD pathophysiological process'. Among 20 patients with possible AD dementia (PosAD), 17 were NI-positive, and six who were both NI- and (11)C-PiB-positive were categorized as having 'PosAD with evidence of the AD pathophysiological process'. Among 25 patients with MCI, 18 were NI-positive, 13 were (11)C-PiB-positive, and 10 who were both NI- and (11)C-PiB-positive were categorized as having 'MCI due to AD-high likelihood'. CONCLUSIONS: Diagnostic concordance between clinical criteria and research criteria may not be high in this study. (11)C-PiB PET may be of value in making the diagnosis of dementia and MCI in cases with high diagnostic uncertainty.

Immunohistochemical characterization of CD33 expression on microglia in Nasu-Hakola disease brains.

Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, characterized by formation of multifocal bone cysts and development of leukoencephalopathy, caused by genetic mutations of either DNAX-activation protein 12 (DAP12) or triggering receptor expressed on myeloid cells 2 (TREM2). Although increasing evidence suggests a defect in microglial TREM2/DAP12 function in NHD, the molecular mechanism underlying leukoencephalopathy with relevance to microglial dysfunction remains unknown. TREM2, by transmitting signals via the immunoreceptor tyrosine-based activation motif (ITAM) of DAP12, stimulates phagocytic activity of microglia, and ITAM signaling is counterbalanced by sialic acid-binding immunoglobulin (Ig)-like lectins (Siglecs)-mediated immunoreceptor tyrosine-based inhibitory motif (ITIM) signaling. To investigate a role of CD33, a member of the Siglecs family acting as a negative regulator of microglia activation, in the pathology of NHD, we studied CD33 expression patterns in five NHD brains and 11 controls by immunohistochemistry. In NHD brains, CD33 was identified exclusively on ramified and amoeboid microglia accumulated in demyelinated white matter lesions but not expressed in astrocytes, oligodendrocytes, or neurons. However, the number of CD33-immunoreactive microglia showed great variability from case to case and from lesion to lesion without significant differences between NHD and control brains. These results do not support the view that CD33-expressing microglia play a central role in the development of leukoencephalopathy in NHD brains.

Autistic-like traits in adult patients with mood disorders and schizophrenia.

Autism spectrum disorder often co-occurs with other psychiatric disorders. Although a high prevalence of autistic-like traits/symptoms has been identified in the pediatric psychiatric population of normal intelligence, there are no reports from adult psychiatric population. This study examined whether there is a greater prevalence of autistic-like traits/symptoms in patients with adult-onset psychiatric disorders such as major depressive disorder (MDD), bipolar disorder, or schizophrenia, and whether such an association is independent of symptom severity. The subjects were 290 adults of normal intelligence between 25 and 59 years of age (MDD, n=125; bipolar disorder, n=56; schizophrenia, n=44; healthy controls, n=65). Autistic-like traits/symptoms were measured using the Social Responsiveness Scale for Adults. Symptom severity was measured using the Positive and Negative Symptoms Scale, the Hamilton Depression Rating Scale, and/or the Young Mania Rating Scale. Almost half of the clinical subjects, except those with remitted MDD, exhibited autistic-like traits/symptoms at levels typical for sub-threshold or threshold autism spectrum disorder. Furthermore, the proportion of psychiatric patients that demonstrated high autistic-like traits/symptoms was significantly greater than that of healthy controls, and not different between that of remitted or unremitted subjects with bipolar disorder or schizophrenia. On the other hand, remitted subjects with MDD did not differ from healthy controls with regard to the prevalence or degree of high autistic-like traits/symptoms. A substantial proportion of adults with bipolar disorder and schizophrenia showed high autistic-like traits/symptoms independent of symptom severity, suggesting a shared pathophysiology among autism spectrum disorder and these psychiatric disorders. Conversely, autistic-like traits among subjects with MDD were associated with the depressive symptom severity. These findings suggest the importance of evaluating autistic-like traits/symptoms underlying adult-onset psychiatric disorders for the best-suited treatment. Further studies with a prospective design and larger samples are needed.

Reduced cerebrospinal fluid ethanolamine concentration in major depressive disorder.

