Mirtazapine Monotherapy for Antipsychotics-refractory Psychosis in a Patient with Very-late-onset Schizophrenia-like Psychosis: A Case Report.

Very-late-onset schizophrenia-like psychosis (VLOSLP) is a condition in which psychotic symptoms emerge after the age of 60 years. Given its heterogeneous nature, VLOSLP remains a diagnostic and therapeutic dilemma. Here, we report a case of a 68-year-old patient with psychosis refractory to antipsychotics who was successfully treated with mirtazapine monotherapy. This case suggests that mirtazapine monotherapy may be effective for the treatment of patients with antipsychotic- refractory VLOSLP.

Autoantibodies against NCAM1 from patients with schizophrenia cause schizophrenia-related behavior and changes in synapses in mice.

From genetic and etiological studies, autoimmune mechanisms underlying schizophrenia are suspected; however, the details remain unclear. In this study, we describe autoantibodies against neural cell adhesion molecule (NCAM1) in patients with schizophrenia (5.4%, cell-based assay; 6.7%, ELISA) in a Japanese cohort (n = 223). Anti-NCAM1 autoantibody disrupts both NCAM1-NCAM1 and NCAM1-glial cell line-derived neurotrophic factor (GDNF) interactions. Furthermore, the anti-NCAM1 antibody purified from patients with schizophrenia interrupts NCAM1-Fyn interaction and inhibits phosphorylation of FAK, MEK1, and ERK1 when introduced into the cerebrospinal fluid of mice and also reduces the number of spines and synapses in frontal cortex. In addition, it induces schizophrenia-related behavior in mice, including deficient pre-pulse inhibition and cognitive impairment. In conclusion, anti-NCAM1 autoantibodies in patients with schizophrenia cause schizophrenia-related behavior and changes in synapses in mice. These antibodies may be a potential therapeutic target and serve as a biomarker to distinguish a small but treatable subgroup in heterogeneous patients with schizophrenia.

AKR1A1 Variant Associated With Schizophrenia Causes Exon Skipping, Leading to Loss of Enzymatic Activity.

Schizophrenia is a heterogeneous psychiatric disorder characterized by positive symptoms such as hallucinations and delusions, negative symptoms such as anhedonia and flat affect, and cognitive impairment. Recently, glucuronate (GlucA) levels were reported to be significantly higher in serum of patients with schizophrenia than those in healthy controls. The accumulation of GlucA is known to be related to treatment-resistant schizophrenia, since GlucA is known to promote drug excretion by forming conjugates with drugs. However, the cause of GlucA accumulation remains unclear. Aldo-keto reductase family one member A1 (AKR1A1) is an oxidoreductase that catalyzes the reduction of GlucA. Genetic loss of AKR1A1 function is known to result in the accumulation of GlucA in rodents. Here, we aimed to explore genetic defects in AKR1A1 in patients with schizophrenia, which may result in the accumulation of GlucA. We identified 28 variants of AKR1A1 in patients with schizophrenia and control subjects. In particular, we identified a silent c.753G > A (rs745484618, p. Arg251Arg) variant located at the first position of exon 8 to be associated with schizophrenia. Using a minigene assay, we found that the c.753G > A variant induced exon 8 skipping in AKR1A1, resulting in a frameshift mutation, which in turn led to truncation of the AKR1A1 protein. Using the recombinant protein, we demonstrated that the truncated AKR1A1 completely lost its activity. Furthermore, we showed that AKR1A1 mRNA expression in the whole blood cells of individuals with the c.753G > A variant tended to be lower than that in those without the variants, leading to lower AKR activity. Our findings suggest that AKR1A1 carrying the c.753G > A variant induces exon skipping, leading to a loss of gene expression and enzymatic activity. Thus, GlucA patients with schizophrenia with the c.753G > A variant may show higher GlucA levels, leading to drug-resistant schizophrenia, since drug excretion by GlucA is enhanced.

Fingertip advanced glycation end products and psychotic symptoms among adolescents.