Amino acids play key roles in the function of the central nervous system, and their alterations are implicated in psychiatric disorders. In the search for a biomarker for major depressive disorder (MDD), we used high-performance liquid chromatography to measure amino acids and related molecules in the cerebrospinal fluid (CSF) of 52 patients with MDD (42 depressed and 10 remitted; DSM-IV) and 54 matched controls. Significant differences were found in four amino acid concentrations between the depressed patients and controls. After Bonferroni correction, only ethanolamine (EA) levels remained significantly reduced in depressed patients (nominal P = 0.0000011). A substantial proportion of the depressed patients (40.5%) showed abnormally low CSF EA levels (<12.1 µM) (P = 0.000033; OR = 11.6, 95% CI: 3.1-43.2). When patients with low EA and those with high EA levels were compared, the former had higher scores for overall depression severity (P = 0.0033) and 'Somatic Anxiety' symptoms (P = 0.00026). In unmedicated subjects, CSF EA levels showed a significant positive correlation with levels of homovanillic acid (P = 0.0030) and 5-hydroxyindoleacetic acid (P = 0.019). To our knowledge, this is the first study showing that patients with MDD have significantly lower CSF EA concentrations compared with control subjects. CSF EA could be a state-dependent biomarker for a subtype of MDD.

Seizure threshold and the half-age method in bilateral electroconvulsive therapy in Japanese patients.

AIM: Seizure threshold (ST) in electroconvulsive therapy (ECT) has not been reported previously in Japanese patients. We investigated ST in bilateral ECT in Japanese patients using the dose-titration method. The associations between demographic and clinical characteristics and ST were analyzed to identify the predictors of ST. Finally, the validity of the half-age method for the stimulus dose was evaluated. METHODS: Fifty-four Japanese patients with mood disorder, schizophrenia, and other psychotic disorders received an acute course of bilateral ECT using a brief-pulse device. ST was determined at the first session using a fixed titration schedule. ST was correlated with age, sex, body mass index, history of previous ECT, and psychotropic drugs on multiple regression analysis. Furthermore, the rate of accomplished seizures was calculated using the half-age method. RESULTS: Mean ST was 136 mC. ST was influenced by age, sex, history of previous ECT, and medication with benzodiazepines. The accomplished seizure rate using the half-age method was 72%, which was significantly lower in men and subjects on benzodiazepines. CONCLUSION: ST in Japanese patients was equal to or slightly higher than that previously reported in other ethnic groups, which might be attributable, at least in part, to high prevalence of and large-dose benzodiazepine prescription. Higher age, male gender, no history of ECT, and benzodiazepines were related to higher ST. The half-age method was especially useful in female patients and subjects without benzodiazepine medication.

Plasma L-tryptophan concentration in major depressive disorder: new data and meta-analysis.

OBJECTIVE: Tryptophan, an essential amino acid, is the precursor to serotonin and is metabolized mainly by the kynurenine pathway. Both serotonin and kynurenine have been implicated in the pathophysiology of major depressive disorder (MDD). However, plasma tryptophan concentration in patients with MDD has not unequivocally been reported to be decreased, which prompted us to perform a meta-analysis on previous studies and our own data. DATA SOURCES: We searched the PubMed database for case-control studies published until August 31, 2013, using the search terms plasma AND tryptophan AND synonyms for MDD. An additional search was performed for the term amino acid instead of tryptophan. We obtained our own data in 66 patients with MDD (DSM-IV) and 82 controls who were recruited from March 2011 to July 2012. The majority of the patients were medicated (N = 53). Total plasma tryptophan concentrations were measured by the liquid chromatography/mass spectrometry method. STUDY SELECTION: We scrutinized 160 studies for eligibility. Original articles that were written in English and documented plasma tryptophan values in patients and controls were selected. DATA EXTRACTION: We included 24 studies from the literature and our own data in the meta-analysis, which involved a total of 744 patients and 793 controls. Data on unmedicated patients (N = 156) and their comparison subjects (N = 203) were also extracted. To see the possible correlation between tryptophan concentrations and depression severity, meta-regression analysis was performed for 10 studies with the Hamilton Depression Rating Scale 17-item version score. RESULTS: In our case-control study, mean (SD) plasma tryptophan level was significantly decreased in the MDD patients versus the controls (53.9 [10.9] vs 57.2 [11.3] µmol/L; P = .03). The meta-analysis after adjusting for publication bias showed a significant decrease in patients with MDD with a modest effect size (Hedges g, -0.45). However, analysis on unmedicated subjects yielded a large effect (Hedges g, -0.84; P = .00015). We found a weak association with depression severity in the meta-regression analysis (P = .049). CONCLUSIONS: This meta-analysis provides convincing evidence for reduced plasma tryptophan levels in patients with MDD, particularly in unmedicated patients.

LC3, an autophagosome marker, is expressed on oligodendrocytes in Nasu-Hakola disease brains.

BACKGROUND: Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder characterized by sclerosing leukoencephalopathy and multifocal bone cysts, caused by a loss-of-function mutation of either DAP12 or TREM2. TREM2 and DAP12 constitute a receptor/adaptor signaling complex expressed exclusively on osteoclasts, dendritic cells, macrophages, and microglia. Neuropathologically, NHD exhibits profound loss of myelin and accumulation of axonal spheroids, accompanied by intense gliosis accentuated in the white matter of the frontal and temporal lobes. At present, the molecular mechanism responsible for development of leukoencephalopathy in NHD brains remains totally unknown. METHODS: By immunohistochemistry, we studied the expression of microtubule-associated protein 1 light chain 3 (LC3), an autophagosome marker, in 5 NHD and 12 control brains. RESULTS: In all NHD brains, Nogo-A-positive, CNPase-positive oligodendrocytes surviving in the non-demyelinated white matter intensely expressed LC3. They also expressed ubiquitin, ubiquilin-1, and histone deacetylase 6 (HDAC6) but did not express Beclin 1 or sequestosome 1 (p62). Substantial numbers of axonal spheroids were also labeled with LC3 in NHD brains. In contrast, none of oligodendrocytes expressed LC3 in control brains. Furthermore, surviving oligodendrocytes located at the demyelinated lesion edge of multiple sclerosis (MS) did not express LC3, whereas infiltrating Iba1-positive macrophages and microglia intensely expressed LC3 in MS lesions. CONCLUSIONS: These results propose a novel hypothesis that aberrant regulation of autophagy might induce oligodendrogliopathy causative of leukoencephalopathy in NHD brains.

[Role of oxidative stress in the pathophysiology of neuropsychiatric disorders].

The brain is particularly vulnerable to oxidative damage because of its high rate of oxygen consumption, abundant lipid content, and relative paucity of antioxidant enzymes compared with other organs. It has been well established that oxidative stress (OS) is involved in the pathogenesis of age-associated neurodegenerative disorders such as Alzheimer's disease (AD). Indeed, a large number of genetic and environmental factors of neurodegenerative disorders are associated with OS. Of note, studies on the levels of oxidative damage in patients with the prodromal stage of AD, transgenic animal models of AD, and induced pluripotent stem (iPS) cells derived from AD patients support the early-stage involvement of OS in the pathological cascade of the disorder. Recently, a growing body of evidence suggests that a considerable number of genetic and environmental factors of psychiatric disorders such as schizophrenia (SZ), bipolar disorders, and depression are associated with OS. Not only genetic polymorphisms in genes encoding antioxidant enzymes but also several known susceptible genes for psychiatric disorders, i. e., Disrupted-in-Schizophrenia-1 (DISC1), Neuregulin 1 (NRG1), proline dehydrogenase (PRODH), and G72, are all associated with increased levels of OS or decreased antioxidant capacities. Moreover, environmental factors such as infection, hypoxia, malnutrition, illicit substance use, and psychosocial stress are possibly associated with OS. In fact, increased levels of oxidized nucleic acids, proteins, and lipids have been described in the postmortem brains of patients with SZ and bipolar disorders, and decreased antioxidant capacities have been described in blood samples obtained from patients with first-episode psychosis. In concordance, iPS cells from SZ patients show an increased level of OS. Of particular interest is a conditional gene knockout mouse model of SZ with the functional elimination of NMDA receptors specifically from cortical interneurons. The NMDA receptor knockout mouse shows behavioral phenotypes resembling symptoms of human SZ. Importantly, a marked increase of OS, particularly in the cortical parvalbumin-positive interneurons, is rapidly exacerbated by post-weaning social isolation, but treatment with antioxidants abolishes OS and partially alleviates the SZ-like behavioral phenotypes. Therefore, it is suggested that OS is a convergence point for genetic and environmental susceptibilities to not only neurodegenerative but also psychiatric disorders. In other words, OS potentially plays a central role in the pathomechanisms that integrate gene-environment interactions in neuropsychiatric disorders. Further investigations into the development of useful OS biomarkers and efficacious OS-targeting interventions may shed light on a promising approach for establishing preemptive strategies against neuropsychiatric disorders.