Case control studies have suggested that advanced glycation end products play a key role in the pathophysiology of chronic schizophrenia. However, the longitudinal association between advanced glycation end products and psychotic symptoms among drug-naïve adolescents remains unclear. This study examined whether advanced glycation end products could predict the trajectory of psychotic symptoms in drug-naive adolescents using data from prospective population-based biomarker subsample study of the Tokyo Teen Cohort. A total of 277 community-dwelling adolescents aged 13 years without antipsychotic medication were analyzed. Fingertip advanced glycation end products were measured in adolescents using noninvasive technology that can be used quickly. The trajectory of psychotic symptoms in a 12-month follow-up was assessed by experienced psychiatrists using a semi-structured interview. Of the 277 participants, 13 (4.7%) experienced persistent psychotic symptoms (psychotic symptoms at baseline and follow-up), 65 (23.5%) experienced transient psychotic symptoms (psychotic symptoms at baseline or follow-up), and 199 (71.8%) did not have psychotic symptoms. Multinomial logistic regression analysis adjusted for age and sex revealed that baseline fingertip advanced glycation end products might predict the risk of persistent psychotic symptoms (odds ratio = 1.68; 95% confidence interval, 1.05-2.69; P = 0.03). Altogether, fingertip advanced glycation end products potentially predicted the trajectory of psychotic symptoms among drug-naive adolescents, which indicated its involvement in the pathophysiology of early psychosis. Further studies are required to identify strategies to reduce adolescent advanced glycation end products, which may contribute to preventing the onset of psychosis.

Advanced glycation end products and cognitive impairment in schizophrenia.

Advanced glycation end products play a key role in the pathophysiology of schizophrenia. Cognitive impairment is one of the central features of schizophrenia; however, the association between advanced glycation end products and cognitive impairment remains unknown. This study investigated whether advanced glycation end products affect the cognitive domain in patients with schizophrenia. A total of 58 patients with chronic schizophrenia were included in this cross-sectional study. Plasma advanced glycation end products were measured using high-performance liquid chromatography (HPLC). Neuropsychological and cognitive functions were assessed using the Wechsler Adult Intelligence Scale, Third Version, and the Wisconsin Card Sorting Test Keio-FS version. Multiple regression analysis adjusted for age, sex, body mass index, educational years, daily dose of antipsychotics, and psychotic symptoms revealed that processing speed was significantly associated with plasma pentosidine, a representative advanced glycation end product (standardized ß = -0.425; p = 0.009). Processing speed is the cognitive domain affected by advanced glycation end products. Considering preceding evidence that impaired processing speed is related to poor functional outcome, interventions targeted at reducing advanced glycation end products may contribute to promoting recovery of patients with schizophrenia as well as cognitive function improvement.

Relationship between late-life depression and life stressors: large-scale cross-sectional study of a representative sample of the Japanese general population.

AIM: The purpose of the present study was to clarify the relationship between late-life depression and daily life stress in a representative sample of 10 969 Japanese subjects. METHODS: Data on 10 969 adults aged > or =50 who participated in the Active Survey of Health and Welfare in 2000, were analyzed. The self-administered questionnaire included items on 21 reasons for life stressors and the magnitude of stress, as well as the Japanese version of the Center for Epidemiologic Studies Depression Scale (CES-D). The relationship between the incidence of life stressors and mild-moderate (D(16)) and severe (D(26)) depressive symptoms was examined using logistic regression analysis. RESULTS: A total of 21.9% of subjects had D(16) symptoms, and 9.3% had D(26) symptoms. Further, increased age and being female were associated with more severe depressive state. Logistic regression analysis indicated that the strongest relationship between both the incidence of D(16) and D(26) symptoms and life stressors stemmed from 'having no one to talk to' (odds ratio = 3.3 and 5.0, respectively). Late-life depression was also associated with 'loss of purpose in life', 'separation/divorce', 'having nothing to do', 'health/illness/care of self', and 'debt'. CONCLUSION: There is a relationship between late-life depression and diminished social relationships, experiences involving loss of purpose in life or human relationships, and health problems in the Japanese general population.

Coping strategies and their correlates with depression in the Japanese general population.

This study's aim was to examine the relation between depression and stress-coping strategy among the general population. The survey was conducted in June 2000, using a large sample representative of the Japanese general population. A total of 24,551 responses from individuals aged 20 years or older were analyzed. The Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess the prevalence of depression with two different cut-off points; 16 and 26. Stress-coping strategies were asked based on given examples of actual behaviors covering problem-focused, emotion-focused, and avoidant ones. There was no marked gender difference in the prevalence of a problem-solving strategy, while various types of gender differences were found with respect to the prevalence of emotion-focused and avoidant strategies. In relation to depression, multivariate logistic regression analyses revealed the significantly highest odds ratios (OR) for avoidant coping strategies and the lowest OR for problem-focused ones in both genders. The fact that depression was associated positively with avoidant strategies but negatively with problem-solving strategies indicates that individual stress-coping strategies have their own significance with respect to depression, and may be utilized in establishing an evidence-based cognitive behavioral approach to depressive patients.