An open-label study of algorithm-based treatment versus treatment-as-usual for patients with schizophrenia.

OBJECTIVE: The use of an algorithm may facilitate measurement-based treatment and result in more rational therapy. We conducted a 1-year, open-label study to compare various outcomes of algorithm-based treatment (ALGO) for schizophrenia versus treatment-as-usual (TAU), for which evidence has been very scarce. METHODS: In ALGO, patients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, fourth edition) were treated with an algorithm consisting of a series of antipsychotic monotherapies that was guided by the total scores in the positive and negative syndrome scale (PANSS). When posttreatment PANSS total scores were above 70% of those at baseline in the first and second stages, or above 80% in the 3rd stage, patients proceeded to the next treatment stage with different antipsychotics. In contrast, TAU represented the best clinical judgment by treating psychiatrists. RESULTS: Forty-two patients (21 females, 39.0 ± 10.9 years-old) participated in this study. The baseline PANSS total score indicated the presence of severe psychopathology and was significantly higher in the ALGO group (n = 25; 106.9 ± 20.0) than in the TAU group (n = 17; 92.2 ± 18.3) (P = 0.021). As a result of treatment, there were no significant differences in the PANSS reduction rates, premature attrition rates, as well as in a variety of other clinical measures between the groups. Despite an effort to make each group unique in pharmacologic treatment, it was found that pharmacotherapy in the TAU group eventually became similar in quality to that of the ALGO group. CONCLUSION: While the results need to be carefully interpreted in light of a hard-to-distinguish treatment manner between the two groups and more studies are necessary, algorithm-based antipsychotic treatments for schizophrenia compared well to treatment-as-usual in this study.

Mood and cognitive function following repeated transcranial direct current stimulation in healthy volunteers: a preliminary report.

Although mood and cognitive function have been reported to change following transcranial direct current stimulation (tDCS) in patients with neurological and psychiatric diseases, little is known about the effects of repeated tDCS on mood and cognition in healthy humans. We recruited 11 healthy male participants for this single-blind, sham-controlled crossover trial. We used Profile of Mood States, brief-form (POMS), and CogHealth (Detection Task, Identification Task, One Back Task, One Card Learning Task and Continuous Monitoring Task) to evaluate the changes in mood and cognitive function, respectively, before and immediately after 4-daily, 20 min, 1 mA sham or anodal tDCS over the left dorsolateral prefrontal cortex (DLPFC). While there were no significant changes in six factors of POMS and performance (speed and accuracy) of CogHealth between sham and anodal stimulation, the accuracy of One Card Learning was increased at the end of the experiment. Signal detection analyses revealed that both hit rate and discriminability were improved in this task. These results suggest that 4-daily anodal tDCS over left DLPFC may not change mood and cognitive function in healthy subjects, and further support the safety of tDCS. A slight improvement in a visual recognition and learning task at the end of experiment may be susceptible to practice effects.

[Will electroconvulsive therapy disappear in the near future?].

Electroconvulsive therapy (ECT) has been widely used, with some modification of its methods, for the treatment of refractory mental disorders. In Japan, brief-pulse ECT was approved in 2002 under conditions that well-trained psychiatrists should administer ECT and that modified ECT is mandatory. However, unmodified ECT is still often performed in Japan. We have to improve safety of ECT further. Major indications for ECT are depression and catatonia. Mechanisms of ECT are still unknown, but the neurogenesis hypothesis is promising. Furthermore, several brain stimulation techniques without seizure induction, such as transcranial magnetic stimulation, vagus nerve stimulation, deep brain stimulation and transcranial direct current stimulation, have been introduced for the treatment of refractory mental disorders. Ethical criteria must be determined for further research and treatment with these techniques.

The earliest stage of cognitive impairment in transition from normal aging to Alzheimer disease is marked by prominent RNA oxidation in vulnerable neurons.

Although neuronal RNA oxidation is a prominent and established feature in age-associated neurodegenerative disorders such as Alzheimer disease (AD), oxidative damage to neuronal RNA in aging and in the transitional stages from normal elderly to the onset of AD has not been fully examined. In this study, we used an in situ approachto identify an oxidized RNA nucleoside 8-hydroxyguanosine (8OHG) in the cerebral cortex of 65 individuals without dementia ranging in age from 0.3 to 86 years. We also examined brain samples from 20 elderly who were evaluated for their premortem clinicaldementia rating score and postmortem brain pathologic diagnoses to investigate preclinical AD and mild cognitive impairment. Relative density measurements of 8OHG-immunoreactivity revealed a statistically significant increase in neuronal RNA oxidation during aging in the hippocampus and the temporal neocortex. In subjects with mild cognitive impairment but not preclinical AD, neurons of the temporal cortex showed a higher burden of oxidized RNA compared to age-matched controls. These results indicate that, although neuronal RNA oxidation fundamentally occurs as an age-associated phenomenon, more prominent RNA damage than in normal aging correlates with the onset of cognitive impairment in the prodromal stage of AD.

Differences in cerebral blood flow between missed and generalized seizures with electroconvulsive therapy: a positron emission tomographic study.

While examining the acute effects of electroconvulsive therapy (ECT) on regional cerebral blood flow (rCBF), we could compare the changes in rCBF between missed (not generalized) and generalized seizures using H(2)(15)O positron emission tomography in patients with depression under anesthesia. In contrast to missed seizures, rCBF was increased extensively, particularly in the centrencephalic structures in generalized seizures. These results further support the centrencephalic theory of seizure generalization.

Chronic repetitive transcranial magnetic stimulation failed to change dopamine synthesis rate: preliminary L-[ß-11C]DOPA positron emission tomography study in patients with depression.

We have examined the effects of repetitive transcranial magnetic stimulation (rTMS) on central dopaminergic function in patients with depression using positron emission tomography with L-[ß-11C]DOPA, a ligand to assess the rate of endogenous dopamine synthesis. Eight patients were treated with 10-daily sessions of rTMS over the left dorsolateral prefrontal cortex. Positron emission tomography scanning was performed in each patient twice, before the first session and 1 day after the last session. Although four out of eight patients responded to rTMS, there were no changes in the striatal dopamine synthesis rate (k) following rTMS. These results suggest that chronic rTMS had a limited effect on the dopaminergic system.

Intraneuronal amyloid beta accumulation and oxidative damage to nucleic acids in Alzheimer disease.

In an analysis of amyloid pathology in Alzheimer disease, we used an in situ approach to identify amyloid-beta (Abeta) accumulation and oxidative damage to nucleic acids in postmortem brain tissue of the hippocampal formation from subjects with Alzheimer disease. When carboxyl-terminal-specific antibodies directed against Abeta40 and Abeta42 were used for immunocytochemical analyses, Abeta42 was especially apparent within the neuronal cytoplasm, at sites not detected by the antibody specific to Abeta-oligomer. In comparison to the Abeta42-positive neurons, neurons bearing oxidative damage to nucleic acids were more widely distributed in the hippocampus. Comparative density measurements of the immunoreactivity revealed that levels of intraneuronal Abeta42 were inversely correlated with levels of intraneuronal 8-hydroxyguanosine, an oxidized nucleoside (r=- 0.61, p<0.02). Together with recent evidence that the Abeta peptide can act as an antioxidant, these results suggest that intraneuronal accumulation of non-oligomeric Abeta may be a compensatory response in neurons to oxidative stress in Alzheimer disease.

Revised psychopharmacological algorithms for the treatment of mood disorders in Japan.

Objective. To revise the psychopharmacology algorithms for the treatment of mood disorders published in 1999 in Japan. Methods. The algorithms were established based on clinical psychopharmacological evidence, the results of a questionnaire survey sent to 200 Japanese psychiatrists, and the consensus of all the research members. Results. Six categorized algorithms have been developed, i.e. mild or moderate major depression, severe non-psychotic major depression, psychotic depression, mania, bipolar depression, and rapid cycling mood disorder. Conclusion. The revised algorithms will be helpful for the treatment of mood disorders in Japan.

[Other treatments for depressive patients].

Electroconvulsive therapy(ECT) is one of the most important methods in treating depressive patients especially who can not be improved with medication. Meta analysis shows that ECT is superior to pharmacotherapy as acute treatment for depression. ECT was invented in 1938, and it took some improvement afterwards such as development of modified ECT and introduction of brief-pulse stimulation for the purpose of reducing adverse effects. However, adverse effects such as cognitive impairment are not completely solved, and some patients do not respond to ECT. Transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS) and deep brain stimulation (DBS) are under investigation to get over the shortcomings of ECT.